bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–06–28
78 papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Engineered Exosomes in Precision Neuro-Oncology: Mechanisms, Therapeutics, and Translational Challenges.
  2. Exosomes as Disease-Informed Nanoplatforms for Pulmonary Fibrosis: From Pathogenic Signaling to Precision Diagnosis and Therapy.
  3. Synergistic "targeting and blockade" strategy via engineered exosomes and clinical ultrasound contrast agent for hepatocyte-targeted mRNA delivery.
  4. iRGD-modified 3D exosomes delivered miR-99b-5p induces ferroptosis to inhibit colorectal cancer progression by regulating FGFR3/PI3K/AKt pathway.
  5. From targeted delivery to inflammation suppression: engineering plant exosomes for heart failure therapy post-infarction.
  6. Exosomes in Ovarian Cancer: Promoters, Biomarkers, and Therapeutic Targets.
  7. 17-DMAG-Loaded HER2-Targeted Extracellular Vesicles Induce PARP/Caspase3-Mediated Apoptosis in Gastric Carcinoma.
  8. Exosomes in Psoriasis: From Pathogenic Mechanisms to Therapeutic Innovations.
  9. Advances in nano biomaterials for biomedical engineering.
  10. Engineering Extracellular Vesicles for Anti-Aging Therapy: Mechanisms, Applications, and Perspectives.
  11. Targeting ncRNA control networks with engineered exosomes to overcome therapy resistance in thyroid cancer.
  12. The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.
  13. Engineering Strategies for Plant-Derived Extracellular Vesicles: Modification, Drug Delivery Performance, and Synergistic Effects with Gel Composite Systems.
  14. Antigen-Pulsed Dendritic Cell-Derived Dexosomes Induce a Robust Th1-Biased Antigen-Specific Humoral and Cellular Immunity in Mice against Latent Mycobacterium tuberculosis Antigen Rv2626c.
  15. Exercise-derived exosomal miR-151-3p: An innovative anti-inflammatory and antioxidant therapeutic for spinal cord injury.
  16. M2 macrophage-derived exosomes promote the malignant progression and glycolysis of cervical cancer via Msi1.
  17. Plant-Derived Exosomes Deliver Theranostic Molecules to Target Cells.
  18. Surface modification strategies of oral liposomes: functional design and barrier enhancement.
  19. Pancreatic tissue engineering: towards a vascularized bioengineered cure for diabetes.
  20. The Gut Microbiome Dependency Continuum in Drug Discovery: A Unified Pharmacology Framework Linking Clinical Drugs, Natural Products, and Engineered Microbial Therapeutics.
  21. Orchestrating Diabetic Wound Healing by a Sunlight-Activated AIEgen-Selenide Nanospray: From Infection Control to Tissue Regeneration.
  22. Cell-Specific Extracellular Vesicles Targeting Strategies for Immune Modulation in Inflammatory Diseases.
  23. Glycosylated Carbonated Apatite Particles for Macrophage-Targeted Delivery of CpG Oligodeoxynucleotides From Streptococcus thermophilus Enhance Immune Activation.
  24. Mannose receptor-targeted MSC-derived exosomes as a high-affinity delivery platform for liver sinusoidal endothelial cells.
  25. Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
  26. Extracellular vesicles (EVs) in neurodevelopment: The emerging role of lipids.
  27. Biomaterial-Focused Strategies Targeting Dendritic Cells for Autoimmune Disease Treatment.
  28. Combined radiofrequency and topical exosomes in atrophic vulvar lichen sclerosus: A case report.
  29. Expression of Concern: Exosomes derived from circRNA Rtn4-modified BMSCs attenuate TNF-α-induced cytotoxicity and apoptosis in murine MC3T3-E1 cells by sponging miR-146a.
  30. Multifaceted Role of Extracellular Vesicles: Intercellular Messengers to Therapeutic Applications: A Narrative Review.
  31. Reprogrammable bacterial nanosyringes to deliver RNA and gene editors.
  32. Antioxidant Polymeric and Non-Polymeric Nanoformulations for the Treatment of Autoimmune Diseases.
  33. Engineering Bone-Targeted LNP Delivery of Anti-Sclerostin Antibody mRNA for the Treatment of Osteoporosis.
  34. Virus-like particles in cancer immunotherapy: bridging human and veterinary medicine through one health.
  35. [Construction of a methanol-free protein expression system in Pichia pastoris based on the enhanced sorbitol assimilation pathway].
  36. Skeletal muscle‑derived extracellular vesicles in multi‑organ degenerative disease: Mechanisms and therapeutic delivery perspectives (Review).
  37. Nanotechnology-Based Cancer Vaccines: Translational Barriers and Emerging Strategies.
  38. A Lung-Targeted Lipid Nanoparticle System Delivers miRNA to Suppress Colorectal Cancer Pulmonary Metastases.
  39. Tracheal Delivery of HO-1-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cells Treats Pulmonary Arterial Hypertension by Enhancing Pulmonary Antioxidant and Anti-inflammatory Responses.
  40. Molecular Glues Recruiting RNF213 As an E3 Ligase for Targeted Protein Degradation: A Minimal Dibromoacetamide Warhead As a Recruitment Ligand.
  41. Stem cell-derived extracellular vesicles for rare diseases: A clinical‑bottleneck‑to‑mechanism framework for translation.
  42. Engineering Pseudomonas protegens as a Targeted Antifungal-Effector Delivery Chassis via Heterologous Type III Secretion System Reconstitution.
  43. The role of the mesenchymal stem cell therapy in bone regeneration of osteoporosis: clinical translation and limitations.
  44. Engineered bacterial membrane vesicles as transdermal cancer vaccines.
  45. Exosomes: A new frontier in the treatment of neurological diseases.
  46. Chimeric antigen receptor-T cell therapy-induced cardiotoxicity: Pathophysiological mechanisms and pharmacological intervention strategies.
  47. Exosomes in Cancer Biology: Emerging Biomarkers and Therapeutic Targets.
  48. Mussel Adhesive Protein/Hyaluronic Acid Hydrogels for EGF Delivery and MRSA-Infected Diabetic Wound Repair.
  49. [Functional characteristics of the SACE_2701-2702 transport system in Saccharopolyspora erythraea and its impact on erythromycin biosynthesis].
  50. Chlorogenic Acid Ameliorates CVB3-Induced Viral Myocarditis by Suppressing Viral Replication and ZBP1-Mediated PANoptosis.
  51. The Efficacy of Mesenchymal Stem Cell-Based Therapy for Sjögren's Syndrome: A Systematic Review and Meta-Analysis of Preclinical Studies.
  52. Miniaturized subcutaneous cellular implants for sustained therapeutic protein delivery in resource-limited settings.
  53. Circulating exosomes convey the cognitive benefits of Tai Chi: The role of miR-625-5p in prefrontal remodeling and therapeutic potential.
  54. Rational design of an optimized ferritin nanoparticle vaccine targeting both SARS-CoV-2 and MERS-CoV.
  55. Engineering immuno-smart bone scaffolds: Macrophage-centric strategies in 3D-printed tissue regeneration.
  56. Multi-Scale Bionic Materials: Interfacial Design, Effective Fabrication and Functional Application.
  57. In Vivo mRNA-Lipid Nanoparticle CAR-T Cell Engineering: Advances, Challenges, and Clinical Translation.
  58. Enhanced repair of type 2 diabetic wounds using combined hyperbaric oxygen and M2 macrophage-derived exosomes: An experimental rat model.
  59. Zinc-Doped Calcium Phosphate Nanoagonists Amplifies cGAS-STING Signaling for Boosting Pyroptosis-Induced Cancer Immunotherapy.
  60. Engineered responsive-hydrogels drive cGAS-STING pathway activation for cancer immunotherapy.
  61. Acid-responsive bone-targeting nanoplatform enables spatiotemporal control of osteogenesis and angiogenesis for osteoporosis rescue.
  62. Aptamer-tagged exosome-coated Bismuth ferrite-mesoporous silica nanoparticle for chemoradiotherapy and CT/MR imaging of non-small cell lung cancer.
  63. Exosomal circ_0050688 Shapes a Chemoresistant Microenvironment by Driving Spatial Resistance Spreading in Glioblastoma via the MDM2 Pathway.
  64. Inflammatory Preconditioning Reprograms Mesenchymal Stromal Cell-Derived Extracellular Vesicles into Distinct Functional States for Immunomodulation and Wound Healing.
  65. Towards an Original Anti-ASFV Vaccine: Cellular Immunity Induced by Extracellular Vesicles Engineered with ASFV Proteins.
  66. Dicliptera chinensis (L.) Juss. polysaccharide alleviates metabolic dysfunction-associated steatotic liver disease by regulating miR-3073b-5p/CAMKK2 via the gut microbiota-bile acid axis.
  67. NORAD Overexpression Enhances hiPSC-CM Regenerative Potency via PUM2/MASTL Signaling.
  68. Bifluorinated Motif-Tailored Hybrid Membranes for Ultra-Permeable CO2 Separation From Air Under High Humidity.
  69. Nanocarrier-Mediated Delivery Systems of Phytochemicals to Enhance and Accelerate Diabetic Wound Healing Processes.
  70. Progress in engineered bacterial cancer therapies.
  71. The gut microbial metabolite 3-indolepropionic acid as a functional neuroprotective agent against intracerebral hemorrhage: integrating epidemiological screening with in vivo validation.
  72. Extracellular vesicle-mediated bidirectional communication between the brain and peripheral organs in Alzheimer's disease: evidence, mechanisms, and translational perspectives.
  73. SIRT6 enhances the therapeutic potential of extracellular vesicles in mitigating osteoarthritis in rat models.
  74. Technological Advances of Cryopreservation in Ovarian Tissue for Female Children: Exploring the Molecular Insights and Mechanisms.
  75. Engineered Lipid Nanoparticles with Promoted Endosomal Escape and R283S-Mediated Stimulator of Interferon Genes (STING) Activation for Pancreatic Cancer Immunotherapy.
  76. Bioactive protopanaxadiol-enriched rice (DJ-PPD) exerts potent anti-inflammatory and antioxidant effects via dual regulation of NF-κB/MAPK/Akt and NRF2/HO-1 signalling.
  77. Effects of Combining Immune-Priming Sub-Lethal Low-Dose Radiation with 4-1BB Activation and Gal-3 Blockade in In Vitro and Preclinical Group-3 Medulloblastoma Models.
  78. Multifunctional nanotherapeutics for targeted modulation of endoplasmic reticulum stress to potentiate cancer therapy.
  1. Cancers (Basel). 2026 Jun 12. pii: 1923. [Epub ahead of print]18(12):
    Engineered Exosomes in Precision Neuro-Oncology: Mechanisms, Therapeutics, and Translational Challenges.
    Nazmul H Khan, Mst Anika Bushra, Fowzia Akter Selina, Ali Syed Arbab.
      Exosomes are small vesicles released by cells that have attracted growing interest as drug delivery vehicles, particularly for brain diseases, where getting therapeutics across the BBB remains a fundamental problem. While conventional platforms such as liposomes, polymeric nanoparticles, and viral vectors often suffer from immune clearance and poor brain accumulation, engineered exosomes leverage natural cellular transport mechanisms to cross the BBB, protect cargo from degradation, and enable biocompatible interactions with target cells. This review takes a mechanistic and translational look at how exosomes are being engineered for CNS disorders, with a particular focus on glioblastoma. We cover exosome biogenesis through ESCRT-dependent and ESCRT-independent pathways, and how the competition between Rab27-driven secretion and Rab7-driven lysosomal degradation determines how many exosomes a cell releases, which has direct consequences for therapeutic production. We then discuss cargo loading strategies, from genetic approaches where donor cells are engineered to package specific molecules during biogenesis to physical methods like electroporation and sonication applied to isolated vesicles, alongside surface modification techniques for directing exosomes toward specific cell types. In glioblastoma, engineered exosomes have shown real promise for delivering chemotherapeutics across the BBB, targeting glioma stem cells, enabling CRISPR-based gene editing, and functioning as combined treatment and imaging tools. Applications in stroke and neurodegenerative diseases, where engineered exosomes carrying microRNAs and neuroprotective cargo have produced encouraging preclinical results, are also discussed. Scalable manufacturing and consistent targeting remain the hardest unsolved problems, and we outline emerging approaches including bioreactor-based production, programmable cargo loading, and patient-specific exosome design that are beginning to address these gaps. Overall, the progress reviewed here suggests that engineered exosomes are moving from an interesting biological concept toward a practically viable platform for CNS drug delivery.
    Keywords:  blood–brain barrier; brain diseases; exosomes; therapeutic payloads
    DOI:  https://doi.org/10.3390/cancers18121923
  2. Pharmaceutics. 2026 May 28. pii: 668. [Epub ahead of print]18(6):
    Exosomes as Disease-Informed Nanoplatforms for Pulmonary Fibrosis: From Pathogenic Signaling to Precision Diagnosis and Therapy.
    Jeong Min Lee, Kyung Tae Kim, Chung-Sung Lee, Hee Sook Hwang.
      Pulmonary fibrosis (PF) is a progressive and often fatal interstitial lung disease for which the currently available pharmacological therapies remain largely limited to slowing disease progression rather than reversing established fibrosis. This limitation has stimulated increasing interest in innovative therapeutic platforms capable of modulating complex fibrotic pathways. In this context, exosomes-nanoscale extracellular vesicles-have emerged as promising cell-free nanocarriers due to their intrinsic biocompatibility, low immunogenicity, and ability to be engineered for targeted drug delivery. In this review, we provide a comprehensive overview of both natural and engineered exosome-based strategies for the diagnosis and treatment of pulmonary fibrosis. We summarize recent advances in exosome engineering, including ligand functionalization, glycoengineering, and therapeutic cargo loading, highlighting how these approaches may support the development of more targeted and potentially personalized nanotherapeutic strategies. We further discuss emerging hybrid delivery platforms, such as exosome-liposome chimeras and hydrogel-based depots, which may enhance pulmonary retention, improve therapeutic durability, and enable controlled drug release. Finally, we outline key challenges and opportunities for clinical translation, including large-scale manufacturing, regulatory considerations, and clinically relevant delivery routes such as inhalation-based administration. Collectively, this review provides a translational perspective on engineered exosomes as emerging nanotherapeutic platforms for pulmonary fibrosis.
    Keywords:  drug delivery; exosomes; nanotherapeutics; precision medicine; pulmonary fibrosis
    DOI:  https://doi.org/10.3390/pharmaceutics18060668
  3. Biomaterials. 2026 Jun 22. pii: S0142-9612(26)00423-0. [Epub ahead of print]335 124399
    Synergistic "targeting and blockade" strategy via engineered exosomes and clinical ultrasound contrast agent for hepatocyte-targeted mRNA delivery.
    Zhelong Li, Bo Zhang, Chunmao Liu, Wei Wang, Guoping Li, Bingzhang Xu, Feng Liu, Xinyu Li, Chuan Dong, Ping Zhao, Changyang Xing, Lijun Yuan.
      Homozygous familial hypercholesterolemia (HoFH) presents a persistent and difficult-to-treat condition. This recalcitrance stems largely from loss-of-function mutations within the low-density lipoprotein receptor (LDLR) gene, which severely undermine the efficacy of standard therapeutic regimens. Here, we report a bioinspired "targeting and blockade" strategy for the efficient delivery of functional Ldlr mRNA to hepatocytes. This approach is realized through a rationally designed platform, Szd + AP@ExoE-Ldlr, which integrates APOA1-functionalized exosomes for hepatocyte-targeted delivery with a preemptive macrophage blockade using the clinical ultrasound contrast agent Sonazoid (Szd). The APOA1 modification confers specific recognition by the scavenger receptor class B type 1 on hepatocytes, while the pre-saturation of Kupffer cells with Szd significantly mitigates nonspecific clearance by the mononuclear phagocyte system (MPS). In a HoFH murine model, this synergistic strategy markedly enhanced the accumulation of exosomes in hepatocytes and achieved robust restoration of hepatic LDLR expression. Consequently, it elicited a profound correction of the atherogenic lipid profile and substantially attenuated the progression of atherosclerosis. A comprehensive biosafety evaluation confirmed the excellent biocompatibility of this platform. Our work provides a promising and broadly applicable solution for the treatment of liver-related genetic disorders by simultaneously overcoming the critical barriers of targeted delivery and MPS evasion.
    Keywords:  Atherosclerosis; Exosomes; Familial hypercholesterolemia; Mononuclear phagocyte system; Targeted therapy; mRNA delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124399
  4. Stem Cell Res Ther. 2026 Jun 23.
    iRGD-modified 3D exosomes delivered miR-99b-5p induces ferroptosis to inhibit colorectal cancer progression by regulating FGFR3/PI3K/AKt pathway.
    Xiao-Huan Li, Fu-Wei Lian, Feng Lv, Xiao-Ling Luo, Bang-Li Hu, Li-Tu Zhang, Shu-Fang Ning.
       BACKGROUND: Mesenchymal stem cells (MSCs)-derived exosomes present great potential as nanocarriers for targeted drug delivery. Moreover, the therapeutic efficacy of exosomes can be substantially enhanced through functional modifications and the incorporation of bioactive molecules.
    METHODS: In this study, the MSCs were cultured under two-dimensional (2D) and three-dimensional (3D) cell culture conditions. The culture supernatants were collected for isolating exosomes. The characteristics and yields of exosomes from 2D and 3D cultures were detected by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), western blot analysis, and bicinchoninic acid (BCA) assay. Subsequently, 3D exosomes were loaded with miR-99b-5p and modified with iRGD peptide were formed into a new engineered exosome, designated as iRGD-Exo-miR-99b-5p. The effects of these engineered exosomes on the progression of colorectal cancer (CRC) were assessed through a series of in vivo and in vitro experiments.
    RESULTS: The 3D-cultured MSCs exhibited a higher yield of exosomes and enhanced uptake by CRC cells. Further in vitro experiments demonstrated that 3D-exosomes loaded with miR-99b-5p effectively inhibit the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells. Results from a xenograft tumor model indicate that iRGD-modified exosomes were significantly enriched at tumor sites. Furthermore, exosomes modified with iRGD and loaded with miR-99b-5p were employed for CRC treatment, resulting in substantial tumor growth inhibition and enhanced the chemotherapy efficacy of 5-fluorouracil (5-FU) in vivo, without inducing notable toxicity or side effects. Mechanistically, exosome-mediated delivery of miR-99b-5p downregulated FGFR3 expression, thereby inhibiting the activation of the PI3K/AKt signaling pathway and promoting ferroptosis, ultimately attenuating CRC progression.
    CONCLUSIONS: Collectively, iRGD-modified 3D exosomes loaded with miR-99b-5p were able to specifically target tumor sites, thereby significantly suppressing CRC growth through the induction of ferroptosis via regulating the FGFR3/PI3K/AKt signaling pathway. These findings suggest that functional engineering and bioactive loading of 3D-exosomes derived from MSCs represent a promising strategy for targeted cancer therapy.
    Keywords:  3D culture; Colorectal cancer; IRGD; Mesenchymal stem cells; MiR-99b-5p
    DOI:  https://doi.org/10.1186/s13287-026-05129-8
  5. Mater Today Bio. 2026 Jun;38 103034
    From targeted delivery to inflammation suppression: engineering plant exosomes for heart failure therapy post-infarction.
    Xi Tan, Simin Lu, Wangbei Qin, Xiaoqin Zhu, Xinlu Wang, Kaiwei Ren, Biwei Cheng, Jiahui Li, Dongze He, Ziran Hu, Yuhua Lei, Lixing Wu, Jing Zhang, Jiaxin Hu.
      Plant-derived exosomes are natural nanovesicles rich in bioactive compounds and show promise for tissue regeneration. However, their clinical use is limited by poor stability and low targeting accuracy. To overcome these issues, we developed an engineered approach to enhance the targeted delivery of plant exosomes, focusing on chronic inflammation-a key driver of heart failure-evaluating their therapeutic potential in myocardial infarction. By optimizing isolation methods and fusing exosomes with synthetic liposomes, we created collagen-targeted hybrid nanovesicles (GEP-NPs). In a mouse model of myocardial infarction, GEP-NPs efficiently accumulated in damaged heart tissue. Compared to non-engineered vesicles, GEP-NPs more effectively reduced fibrosis, suppressed ventricular remodeling, and modulated chronic post-infarction inflammation, thereby preventing progression from acute injury to chronic heart failure. Mechanistic studies showed that GEP-NPs may inhibit the overactive PI3K-AKT-mTOR pathway, which regulates inflammation, cell survival, and metabolism. The bioactive components from plant exosomes likely act effectively within the engineered vesicles to suppress this pathway, reducing persistent inflammation and promoting tissue repair. This work provides a scalable, reproducible method for engineering plant exosomes, improving both delivery precision and stability, and offering a promising strategy for treating chronic cardiac inflammation and preventing heart failure.
    Keywords:  Chronic inflammation; Myocardial infarction; Plant-derived exosomes; Quantitative proteomics; Targeted delivery
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103034
  6. Int J Nanomedicine. 2026 ;21 606735
    Exosomes in Ovarian Cancer: Promoters, Biomarkers, and Therapeutic Targets.
    Fengyi Wang, Haiyan Dong, Yuli Song, Yi Zhang.
      Ovarian cancer is an aggressive malignancy treated primarily with surgery and platinum-based chemotherapy. The high recurrence rate and platinum resistance are the primary reasons for poor prognosis in ovarian cancer. Early screening can improve patient survival, but there are currently no high-precision biomarkers available. Exosomes are nanoscale vesicles that mediate intercellular communication by transferring bioactive molecules, and their composition reflects pathological states. Late diagnosis is the primary cause of poor prognosis in patients with ovarian cancer. Owing to the high stability conferred by their unique structure, exosomes can serve as an efficient, non-invasive approach for early screening. In the context of drug delivery, engineered exosomes using novel advanced technologies can enhance the specificity of clinical pharmacotherapy and reduce adverse toxic reactions. This review summarizes the latest research findings on ovarian cancer-related exosomes and introduces their important roles in exploring the mechanisms of ovarian cancer progression, metastasis, and chemoresistance, as well as their potential as prognostic biomarkers and therapeutic targets.
    Keywords:  biomarker; cancer metastasis; chemoresistance; engineered exosomes; exosomes; extracellular vesicles; ovarian cancer
    DOI:  https://doi.org/10.2147/IJN.S606735
  7. Int J Mol Sci. 2026 Jun 15. pii: 5377. [Epub ahead of print]27(12):
    17-DMAG-Loaded HER2-Targeted Extracellular Vesicles Induce PARP/Caspase3-Mediated Apoptosis in Gastric Carcinoma.
    Sin Hye Park, Deok Yong Sim, Do Sang Lee, Chan Mi Lee, Joo Won Moon, Ji Won Choi, Dong Jin Kim.
      Gastric cancer remains a major clinical challenge, underscoring the need for more effective drug delivery strategies. Approximately 10-20% of gastric cancers overexpress HER2, conferring aggressive tumor characteristics and poor survival, yet resistance to trastuzumab-based targeted therapy and limited intratumoral antibody penetration continue to restrict clinical outcomes. This study evaluated HER2-targeted exosomes as a delivery platform. Exosomes were engineered to express the p51 peptide, a high-affinity HER2-binding ligand, and loaded with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a potent HSP90 inhibitor. The cellular uptake and antitumor efficacy of p51-Exo17-DMAG were assessed in vitro using NCI-N87 and AGS cells and in vivo using a mouse xenograft model. p51-modified exosomes exhibited superior HER2 specific uptake. Treatment with p51-Exo17-DMAG significantly increased apoptosis, as demonstrated by elevated PARP and caspase3 cleavage, and downregulated oncogenic signaling molecules, including p-AKT, CDK2, VEGF, and c-Myc. Furthermore, p51-Exo17-DMAG increased the number of TUNEL-positive cells. In the NCI-N87 xenograft model, systemic administration of p51-Exo17-DMAG significantly inhibited tumor growth without toxicity or histological damage to major organs. Tumor analysis confirmed increased apoptosis and reduced proliferation in vivo. These findings demonstrate that p51-engineered exosomes provide an efficient, selective, and safe platform for HER2-targeted delivery of 17-DMAG, offering a promising precision medicine strategy for HER2-positive gastric cancer.
    Keywords:  17-DMAG; HER2; apoptosis; exosomes; gastric cancer
    DOI:  https://doi.org/10.3390/ijms27125377
  8. Clin Cosmet Investig Dermatol. 2026 ;19 606845
    Exosomes in Psoriasis: From Pathogenic Mechanisms to Therapeutic Innovations.
    Qi Xu, Wenting Liu, Siqing Zhang, Lin Zhou.
      Psoriasis is a chronic recurrent inflammatory disease driven by keratinocytes and immune cells. Exosomes, as key mediators of intercellular communication, play multidimensional roles in this disease. In terms of pathogenic mechanisms, exosomes released from psoriatic lesions carry non‑coding RNAs and proteins that program T‑cell polarization, drive M1 macrophage activation, and amplify keratinocyte inflammation, thereby sustaining the IL‑23/Th17 immune axis. Translational breakthroughs have repurposed these same vesicles into diagnostic and therapeutic tools. Circulating exosomal fingerprints offer non‑invasive biomarkers for disease activity and psoriatic arthritis differentiation. Leveraging their biocompatibility and low immunogenicity, exosomes from mesenchymal stem cells, plants, and microbes serve as cell‑free platforms achieving immune regulation, antioxidant effects, and microecological repair. Engineering strategies-including cargo loading, membrane surface modification and intelligent microneedle delivery systems-further enhance targeting and efficacy. Despite these advances, clinical translation faces fundamental challenges: lack of production standardization, undefined core active components and insufficient high‑level clinical evidence. Future efforts should prioritize international standards, rational design, and rigorous trials to accelerate exosome‑based precision medicine for psoriasis.
    Keywords:  biomarkers; cell-free therapy; exosomes; immunomodulation; psoriasis
    DOI:  https://doi.org/10.2147/CCID.S606845
  9. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(26)00033-X. [Epub ahead of print]405 47-110
    Advances in nano biomaterials for biomedical engineering.
    Poojan Chaniyara, Mohnish Gandhi, Dhruvesh Maiya, Tvarit Patel.
      Systemic toxicity and off target effects are some of the major drawbacks of traditional, broad-spectrum therapies. Nanotechnology effectively counters these by offering precise, targeted alternatives and hence, reshaping biomedical engineering, therapeutics, diagnostics and even tissue regeneration. We explore six key nano-biomaterial platforms that exemplify this technological revolution. Silk fibroin nano-patches with engineered exosomes help diabetic wounds heal by producing collagen. Hydrogel activated with nanoparticle form nanoadhesives that bond well with wet environments, such as surgical sites. Graphene-based neural interfaces are characterized by high electrical conductivity with low immunogenicity. Bioelectronic-hydrogel composites adapt tissue mechanics for better physiological sensing. The pH-responsive metal-organic frameworks show remarkable potential in cancer treatment enabling targeted drug delivery, reducing harm to surrounding healthy tissue, and magnetic nanoparticles coated in cancer cell membranes improve natural killer-cell therapies. Despite these remarkable advances, the challenge of transition from laboratories to clinics faces many hurdles. Demands for scalable manufacturing techniques, strategies to suppress undesirable immune reactions and passing through safety and regulatory standards are some of the major challenges in Nanotechnology. Collaborative approaches from interdisciplinary fields like material science, biology, engineering and clinics may present a positive outlook to these issues. Nanotechnology can offer promising precision medicine tailored to an individual's safety and dosage profiles, minimising off target interaction risks.
    Keywords:  Advanced biomaterials; Biodegradability; Graphene-based materials; Metal-organic frameworks (MOFs); Nanohesives; Silk-based nanomaterials
    DOI:  https://doi.org/10.1016/bs.ircmb.2026.04.001
  10. Aging Cell. 2026 Jul;25(7): e70607
    Engineering Extracellular Vesicles for Anti-Aging Therapy: Mechanisms, Applications, and Perspectives.
    Xian Huang, Qiujie Li, Guofang Tao, Xulin Gan, Jiangjie Lu, Sergei Krasny, Liyun Shi.
      Aging is a multifactorial process driven by interconnected hallmarks, including chronic inflammation, mitochondrial dysfunction, genomic and epigenetic alterations, and dysregulated intercellular communication. Extracellular vesicles (EVs), naturally derived nanoscale membrane vesicles capable of transporting diverse bioactive cargoes across tissues and biological barriers, have emerged as a highly promising platform for regenerative and anti-aging therapeutics. In this review, we systematically summarize the multifaceted anti-aging mechanisms of EVs, including suppression of the senescence-associated secretory phenotype (SASP), remodeling of the immune microenvironment, mitochondrial restoration and metabolic reprogramming, DNA damage repair, epigenetic modulation, recovery of proteostasis, activation of regenerative signaling pathways, and cross-organ communication-mediated rejuvenation. Beyond mechanistic insights, we integrate the targeting biology and cellular entry properties of EVs, encompassing natural tropism determinants, engineered targeting strategies, biodistribution profiles, receptor-ligand interactions, intracellular trafficking, and subcellular cargo release. Unlike previous reviews focusing on a single EV source or isolated pathways, we establish a comprehensive framework connecting molecular mechanisms with delivery engineering, tissue targeting, biosafety assessment, scalable manufacturing, and clinical translation. We address major technical bottlenecks limiting EV therapeutics-including EV heterogeneity, suboptimal delivery efficiency, endosomal degradation, and the lack of standardized quality-control frameworks-while highlighting emerging solutions such as bioengineered EVs, hybrid vesicle platforms, biomaterial-assisted delivery systems, and ultrasound-enhanced targeting technologies. By bridging fundamental biology, nanomedicine engineering, and clinical translation, this review provides a strategic roadmap for the development of next-generation precision anti-aging nanotherapeutics with systemic regulatory capacity, translational feasibility, and broad clinical potential.
    Keywords:  aging; clinical translation; extracellular vesicles; targeted delivery
    DOI:  https://doi.org/10.1111/acel.70607
  11. Crit Rev Oncol Hematol. 2026 Jun 20. pii: S1040-8428(26)00326-4. [Epub ahead of print]226 105439
    Targeting ncRNA control networks with engineered exosomes to overcome therapy resistance in thyroid cancer.
    Anjani H Turaga, Brenden M Finnerty, Rasa Zarnegar, Thomas J Fahey.
      Papillary thyroid cancer (PTC) is the most prevalent endocrine malignancy, accounting for over 90% of thyroid cancers. While differentiated thyroid cancers (DTCs) typically have favorable outcomes, a significant subset progresses to radioactive iodine-refractory (RAIR) disease, characterized by impaired iodine uptake and a 10-year survival rate below 10%. Genetic alterations and dysregulated signaling pathways underlie this transition. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), play critical regulatory roles in tumor biology and may be transported via exosomes, facilitating intercellular communication and contributing to RAIR-PTC. This systematic review, conducted according to PRISMA 2020 guidelines, evaluated the role of exosomal ncRNAs in RAIR-PTC. A comprehensive search of PubMed, PubMed Central, and Google Scholar identified studies published within the past 15 years in English. Following stringent quality appraisal, studies with a non-bias score above 40% were included. Of 961 identified publications, 96 high-quality studies met inclusion criteria. Evidence indicates that therapy resistance in RAIR-PTC is driven by convergent ncRNA regulatory networks that suppress sodium-iodide symporter (NIS) expression and activate oncogenic pathways, most notably MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. Multiple ncRNAs converge on key regulatory nodes, forming redundant circuits that sustain dedifferentiation, metabolic adaptation, and impaired iodide transport. Several consistently dysregulated ncRNAs directly or indirectly regulate NIS expression and trafficking, highlighting actionable targets. Exosomes emerge as biologically compatible, programmable delivery vehicles capable of transporting therapeutic ncRNA payloads independent of endogenous packaging mechanisms. These findings support a precision therapeutic paradigm in which engineered exosomes reprogram ncRNA networks to restore iodine-handling pathways and overcome therapy resistance in RAIR-PTC.
    Keywords:  Exosomes; MicroRNA, (miRNA); Non-Coding RNAs; Radioiodine-refractory thyroid cancer; Sodium-iodide symporter (NIS)
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105439
  12. Mol Neurobiol. 2026 Jun 25. pii: 723. [Epub ahead of print]63(1):
    The Biological Basis, Mechanisms of Action, and Optimization Strategies of Exosomes Derived from Mesenchymal Stem Cells for the Treatment of Alzheimer's Disease.
    Can Zhang, Weihong Long, Junjie Ni, Zhuo Chen, Xu Wu, Mingxing Li, Fukuan Du, Yueshui Zhao, Jing Shen, Chi Hin Cho, Xi He, Zhangang Xiao.
      Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathological process involves multiple mechanisms, including Aβ deposition, tau protein abnormalities, neuroinflammation, synaptic damage, and neuronal loss. Current therapeutic approaches remain ineffective in halting disease progression; therefore, the development of multi-targeted, low-immunogenicity therapeutic strategies with efficient brain delivery is of great significance. Mesenchymal stem cell-derived exosomes (MSC-derived exosomes) inherit the immunomodulatory, neuroprotective, and tissue-repairing properties of MSCs, and possess good biocompatibility and the potential to cross the blood-brain barrier. Studies have shown that MSC-derived exosomes exert therapeutic effects by modulating neuroinflammation, promoting neurogenesis and synaptic plasticity, reducing Aβ deposition and tau pathology, and regulating multiple AD-related signaling pathways. At the same time, the molecular composition and functions of MSC-derived exosomes derived from different tissues exhibit heterogeneity, and their therapeutic efficacy is influenced by factors such as the source cells, culture conditions, preparation processes, and administration methods. In recent years, strategies such as engineered surface modification, functional molecule loading, three-dimensional culture, microenvironment pretreatment, large-scale production, as well as intranasal administration and biomaterial delivery systems have provided new directions for enhancing the brain-targeting ability, stability, yield, and therapeutic efficacy of MSC-derived exosomes. This review summarizes the biological basis of MSC-derived exosomes, their mechanisms of action in AD treatment, and optimization strategies, providing a reference for their further development and translational application as a cell-free therapeutic approach for AD.
    Keywords:  Alzheimer’s disease; Aβ amyloid protein; Mesenchymal stem cell-derived exosomes; Microglia
    DOI:  https://doi.org/10.1007/s12035-026-06002-8
  13. Pharmaceutics. 2026 May 27. pii: 659. [Epub ahead of print]18(6):
    Engineering Strategies for Plant-Derived Extracellular Vesicles: Modification, Drug Delivery Performance, and Synergistic Effects with Gel Composite Systems.
    Xiaoxiao Qiu, Yilixiati Wusiman, Nazhakaiti Yusufujiang, Dilihuma Dilimulati, Alhar Baishan, Yipaerguli Paerhati, Alifeiye Aikebaier, Wenting Zhou.
      Plant-derived extracellular vesicles (PDEVs) are a novel category of natural nanocarriers with widespread availability, low immunogenicity, high biocompatibility, and inherent pharmacological activity. These features underscore their value as dual-function systems capable of serving as both carriers and bioactive agents. Unlike previous reviews that focused primarily on disease-specific applications or on individual engineering techniques, this review established a conceptual framework integrating three interconnected dimensions: (i) engineering strategies that address the inherent limitations of PDEVs (targeting, stability, loading efficiency); (ii) the carrier-performance-synergy paradigm linking PDEV composition to therapeutic outcomes; and (iii) gel-composite design principles that transform local retention into a controllable delivery platform. This review delves into various engineering methodologies, including targeted modification, enhanced stability, and optimized drug loading, while elucidating the performance characteristics of PDEVs as drug carriers, focusing on their protective, targeting, and controlled-release properties. It notably investigates the synergistic interactions between the intrinsic bioactivity of PDEVs and the drugs they deliver. Furthermore, this review highlights advanced applications of PDEV gel composites in localized drug delivery, specifically emphasizing their clinical potential for treating dermatological conditions. Finally, it highlights the current challenges faced by PDEVs and anticipates future research directions, such as synthetic biology, multi-omics analysis, and clinical translation. This review provides a theoretical framework for the rational design and clinical translation of PDEVs. It thereby promotes their innovative development in precision nanomedicine.
    Keywords:  drug delivery; engineered modification; gel composites; nanocarriers; plant-derived extracellular vesicles; synergistic therapy
    DOI:  https://doi.org/10.3390/pharmaceutics18060659
  14. ACS Infect Dis. 2026 Jun 25.
    Antigen-Pulsed Dendritic Cell-Derived Dexosomes Induce a Robust Th1-Biased Antigen-Specific Humoral and Cellular Immunity in Mice against Latent Mycobacterium tuberculosis Antigen Rv2626c.
    Saima Naz, Bandi Dharani, Farhan Ahmed, Suman Singh, Duvvada Srinivas, Manaswini Jagadeb, Kala Jyothi Kanaparthi, Shabbir Ahmad, Nooruddin Khan, Sharmistha Banerjee.
      Tuberculosis (TB) continues to be a leading health crisis globally, with latent tuberculosis infection (LTBI) affecting approximately 1.7 billion people worldwide. The current BCG vaccine does not provide consistent protection against pulmonary TB in adults, underscoring the need for innovative vaccine strategies that target both active and latent Mycobacterium tuberculosis (Mtb) infections. In this study, we introduced a vaccine engineering approach to enhance the immunogenicity of candidate vaccine antigens by utilizing exosomes derived from antigen-pulsed dendritic cells (dexosomes). We focused on a representative latency-associated Mtb protein, Rv2626c, which immunoinformatics studies predicted to contain epitopes capable of eliciting a cell-mediated response biased toward Th1 cells. Rv2626c was cloned, purified, and the recombinant form (rRv2626c) was used to generate antigen-pulsed dexosomes. Rv2626c-pulsed dexosomes were successfully isolated, characterized, and evaluated for their immunomodulatory properties. In vitro studies demonstrated that dendritic cells treated with Rv2626c-pulsed dexosomes exhibited enhanced antigen uptake, improved antigen presentation, and increased expression of costimulatory signals. When immunized with Rv2626c-pulsed dexosomes, mice displayed robust antigen-specific CD8+ and CD4+ T-cell responses, marked by elevated production of IL-2 and IFN-γ compared to those receiving Rv2626c alone. Additionally, significant antigen-specific antibody responses were observed, with increased IgG2a/IgG1 and IgG2b/IgG1 ratios, indicating a Th1-biased immune response. The sustained antibody response suggests potential for long-lasting protection against latent Mtb bacilli. These findings represent an initial report on the use of dexosomes pulsed with a latency-associated antigen to elicit potent antigen-specific immunological responses. By enhancing both cellular and humoral immune responses, Rv2626c-pulsed dexosomes present a promising platform for the development of next-generation efficacious TB vaccines aimed at targeting LTBI and preventing the reactivation of latent Mtb infections. This research paves the way for further exploration of exosome-based delivery systems as immunomodulatory vehicles for TB vaccine development.
    Keywords:  Rv2626c; dendritic cell-derived exosomes; dexosomes; extracellular vesicles; latency associated antigen; latent tuberculosis
    DOI:  https://doi.org/10.1021/acsinfecdis.5c01111
  15. Bioact Mater. 2026 Nov;65 535-555
    Exercise-derived exosomal miR-151-3p: An innovative anti-inflammatory and antioxidant therapeutic for spinal cord injury.
    Xinwang Ying, Jiamen Shen, Yanfang Zhao, Tiantaixi Tu, Yi Jiang, Bo Chen, Zhiyang Huang, Qingfeng Xie, Liuxi Chu, Junqing Huang, Yanming Zuo, Ao Fang, Ping Wu, Qian Xu, Xiaokun Li, Chang Jiang, Zhouguang Wang.
      Exercise (Exe) training is a cornerstone of multimodal rehabilitation of patients with spinal cord injury (SCI), yet the precise mechanisms through which it exerts its therapeutic benefits remain unclear. Exosomes (Exos) are key mediators of intercellular communication and promising vehicles for targeted therapy. This study aimed to investigate the function and underlying mechanism of exercise-derived exosomes (Exe-Exos) in SCI recovery. Circulating Exos were isolated from rats subjected to a 4-week treadmill Exe regimen and from sedentary controls. A gelatin methacrylate (GelMA) hydrogel microneedles (Hyd MNs) system was developed for the targeted, sustained delivery of these Exos directly to the injury epicenter at the T10 spinal segment in a rat SCI model. Using integrated in vitro and in vivo approaches, we showed that Exe-Exos significantly promoted motor function recovery, attenuated tissue damage, reduced apoptosis, and alleviated both inflammation and oxidative stress (Oxs) after SCI. Small RNA sequencing revealed that miR-151-3p is a key functional cargo that is enriched in Exe-Exos. Gain- and loss-of-function studies revealed that exosomal miR-151-3p exerts its protective effects by directly targeting the mitochondrial membrane protein ROMO1. This targeting led to the coordinated inhibition of the pro-apoptotic JNK/Caspase pathway, suppression of the NF-κB-mediated inflammatory cascade, and activation of the Nrf2/HO-1 antioxidant axis. Collectively, our findings establish Exe-Exos, specifically exosomal miR-151-3p, as an exercise-responsive circulating signaling axis that orchestrates multifaceted protection against secondary injury after SCI, offering an innovative, mechanism-based strategy for neuroregenerative therapy.
    Keywords:  Exercise; Exosomes; Hydrogel microneedles; ROMO1; miR-151-3p
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.06.009
  16. Hereditas. 2026 Jun 25.
    M2 macrophage-derived exosomes promote the malignant progression and glycolysis of cervical cancer via Msi1.
    Liting Sun, Abudureyimu Tunishahan, Xiaowen Li.
       BACKGROUND: Cervical cancer is a common gynecologic malignancy characterized by high recurrence and metastasis rate. Exosomes derived from M2-polarized tumor-associated macrophages play a key role in promoting tumorigenesis and cancer progression. Additionally, musashi1 (Msi1) is a key oncoprotein across multiple malignancies. Therefore, this study aims to determine the role of M2 macrophage-derived exosomal Msi1 in cervical cancer progression and glycolysis and to clarify the underlying mechanism.
    METHODS: M2 macrophages were identified using microscope, flow cytometry, and western blot. Gene mRNA and protein expression levels were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The cell proliferation, invasion, apoptosis, and sphere formation were assessed using 5-Ethynyl-2'-deoxyuridine (EdU) staining, Transwell, flow cytometry, and sphere formation assay, respectively. The glucose uptake and lactate production were determined using commercial kits. Exosomes were identified using western blot, transmission electron microscopy, and nanoparticle tracking analysis (NTA). Cellular uptake of exosomes was assessed by incubating SiHa and Ca Ski cells with PKH67-labeled exosomes. Cervical cancer xenograft mouse models were established to analyze the role of M2 macrophage-derived exosomal Msi1.
    RESULTS: Msi1 expression was increased in M2 macrophages (**P < 0.01 and ***P < 0.001). Functionally, M2 macrophages enhanced cervical cancer cell proliferation, invasion, aerobic glycolysis, and stemness as well as suppressed cell apoptosis through secreting exosomes (*P < 0.05, **P < 0.01, and ***P < 0.001). Importantly, Msi1 expression was increased in M2 macrophage-derived exosomes (***P < 0.001). Mechanically, M2 macrophage-derived exosomes promoted malignancy and glycolysis by carrying Msi1 (*P < 0.01 and ***P < 0.001). In vivo, M2 macrophage-derived exosomal Msi1 accelerated cervical cancer progression (***P < 0.001).
    CONCLUSION: M2 macrophage-derived exosomes promote cervical cancer progression and glycolysis by delivering Msi1 to recipient cells.
    Keywords:  Cervical cancer; Exosomes; Glycolysis; M2 macrophages; Musashi1
    DOI:  https://doi.org/10.1186/s41065-026-00703-9
  17. Nanomaterials (Basel). 2026 Jun 14. pii: 744. [Epub ahead of print]16(12):
    Plant-Derived Exosomes Deliver Theranostic Molecules to Target Cells.
    Davide Mizzoni, Rossella Di Raimo, Antonella Aloi, Giuseppina Poppa, Vincenza Dolo, Mariantonia Logozzi, Stefano Fais.
      More specific targeted drug delivery systems with low immunogenicity and toxicity are expected to increase the efficacy of therapeutic molecules. The extracellular nanovesicles have been introduced as natural delivery systems for therapeutic molecules. More recently, considerable interest has emerged in plant-derived exosomes and their natural commitment to deliver molecules of various origins. Acridine Orange (AO) is an acidophilic dye with a strong tumoricidal action following excitation with a light source at 466 nm, but its clinical use is limited by the potential systemic toxicity. In this study we investigated the ability of exosomes from Citrus Sinensis to be successfully uploaded with AO (Exo-AO). We also studied the ability of the exosomes to be uploaded into target cells, as compared to the free molecules. We found that AO was efficiently uploaded into exosomes through electroporation. In fact, Exo-AO entered into the target cells significantly better than the free molecules, leading to both a marked intracellular AO delivery into target cells and an increase in the cytotoxic effect after excitation under a fluorescence microscope. This study shows a promising new approach for a more effective and less toxic drug delivery through the use of plant-derived extracellular nanovesicles.
    Keywords:  acridine orange; anti-tumor effect; drug delivery; exosomes; plant
    DOI:  https://doi.org/10.3390/nano16120744
  18. Front Pharmacol. 2026 ;17 1801527
    Surface modification strategies of oral liposomes: functional design and barrier enhancement.
    Pengyu Jin, Siyuan Wu, Ying Wang, Yiran Ni, Qingxiao Ruan, Ziang Yuan, Haiping Yao, Junming Li.
      Oral administration is the most prevalent and preferred clinical route due to its non-invasiveness, high patient compliance, and convenience. However, the oral delivery of many therapeutic drugs is hindered by low bioavailability, attributed to multiple gastrointestinal (GI) barriers including acid degradation, enzymatic hydrolysis, poor epithelial permeability, and first-pass metabolism. Liposomes have emerged as promising oral nanocarriers owing to their biocompatibility, versatile drug-loading capacity, and biomimetic membrane structure. Nevertheless, their poor physicochemical stability and inadequate cargo protection in the harsh GI environment limit clinical applications. This review summarizes the latest advances in surface modification strategies for liposomes to address these challenges. Synthetic polymer modifications (e.g., PEG, TPGS, pH-responsive Eudragit, and polydopamine) significantly boost the physicochemical stability of liposomes, prevent drug efflux, and improve mucus penetration. Natural biomacromolecule modifications (e.g., natural polysaccharides, proteins, peptides, and aptamers) effectively enhance mucoadhesion, cellular internalization, and active targeting capabilities. Meanwhile, small-molecule ligand modifications (e.g., folic acid, vitamin B12, and bile acids) actively promote intestinal transcytosis and targeted absorption by hijacking specific endogenous transporters. Notably, composite or multi-layer modification strategies (e.g., layer-by-layer assembly) achieve synergistic effects in effectively overcoming successive GI barriers. Furthermore, this review addresses the critical translational hurdles from bench to bedside, emphasizing that overcoming industrial scale-up bottlenecks (e.g., via microfluidic technologies) and conducting rigorous long-term biosafety evaluations are pivotal for the future clinical and commercial success of these advanced nanocarriers. Ultimately, these sophisticated surface engineering technologies remarkably enhance the physicochemical integrity, mucus penetration ability, and cellular uptake efficiency of liposomes, laying a solid foundation for translating efficient oral nanotherapeutics from bench to market.
    Keywords:  bioavailability; liposomes; nanocarriers; oral drug delivery; surface modification; targeted delivery
    DOI:  https://doi.org/10.3389/fphar.2026.1801527
  19. Front Transplant. 2026 ;5 1768497
    Pancreatic tissue engineering: towards a vascularized bioengineered cure for diabetes.
    Ji Ho Park, Khadijat A Olawuyi, Neekita R Jikaria, Jazzmyn S Dawes, Ishak E Dabsha, André A Dick, Dino J Ravnic.
      Type 1 diabetes results from autoimmune destruction of pancreatic β-cells, and while whole-organ pancreas and islet transplantation can restore endogenous insulin secretion, both are limited by donor scarcity, early inflammatory injury, hypoxia, and the need for lifelong immunosuppression. Pancreatic tissue engineering has therefore emerged as a strategy to generate scalable, transplantable constructs capable of reestablishing physiological glucose regulation. However, as native islets depend on a robust microvascular network for oxygen delivery, nutrients and coordinated hormone secretion, insufficient vascularization remains the dominant cause of engineered graft failure. This review provides an overview of (a) the current state of pancreas transplant, (b) strategies for vascularized and immunoprotective pancreatic constructs, (c) cell differentiation strategies beyond of pancreatic β-cells, (d) translational progress in animal and human clinical trials, (e) key challenges in clinical translation, (f) ethical and regulatory considerations, and (g) future directions for tissue engineered pancreatic constructs. Our goal is to provide the reader with a translational overview that spans biology, tissue engineering, and clinical translation.
    Impact statement: This translational review provides a concise review of tissue engineering efforts to date within the context of engineered pancreatic constructs. Our paper systematically and logically discusses current developments, challenges, and novel approaches in pancreatic tissue engineering. It provides a digestible starting point for understanding the various approaches and the implications of successful tissue engineering strategies that can be used to develop transplantable pancreatic constructs.
    Keywords:  diabetes; islet cell; pancreas; tissue engineering; transplant; vascularization
    DOI:  https://doi.org/10.3389/frtra.2026.1768497
  20. BioTech (Basel). 2026 Jun 10. pii: 43. [Epub ahead of print]15(2):
    The Gut Microbiome Dependency Continuum in Drug Discovery: A Unified Pharmacology Framework Linking Clinical Drugs, Natural Products, and Engineered Microbial Therapeutics.
    Solomon Habtemariam.
      Highlighting its pivotal role in modern pharmacology, the gut microbiome is emerging as a key determinant of drug efficacy, toxicity, and bioavailability. This review proposes the Gut Microbiome Dependency Continuum, a four-layer framework describing progressively deeper levels of microbiome involvement in drug discovery and therapeutic function. The first layer, intact functional microbiome-dependent therapeutics and includes interventions such as faecal microbiota transplantation and defined microbial consortia. The second layer, microbiome-modulated approved drugs include widely used therapeutics whose pharmacokinetics or pharmacodynamics are strongly influenced by microbial metabolism. Examples include metformin, irinotecan, levodopa, and digoxin, where gut microbial interactions influence efficacy, toxicity, and inter-individual variability in treatment outcomes. The third layer, microbiota-transformable natural products, encompasses dietary and plant-derived compounds such as polyphenols, ginsenosides, alkaloids, fibres, isoflavones, lignans, and glucosinolates. Their biological activity depends on microbial biotransformation into bioactive metabolites. The fourth layer, engineered microbiome therapeutics, includes synthetic biology approaches such as programmable microbial systems, engineered probiotics, CRISPR-based microbiome editing, and microbiome-responsive drug delivery systems. It also includes synthetic microbial consortia, enabling targeted sensing, therapeutic delivery, and ecological reprogramming of gut microbial communities. Altogether, these layers define a continuum in which the gut microbiome evolves from a passive modulator to an essential metabolic organ and ultimately a programmable therapeutic platform. The article provides an integrated framework for microbiome-informed drug discovery. It also supports the development of precision, ecology-aware, and engineered microbial therapeutics.
    Keywords:  CRISPR-based microbiome editing; drug discovery; engineered probiotics; faecal microbiota transplantation; gut microbiome; microbiome therapeutics; microbiome-responsive drug delivery systems; natural products; programmable microbial systems; synthetic microbial consortia
    DOI:  https://doi.org/10.3390/biotech15020043
  21. ACS Appl Mater Interfaces. 2026 Jun 25.
    Orchestrating Diabetic Wound Healing by a Sunlight-Activated AIEgen-Selenide Nanospray: From Infection Control to Tissue Regeneration.
    Anum Kayani, Arsalan Raza, Qinghao Zhou, Cheng Li, Zhidong Wang, Khurshed Bozorov, Yuanyuan Ji, Feng Wang, Zhishen Ge.
      Diabetic wounds, particularly diabetic ulcers (DUs), are life-threatening complications driven by bacterial infection, persistent inflammation, oxidative stress, and a dysfunctional immune microenvironment. Addressing these interconnected barriers requires a therapeutic strategy capable of coordinating infection control with tissue repair. Here, we report a sunlight-activated nanospray formulation (C@PSe) based on a covalently engineered aggregation-induced emission luminogen (AIEgen)-selenide triblock copolymer micelle that encapsulates curcumin (Cur). This system integrates three complementary functions into a single micellar platform. The AIEgen enables on-demand antimicrobial photodynamic therapy (aPDT) under natural sunlight, achieving precise bacterial elimination. The selenide block exerts glutathione peroxidase (GPx)-like activity to scavenge excess reactive oxygen species (ROS), alleviating oxidative stress and modulating the nuclear factor kappa-B (NF-κB)-associated inflammatory signaling. Simultaneously, Cur promotes anti-inflammatory macrophage polarization and drives pro-angiogenic signaling to support tissue regeneration. In a Staphylococcus aureus-infected diabetic mouse model, C@PSe effectively resolved bacterial infection, reduced ROS-driven inflammation, and accelerated wound closure with full re-epithelialization and enhanced neovascularization. By integrating sequential antibacterial, antioxidant, and regenerative actions within a single, patient-friendly nanospray that operates under sunlight, this platform overcomes key limitations of conventional photodynamic therapy (PDT) and offers a comprehensive strategy for treating chronic diabetic wounds.
    Keywords:  antibacterial; antimicrobial photodynamic therapy; diabetic wounds; macrophage repolarization; oxidative stress
    DOI:  https://doi.org/10.1021/acsami.6c10747
  22. Pharmaceutics. 2026 Jun 05. pii: 697. [Epub ahead of print]18(6):
    Cell-Specific Extracellular Vesicles Targeting Strategies for Immune Modulation in Inflammatory Diseases.
    Junha Lee, Suan Kwon, Yoosoo Yang, Jiwoong Choi.
      Extracellular vesicles (EVs) have attracted considerable attention as natural nanocarriers for immune modulation owing to their intrinsic biocompatibility, nanoscale size, and capacity to transport diverse bioactive cargos. In inflammatory diseases, EV-based therapeutics provide unique opportunities to regulate dysregulated immune responses; however, their clinical translation remains constrained by limited cell-specific targeting efficiency and uncontrolled biodistribution. Achieving precise and selective delivery to immune cells and other inflammation-associated cellular components within diseased tissues is therefore critical for maximizing therapeutic efficacy while minimizing off-target effects. This review comprehensively summarizes recent advances in cell-specific EV-targeting strategies for immune modulation in inflammatory diseases, with a particular focus on active targeting approaches enabled by EV surface engineering. A range of targeting ligands, including antibodies, peptides, aptamers, glycans, and membrane proteins, is discussed in the context of enhancing selective interactions between EVs and specific immune cell subsets. Special emphasis is placed on cell-directed targeting strategies toward diverse immune cell populations, including macrophages and T cells, highlighting how rational control of EV-cell interactions can be utilized to reprogram immune phenotypes, suppress pathological inflammation, and restore immune homeostasis. Accordingly, this review integrates recent progress in cell-specific EV targeting into a coherent conceptual framework, which may assist researchers in the rational design of EV-based immunomodulatory therapeutics.
    Keywords:  cell targeting; chemical conjugation; extracellular vesicles; inflammatory diseases; surface engineering
    DOI:  https://doi.org/10.3390/pharmaceutics18060697
  23. Anim Sci J. 2026 Jan-Dec;97(1):97(1): e70209
    Glycosylated Carbonated Apatite Particles for Macrophage-Targeted Delivery of CpG Oligodeoxynucleotides From Streptococcus thermophilus Enhance Immune Activation.
    Md Rayhan Chowdhury, Mitsuaki Goto, Ariful Islam, Takeshi Shimosato.
      Immunostimulatory CpG oligodeoxynucleotides (CpG-ODNs) are potent activators of innate immunity with promising applications in human and veterinary medicine. We previously developed carbonate apatite-based oligonucleotide particles (ODNcaps) for oral delivery, which are efficiently taken up by macrophages in jejunal Peyer's patches. To enhance macrophage-specific targeting, we introduced glycan modifications to ODNcaps, exploiting carbohydrate-binding receptors on macrophages. In this study, glycosylated ODNcaps were synthesized through N-acetylglucosamine (GlcNAc) conjugation and evaluated for cellular uptake and immunostimulatory activity in mouse peritoneal macrophages. Uptake efficiency was quantified using fluorescently labeled CpG-ODNs, and immune activation was assessed by IL-6 mRNA expression and IL-6 secretion. GlcNAc-modified ODNcaps showed markedly higher uptake and induced the strongest IL-6 responses at both transcriptional and protein levels compared with non-glycosylated controls. These results demonstrate that glycosylation is a simple yet effective strategy to improve macrophage targeting and immunostimulation by CpG-ODNs. Beyond murine models, this platform may hold promise for oral or mucosal immune modulation in livestock such as cattle, poultry, and swine, offering a novel approach to enhance antigen-presenting cell activation and strengthen mucosal immunity in animal production.
    Keywords:  CpG‐ODNs; glycosylation; macrophage; mucosal immunity; vaccine adjuvant
    DOI:  https://doi.org/10.1111/asj.70209
  24. Drug Deliv Transl Res. 2026 Jun 26.
    Mannose receptor-targeted MSC-derived exosomes as a high-affinity delivery platform for liver sinusoidal endothelial cells.
    Ji Won Lee, Jin Suk Lee, Kangchan Choi, Mi Ra Lee, Seul Ki Han, Soon Koo Baik, Yong Serk Park, Moon Young Kim.
      Liver sinusoidal endothelial cells (LSECs) play a crucial role in the progression of liver fibrosis. While mesenchymal stem cell-derived exosomes (MSC-Exos) hold potential for liver regeneration, their therapeutic efficacy is often limited by poor target specificity and rapid clearance. Here, we developed mannose receptor-targeting MSC-Exos (Man-Exos) by incorporating DSPE-PEG-Mannose via a post-insertion method to enhance LSEC-specific delivery. The physicochemical stability and targeting efficiency of Man-Exos were evaluated both in vitro and in vivo. Man-Exos exhibited high stability in various conditions and showed significantly enhanced binding affinity to LSECs compared to non-targeted exosomes. Notably, in a co-culture system of LSECs and macrophages, Man-Exos demonstrated superior selectivity for LSECs. In vivo biodistribution studies further confirmed that Man-Exos predominantly accumulated in the liver, specifically colocalizing with LSECs for up to 48 h. Our findings suggest that Man-Exos can serve as a highly efficient and stable delivery platform for LSEC-targeted therapy, providing a promising strategy for enhancing the translational potential of exosome-based regenerative medicine in liver fibrosis.
    Keywords:  Exosomes; Liver fibrosis regeneration; Liver sinusoidal endothelial cells-target; Mannose ligand; Mesenchymal stem cells
    DOI:  https://doi.org/10.1007/s13346-026-02169-8
  25. Immunity. 2026 Jun 25. pii: S1074-7613(26)00270-0. [Epub ahead of print]
    Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
    Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B Schroer, Daniel J Richard, Gita C Abhiraman, Andy P Tsai, Eric D Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y Zhou, Matthew T Buckley, Karen E Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A Saxton, Ricardo A Fernandes, Saul A Villeda, K Christopher Garcia, Anne Brunet.
      
    DOI:  https://doi.org/10.1016/j.immuni.2026.06.019
  26. Biochem Pharmacol. 2026 Jun 23. pii: S0006-2952(26)00514-9. [Epub ahead of print] 118175
    Extracellular vesicles (EVs) in neurodevelopment: The emerging role of lipids.
    Lorenzo Germelli, Simona Daniele, Claudia Martini, Eleonora Da Pozzo.
      Lipid‑dependent mechanisms of exosome biogenesis are increasingly recognized as key regulators of neurodevelopment, shaping neuronal differentiation, synaptogenesis, glia-neuron communication, and myelination. In this review we summarize recent multi‑omic, cellular, organoid, and in vivo studies showing that extracellular vesicles (EVs) influence neurodevelopmental trajectories both by delivering trophic signals that promote neurite outgrowth and synapse formation and by modulating glia-neuron crosstalk controlling inflammation, myelination, and synaptic pruning. Alterations in lipid metabolism, including cholesterol, sphingomyelin, ceramides, phosphatidylserine, and related bioactive lipids, directly affect multivesicular body formation, intraluminal vesicle budding, and cargo selection, thereby reshaping EV lipidomes and signaling during critical windows of brain maturation. Across neurodevelopmental disorders (NDDs), convergent evidence shows that EV biogenesis, lipid composition, and cargo loading are disrupted. In this sense, we discuss translational opportunities: small‑molecule modulators of sphingolipid and cholesterol pathways, dietary and metabolic interventions, and engineered EVs enriched in pro‑neurogenic miRNAs as tractable strategies to restore EV cargo composition and intercellular signalling. Collectively, the review highlights as targeting lipid pathways that govern EV biogenesis and cargo loading offers promising avenues for biomarker discovery and therapeutic intervention across NDDs.
    Keywords:  Diet; EV Engineering; Extracellular Vesicles; Lipidomics; Neurodevelopmental disorders; Therapeutic cargo
    DOI:  https://doi.org/10.1016/j.bcp.2026.118175
  27. J Biomed Mater Res A. 2026 Jul;114(7): e70107
    Biomaterial-Focused Strategies Targeting Dendritic Cells for Autoimmune Disease Treatment.
    Aiswarya Venkata Suresh Kumar, Julia Babensee.
      Autoimmune diseases encompass over 100 distinct diseases where the immune cells betray our body by attacking the tissues they are meant to protect. Even though rare, 15 million Americans are collectively affected by autoimmune diseases, a number that continues to rise every year. Current treatment modalities primarily focus on alleviating symptoms rather than providing prevention or a cure. Tolerogenic dendritic cells (tolDCs) have gained popularity for autoimmune disease treatment as an alternative to traditional systemic immunosuppressive therapies due to their ability to restore immune homeostasis. However, clinical translation of tolDC therapies faces significant hurdles once injected into the body due to suboptimal delivery routes, systemic distribution throughout the body, faster clearance rate, phenotypic instability, and inefficient homing. So, the big question here is: How can we retrain dendritic cells to restore the immune balance while overcoming these challenges? Engineered biomaterials such as nanoparticles, microparticles, hydrogels, and polymer scaffolds offer innovative solutions by enabling targeted delivery of ex vivo-generated tolDCs or in situ reprogramming of endogenous dendritic cells (DCs) by delivering drugs and other bioactive agents at strategic locations. These platforms provide tunable release kinetics, enhanced targeting specificity, improved safety profiles, and high potency, highlighting their importance as a promising alternative to conventional administration methods. Biomaterials can modulate immune responses from inflammatory immune activation to immune tolerance, which is essential for long-term disease management. This review highlights recent advances in biomaterial-based delivery systems for DC delivery and their potential to redefine therapeutic strategies for autoimmune diseases.
    Keywords:  autoimmune diseases; biomaterials; hydrogels; immune modulation; microparticles; nanoparticles; scaffolds; tissue engineering; tolerogenic dendritic cells
    DOI:  https://doi.org/10.1002/jbm.a.70107
  28. Int J Gynaecol Obstet. 2026 Jun 23.
    Combined radiofrequency and topical exosomes in atrophic vulvar lichen sclerosus: A case report.
    Luisa Mendonca de Oliveira, Narciso DiLorenzo Machado Dias, Jacqueline Maia Ferraz, Patricia da Silva Oliveira.
      Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatological-gynecological condition. Conventional first-line treatment comprises topical corticosteroids; however, many patients remain refractory. Energy-based devices, including radiofrequency (RF), have shown promising results in VLS, with symptomatic and functional improvement. Exosomes are vesicles containing bioactive molecules involved in tissue regeneration; their lyophilized form, stabilized for topical application, has been combined with energy-based therapies with satisfactory results in other dermatological conditions. To our knowledge, this is the first report of ablative RF combined with topical lyophilized exosomes for VLS. We present the case of a 38-year-old woman with biopsy-confirmed VLS refractory to standard treatment, who underwent ablative fractional RF combined with topical lyophilized exosomes derived from amniotic fluid stem cells. The patient showed improvement in pruritus, dyspareunia, and sexual function, and reported satisfaction with the combined therapy.
    Keywords:  exosomes; lichen sclerosus; radiofrequency; vulvar disorders
    DOI:  https://doi.org/10.1002/ijgo.71178
  29. Biosci Rep. 2026 07 22. pii: BSR20193436_EOC. [Epub ahead of print]46(7):
    Expression of Concern: Exosomes derived from circRNA Rtn4-modified BMSCs attenuate TNF-α-induced cytotoxicity and apoptosis in murine MC3T3-E1 cells by sponging miR-146a.
    Guijun Cao, Xianqing Meng, Xiaodong Han, Jinhua Li.
      
    Keywords:  bone marrow-derived mesenchymal stromal cell; circular RNA Rtn4; exosomes; miR-146a; tumor necrosis factor-alpha
    DOI:  https://doi.org/10.1042/BSR20193436_EOC
  30. Health Sci Rep. 2026 Jun;9(6): e72638
    Multifaceted Role of Extracellular Vesicles: Intercellular Messengers to Therapeutic Applications: A Narrative Review.
    Kajal Kamra, Satya Kumar Lalam, Shefali Srivastava, Madan Kumar Arumugam, Lokesh Kumar Boopathy, Simran Takkar, Zhiqiu Xia, Sabarinath Peruvemba Subramanian.
       Background and Aims: Extracellular vesicles (EVs) are nanoscale carriers, including exosomes, microvesicles, and apoptotic bodies, that mediate intercellular communication by transporting proteins, nucleic acids, lipids, and metabolites. They regulate immunity, tissue repair, and cell differentiation. Increasing evidence highlights their dual roles in disease, where they may promote tumor growth and immune evasion but also serve as diagnostic and therapeutic tools. This review synthesizes advances in EV biology, their roles in health and disease, and their therapeutic potential.
    Methods: We conducted a narrative review of recent literature, focusing on EV isolation methods, biological functions, and clinical applications. Sources were selected to capture both mechanistic insights and translational perspectives.
    Results: Advances in isolation technologies, from ultracentrifugation to microfluidics, have improved the precision of EV characterization. EVs exhibit distinct molecular signatures, positioning them as promising biomarkers in cancer, cardiovascular, neurodegenerative, autoimmune, and infectious diseases. Mechanistic studies demonstrate their roles in immune modulation, tissue remodeling, and regeneration. As therapeutic agents, EVs show promise as drug delivery systems and as platforms for gene and immunotherapies, offering enhanced targeting and reduced toxicity compared to synthetic nanoparticles. Engineered EVs and hybrid EV-liposome systems further expand their applications, though challenges persist in scalability, standardization, and safety.
    Conclusion: EVs are central mediators of intercellular communication with transformative potential in diagnostics and therapeutics. Their biological properties position them as valuable biomarkers and delivery vehicles in precision medicine. Overcoming translational challenges, such as immunogenicity, oncogenic risks, and manufacturing limitations, will be essential for their successful clinical integration.
    Keywords:  biomarker; disease pathogenesis; extracellular vesicles; intercellular communication; therapeutic applications
    DOI:  https://doi.org/10.1002/hsr2.72638
  31. Trends Biotechnol. 2026 Jun 22. pii: S0167-7799(26)00237-4. [Epub ahead of print]
    Reprogrammable bacterial nanosyringes to deliver RNA and gene editors.
    Haishan Xu, Lei Feng, Ningning Song, Xiangxiang Zhao, Xianchao Feng.
      The engineered Photorhabdus virulence cassette (PVC) enables precise protein delivery but has not yet achieved RNA packaging and injection delivery. In this study, we achieved intraluminal RNA loading via the U1A RNA-binding domain, anchoring it to the PVC inner tube and establishing DART (PVC Docker-based All-purpose RNA Injection Delivery Tool). This enabled the protective loading of diverse RNAs, including Pepper RNA, guide RNA, siRNA, miRNA, and mRNA. Through the co-delivery of Cas9 in vitro, DART also drove effective knockouts of enhanced green fluorescent protein gene (EGFP), Kirsten rat sarcoma viral oncogene homolog (KRAS), and programmed death-ligand 1 (PD-L1), representing reporter, oncogenic, and immune-related targets for evaluating DART-mediated gene editing. Notably, DART-mediated KRAS knockout produced a significant antitumor effect in a subcutaneous mouse tumor model. Complementary to the external spike-surface fusion strategy of SPEAR (a PVC system termed spike engineering and retargeting), as an intraluminal nanosyringe platform, DART employs internal engineering to expand PVC from protein to RNA delivery.
    Keywords:  CRISPR/Cas9; PVC nanosyringes; RNA delivery; gene knockout in vivo; tumor therapy
    DOI:  https://doi.org/10.1016/j.tibtech.2026.05.024
  32. Curr Issues Mol Biol. 2026 May 26. pii: 557. [Epub ahead of print]48(6):
    Antioxidant Polymeric and Non-Polymeric Nanoformulations for the Treatment of Autoimmune Diseases.
    Michail Varras, Fani-Niki Varra, Viktoria-Konstantina Varra, Panagiotis Theodosis-Nobelos.
      Autoimmune diseases are characterized by chronic inflammation, immune dysregulation, and excessive oxidative stress, which collectively contribute to a progressive tissue damage and organ dysfunction. Although conventional immunosuppressive and anti-inflammatory therapies remain the main therapeutic approach, their clinical efficacy is often limited by poor pharmacokinetic properties, low tissue selectivity, systemic toxicity, and adverse effects following long-term administration. In this context, antioxidant-based nanoformulations have emerged as promising multi-target therapeutic strategies for the modulation of oxidative and inflammatory pathways involved in autoimmune disorders. This review focuses on polymeric and non-polymeric nanoformulations designed to improve the solubility, stability, bioavailability, controlled release, and targeted delivery of antioxidant and anti-inflammatory agents for autoimmune disease treatment. Recent advances in nanocarrier systems applications, including nanogels, poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), polymethacrylate, chitosan, hyaluronic acid, hydroxyapatite (HAP), lipid-based and ROS-responsive nanosystems, are discussed. The therapeutic potential of nanoencapsulated steroidal and non-steroidal anti-inflammatory drugs, antioxidant compounds, enzymes, inorganic elements, and nucleic acid-binding systems is evaluated through preclinical and limited clinical evidence. Many of these reported nanoformulations exhibit enhanced therapeutic efficacy, improved tissue targeting, reduced systemic toxicity, and the ability to simultaneously modulate oxidative stress and inflammatory signaling pathways. Despite the encouraging findings, important challenges remain regarding clinical translation, long-term safety, reproducibility, and large-scale production. In overall, antioxidant nanoformulations represent a promising and evolving platform for the development of more effective and targeted therapies against autoimmune diseases.
    Keywords:  antioxidant nanoformulations; autoimmune diseases; inflammation; nanomedicine; oxidative stress; polymeric nanoparticles; targeted drug delivery
    DOI:  https://doi.org/10.3390/cimb48060557
  33. J Biomed Mater Res A. 2026 Jul;114(7): e70103
    Engineering Bone-Targeted LNP Delivery of Anti-Sclerostin Antibody mRNA for the Treatment of Osteoporosis.
    Pengcheng Ren, Diaodiao Wang, Wenqiang Sun, Danning Li, Sidong Yang, Shudong Zhang, Yiquan Zhang, Yubo Liu, Peng Hu, Jiaxin Li, Qi Yao.
      Messenger RNA (mRNA) therapy represents a transformative platform in regenerative medicine, but its application to skeletal disorders remains limited by the pronounced hepatic tropism of conventional lipid nanoparticle (LNP) delivery systems. To redirect the distribution of biomolecules to bone tissue, we developed a bone-targeting mRNA nanocarrier (SA@LNP-D) through microfluidic synthesis followed by surface conjugation of the Asp8 peptide (binding to hydroxyapatite). This system enables efficient expression of anti-sclerostin antibody mRNA in bone tissue, thereby achieving therapeutic effects for osteoporosis treatment. Our in vitro experimental results have demonstrated that LNP modified with bone-targeting peptides exhibits significant bone affinity and can efficiently bind to hydroxyapatite and isolated bone. Furthermore, the in vivo results confirmed that SA@LNP-D effectively reduces hepatic sequestration and specifically accumulates in bones through mineral-directed anchoring. In a murine ovariectomy model of osteoporosis, systemic delivery of bone-targeted LNP demonstrated a stronger therapeutic effect compared to conventional LNP. It not only stimulated bone formation but also inhibited bone resorption, thereby significantly restoring trabecular bone mass and microstructure. Together, this work establishes a targeted, nonhepatic mRNA delivery strategy that offers a safe and effective therapeutic option for osteoporosis and related skeletal conditions.
    Keywords:  LNP; bone‐affinity peptide; mRNA; osteoporosis; sost‐antibody
    DOI:  https://doi.org/10.1002/jbm.a.70103
  34. J Nanobiotechnology. 2026 Jun 25.
    Virus-like particles in cancer immunotherapy: bridging human and veterinary medicine through one health.
    Yingqi Zhu, Zhuangli Bi, Zichen Zhang, Miao Zhang, Qingqing Du, Mingxing Hu, Ting Zhou, Yiming Fan, Shu Zhang, Guijun Wang, Guangqing Liu.
      Virus-like particles (VLPs) are engineered nanoplatforms that mimic viral structures, offering high immunogenicity, biocompatibility, and functional versatility for cancer immunotherapy. While widely explored in human oncology as nanovaccines and targeted delivery systems for chemo-/immuno-therapeutics and genetic payloads (e.g., mRNA, siRNA, and CRISPR/Cas systems), their potential in veterinary oncology remains underexploited. This review synthesizes recent advances in VLP design, including scaffold engineering, antigen display, cargo encapsulation, and surface functionalization, and discusses the mechanistic basis of VLP-induced antitumor immunity, encompassing dendritic cell activation, adaptive immune amplification, and tumor microenvironment remodeling. Importantly, we highlight the emerging role of companion animals with spontaneous tumors-such as lymphoma, melanoma, and mammary carcinoma-as immunocompetent translational models within the One Health framework. Comparative oncology reveals striking parallels in oncogenic pathways, immune landscapes, and therapeutic responses, supporting the use of canine and feline cancers as biologically relevant intermediates between murine studies and human clinical trials. We provide an evidence-based assessment of representative VLP platforms, evaluate their translational readiness, and examine cross-species opportunities for shared target development, biomarker discovery, and regulatory convergence, while also addressing species-specific biological and technical limitations. Finally, we propose a forward-looking roadmap that prioritizes manufacturing standardization, biomarker development, comparative validation, precision engineering, and emerging technologies such as AI-guided design and tumor-on-chip systems. Collectively, we position One Health as an operational strategy to accelerate the bidirectional translation of VLP-based immunotherapies for both human and veterinary cancer patients.
    Keywords:  Cancer immunotherapy; Companion animals; Comparative oncology; Drug delivery; Nanovaccine; One health; Virus-like particles (VLPs)
    DOI:  https://doi.org/10.1186/s12951-026-04703-9
  35. Sheng Wu Gong Cheng Xue Bao. 2026 Jun 25. pii: 1000-3061(2026)06-2599-12. [Epub ahead of print]42(6): 2599-2610
    [Construction of a methanol-free protein expression system in Pichia pastoris based on the enhanced sorbitol assimilation pathway].
    Shuiyuan Zhou, Jiayu Fang, Guoxia Liu, Yanping Zhang, Yin Li, Fuhang Song, Taicheng Zhu.
      The AOX1 promoter in Pichia pastoris is conventionally induced by methanol. However, methanol-based processes arouse safety concerns and operational complexity in industrial fermentation. Sorbitol has emerged as a promising alternative carbon source due to its favorable safety profile and minimal repressive effect on AOX1. To eliminate methanol dependence in the conventional AOX1-based expression system, in this study, the engineered strain GS-aCe, capable of secreting chondroitin hydrolase, was employed as a model to establish a methanol-free AOX1 expression system through coordinated engineering of transcriptional regulation and carbon metabolism. Overexpression of the transcriptional activator Mit1 in strain GS-aCe-Mit1 effectively activated the AOX1 promoter under sorbitol conditions, achieving 91.6% of the enzyme activity observed in the methanol-induced parental strain. Further co-expression of sorbitol dehydrogenase and hexokinase to enhance sorbitol assimilation significantly improved the growth performance of the resulting strain GS-aCe-Mit1-SH. In 1-L fermenters, the sorbitol consumption and biomass of GS-aCe-Mit1-SH increased by 82.0% and 90.5%, respectively, compared with those of GS-aCe-Mit1. The final biomass was 10.6% higher than that achieved in the methanol system, and the enzyme yield reached 1.10×106 U/g, which was comparable to that of the methanol-induced system (1.14×106 U/g), with no detectable accumulation of residual sorbitol. Collectively, integration of Mit1-mediated AOX1 transcriptional activation with reinforced sorbitol assimilation enabled efficient heterologous protein expression in P. pastoris under methanol-free conditions. This work provides a practical strategy for developing safe carbon source alternatives for AOX1-driven expression systems.
    Keywords:  AOX1 promoter; Pichia pastoris (Komagataella phaffii); chondroitin hydrolase; induction by methanol-free carbon source; sorbitol; transcriptional activator
    DOI:  https://doi.org/10.13345/j.cjb.260087
  36. Int J Mol Med. 2026 Sep;pii: 232. [Epub ahead of print]58(3):
    Skeletal muscle‑derived extracellular vesicles in multi‑organ degenerative disease: Mechanisms and therapeutic delivery perspectives (Review).
    Xianji Wei, Chengyan Guo, Wei Zhang, Guanyi Wang, Wenjing Li, Binghong Gao, Bo Gao, Lingli Zhang.
      Multi‑organ degenerative diseases are age-associated or chronic disorders marked by progressive tissue deterioration, impaired repair and functional decline, with representative conditions including sarcopenia, osteoporosis, osteoarthritis, neurodegenerative or ischemia‑associated neurological disorders, heart failure, chronic kidney disease and diabetes‑associated tissue dysfunction. Their frequent coexistence in aging populations limits the effectiveness of therapeutic strategies directed at a single organ or pathway. Extracellular vesicles (EVs) are lipid bilayer‑enclosed particles that shuttle proteins, lipids, metabolites and regulatory RNAs between cells and tissue. As a highly metabolic and secretory tissue, skeletal muscle releases skeletal muscle‑derived EVs (SkM‑EVs) that may carry muscle‑enriched microRNAs, together with other regulatory cargo molecules involved in local tissue remodeling and systemic signaling. SkM‑EVs have therefore been proposed as mediators of muscle‑centered cross‑organ communication and potential delivery vehicles for molecular intervention, although therapeutic evidence remains largely preclinical. The present review examines the biological functions of SkM‑EVs, their regulation by exercise, aging and metabolic stress and their potential involvement in multi‑organ degenerative diseases. The present study aimed to discuss engineering strategies for SkM‑EVs, including cargo loading, surface modification and targeted delivery, with particular attention to controversies, methodological limitations, quality control requirements and barriers to clinical translation.
    Keywords:  EV engineering; SkM‑EV; degenerative disease; extracellular vesicle; interorgan communication; myomiR; skeletal muscle; targeted delivery
    DOI:  https://doi.org/10.3892/ijmm.2026.5903
  37. Vaccines (Basel). 2026 May 22. pii: 463. [Epub ahead of print]14(6):
    Nanotechnology-Based Cancer Vaccines: Translational Barriers and Emerging Strategies.
    Muneera Anwer, Rifat Rahman.
      Cancer vaccines represent a promising strategy in cancer immunotherapy by inducing tumour-specific immune responses. However, their clinical efficacy remains limited due to challenges in antigen selection, including the distinction between self and non-self-antigens, as well as issues related to antigen delivery, immune activation, and tumour immune evasion. Advances in nanotechnology have introduced innovative approaches to improve vaccine stability, targeted delivery, and immunogenicity. Nanoparticle-based platforms, including lipid, polymeric, inorganic nanoparticles, and virus-like particles, enable efficient delivery of tumour antigens and immunostimulatory adjuvants to antigen-presenting cells, thereby enhancing adaptive immune responses. Despite these advances, several translational challenges persist, including immunosuppressive tumour microenvironments, inefficient lymph node targeting, safety concerns, and manufacturing limitations. This review summarizes key nanoparticle platforms used in cancer vaccine development and discusses major barriers to their clinical translation. We also emphasize platform-selection criteria, cargo-dependent carrier design, nanoparticle size constraints, engineering strategies used to improve cytosolic delivery and endosomal escape, and the current clinical pipeline of cancer nanovaccines. Additionally, emerging strategies such as personalized nanovaccines, mRNA vaccine platforms, and combination immunotherapies are highlighted as promising approaches to improve therapeutic efficacy. These advances are expected to accelerate the clinical translation of nanotechnology-enabled cancer vaccines and support the development of next-generation cancer immunotherapies.
    Keywords:  cancer vaccines; combination immunotherapy; mRNA vaccines; nanoparticle delivery systems; nanotechnology; personalized nanovaccines; translational barriers
    DOI:  https://doi.org/10.3390/vaccines14060463
  38. Pharmaceutics. 2026 May 27. pii: 660. [Epub ahead of print]18(6):
    A Lung-Targeted Lipid Nanoparticle System Delivers miRNA to Suppress Colorectal Cancer Pulmonary Metastases.
    Yuxiang Gantai, Ziyan Yang, Yinshuang Chen, Mengxi Chen, Yu Hu, Tingwei Ye, Jiayu Xu, Shenyue Zhou, Yuanyuan Yu, Yan Chen, Mengmeng Wang, Weitao Zhang, Jianqing Ruan, Haiyang Zhang, Weipeng Wang.
      Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with more than 90% patients dying from metastasis due to limited treatment options. Although miRNA-based therapeutics represent a promising strategy, their clinical application has been hindered by poor stability in vivo and the lack of efficient organ-specific delivery systems. Methods: In this study, we developed a lung-targeted lipid nanoparticle (LuT-LNP) platform for the delivery of a chemically modified miRNA, AM22, which demonstrated enhanced tumor-suppressive activity. By replacing cholesterol and helper lipids with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), the most abundant lipid in pulmonary surfactant, and systematically optimizing the ratios of ionizable and cationic lipids, we obtained a LuT-LNP formulation with superior lung tropism. Results: The resulting LuT-LNPs exhibited excellent stability, biocompatibility, and efficient encapsulation and protection of AM22. Both in vitro and in vivo, AM22-loaded LuT-LNP (AM22@LuT-LNP) significantly inhibited the proliferation and migration of CRC cells and markedly suppressed lung metastasis in a mouse model. Mechanistic studies revealed that AM22 acts by targeting Poly (ADP-ribose) polymerase 1 (PARP1), inducing DNA damage, and inhibiting the epithelial-mesenchymal transition (EMT) process. Conclusions: These findings established a lung-targeted delivery platform for miRNA-based therapy, offering a promising strategy for the treatment of colorectal cancer pulmonary metastasis (CRPM).
    Keywords:  AM22; LuT-LNP; PARP1; colorectal cancer pulmonary metastasis; miRNA
    DOI:  https://doi.org/10.3390/pharmaceutics18060660
  39. Transl Res. 2026 Jun 24. pii: S1931-5244(26)00132-5. [Epub ahead of print]
    Tracheal Delivery of HO-1-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cells Treats Pulmonary Arterial Hypertension by Enhancing Pulmonary Antioxidant and Anti-inflammatory Responses.
    Chen Riken, Chen Xing, Liang Limei, Li Huan, Xu Liping, Huang Dongjie, Liu Yong, Zhou Deyi, Ye Weilong, Zhou Shuyue, Su Yihuan, Nie Dekang, Zheng Zhenzhen, Deng Yan.
       OBJECTIVE: Pulmonary arterial hypertension (PAH) is a life-threatening cardiovascular disease, with current treatments only alleviating symptoms. Mesenchymal stem cells (MSCs) possess immune-regulatory and reparative properties, and HO-1-modified MSCs enhance their anti-inflammatory and antioxidant effects. This study aims to investigate the potential of tracheal delivery of HO-1-modified MSCs for the treatment of PAH.
    METHODS: This study first assessed the levels of inflammation and oxidative stress in the lung tissue pathology of donors and IPAH patients, detecting F4/80, IL-6, and the oxidative stress marker 8-OHdG. Subsequently, in MCT-induced rat and hypoxia-exposed mouse models, we evaluated lung tissue sections for HE staining and α-SMA immunohistochemistry, along with antioxidant enzymes (SOD, CAT, GSH) and inflammatory factors (TNF-α, IL-18, IL-6, IL-1β) at 1, 2, 3, 4, and 5 weeks to assess the effects of various treatments. Next, we compared the anti-inflammatory and antioxidant capacities of HO-1-modified MSCs derived from umbilical cord (UC-MSCs) and adipose tissue (AD-MSCs), selecting the best cell intervention strategy. Using in vivo imaging, we assessed the cell homing of intravenously injected cells and drug retention after tracheal delivery. After tracheal delivery of HO-1-MSCs at 3, 4, and 5 weeks, we analyzed IHC staining for α-SMA, right heart catheterization, lung tissue inflammation, and antioxidant stress markers to identify the optimal intervention window. The efficacy was also compared with traditional HO-1 pharmacological agonists. Finally, the effects of HO-1-MSCs on vascular cells (PAECs, PASMCs) and immune cells (myeloid-derived/macrophage, myeloid-derived neutrophils) in vivo were further explored to evaluate their potential and mechanisms in PAH treatment.
    RESULTS: Compared to donor controls, IPAH patient lung tissues exhibited significant inflammation and oxidative stress, with increased macrophage infiltration and elevated levels of IL-6 and 8-OHdG. In MCT rat and hypoxia mouse models, PAH development was associated with vascular remodeling, persistent inflammation, and oxidative stress. UC-MSCs showed stronger anti-inflammatory and antioxidant effects than AD-MSCs. Tracheal delivery of HO-1-MSCs significantly improved outcomes at weeks 3 and 4, reversing pulmonary vascular remodeling, reducing pulmonary artery pressure, inhibiting IL-6 and IL-18 expression, and restoring antioxidant enzyme activity (SOD and CAT). Compared to traditional HO-1 agonists, HO-1-MSCs demonstrated superior efficacy. Additionally, HO-1-MSCs effectively inhibited PAEC proliferation, suppressed the activation of the ERK/AKT pathway, reduced smooth muscle cell proliferation and migration, significantly decreased neutrophil activation, and promoted M2 macrophage polarization while reducing the M1 macrophage population.
    CONCLUSION: Tracheal delivery of HO-1-(UC)-MSCs effectively alleviates inflammation and oxidative stress in PAH, improves vascular remodeling and pulmonary artery pressure, and offers a promising new therapeutic strategy for PAH treatment.
    Keywords:  Pulmonary arterial hypertension; gene-modified mesenchymal stem cells; macrophages; neutrophils; oxidative stress
    DOI:  https://doi.org/10.1016/j.trsl.2026.06.015
  40. J Am Chem Soc. 2026 Jun 23.
    Molecular Glues Recruiting RNF213 As an E3 Ligase for Targeted Protein Degradation: A Minimal Dibromoacetamide Warhead As a Recruitment Ligand.
    Jingyi Jiang, Yubin Chen, Rui Wan, Chaoming Huang, Tao Xiang, Chuixing Luo, Jianxiong Deng, Zhang Zhang, Tongzheng Liu, Yi Tan, Zhengqiu Li.
      Targeted protein degradation (TPD) is a promising therapeutic strategy, yet its application remains constrained by the limited repertoire of available E3 ubiquitin ligases, primarily CRBN and VHL. Here, we identify RNF213 as a recruitable E3 ligase that mediates protein degradation induced by molecular glue degraders. We developed CYB-5067 by equipping the pan-FGFR inhibitor Infigratinib with a minimal dibromoacetamide covalent warhead. This covalent molecular glue recruits RNF213 to potently degrade FGFR1-4, with the strongest effect on FGFR2 (DC50 = 27 nM, Dmax = 96%). CYB-5067 outperforms parent inhibitors in vitro (IC50 = 3.8 nM) and shows comparable antitumor efficacy in vivo (TGI = 94.6%), with sustained target suppression and no apparent hook effects under the tested conditions. Notably, the dibromoacetamide warhead is transplantable, enabling selective degradation of other challenging targets such as WEE1 and CDK12, which regulate cell-cycle progression and transcription. This offers a rational strategy for creating molecular glues. Our work identifies RNF213 as an exploitable ligase for TPD and establishes covalent molecular glues as a modular platform. This strategy expands the scope of degrader design beyond conventional E3 ligases, offering an avenue for developing potent and selective therapeutics.
    DOI:  https://doi.org/10.1021/jacs.6c03429
  41. Biosci Trends. 2026 Jun 20.
    Stem cell-derived extracellular vesicles for rare diseases: A clinical‑bottleneck‑to‑mechanism framework for translation.
    Yue Han, Nuo Chen, Peipei Song, Yanling Chen, Wei Tang.
      Rare diseases impose a disproportionate clinical burden, and yet therapeutic progress is hindered by small cohorts, biological heterogeneity, and limited disease-specific options. Stem cell-derived extracellular vesicles (EVs), and especially exosome-enriched products, are emerging as adaptable cell-free therapeutics that preserve key paracrine activities of parent cells while offering improved controllability, engineering flexibility, and potentially lower acute immunogenicity than living-cell products. This review proposes a clinically driven bottleneck-to-mechanism framework for rare-disease translation, matching each disease class to its dominant pathological barrier, mechanism-relevant EV function, route-aware delivery strategy, and measurable potency endpoint. Using this framework, EVs may enable immune circuit rewiring in autoimmune disorders, neuroprotection and toxic-protein clearance in neurodegeneration, osteogenic and matrix-supportive repair in skeletal/connective tissue diseases, and metabolic rescue in lysosomal or mitochondrial disorders. We further highlight a key conceptual distinction between EVs as active biologics and EVs as engineered delivery vehicles. Successful translation will depend on integrating cargo design, surface targeting, biodistribution-aware administration, scalable manufacturing, and quality-by-design control, while anticipating repeat-dose pharmacokinetics/pharmacodynamics (PK/PD), immunogenicity, complement activation, procoagulant risk, impurity control, and off-target organ-accumulation challenges. Multi-omics and artificial intelligence may further refine target selection and precision engineering. Overall, stem cell-derived EVs constitute a versatile platform for treating rare diseases, but clinical success requires closer alignment among mechanism, disease specificity, product definition, and translational endpoints.
    Keywords:  artificial intelligence; cargo engineering; exosomes; extracellular vesicles; mesenchymal stem cells; rare diseases; surface targeting
    DOI:  https://doi.org/10.5582/bst.2026.01150
  42. Microb Biotechnol. 2026 Jun;19(6): e70403
    Engineering Pseudomonas protegens as a Targeted Antifungal-Effector Delivery Chassis via Heterologous Type III Secretion System Reconstitution.
    Yuyuan Peng, Simei He, Guofan Zhang, Jiatao Yang, Rong Fan, Chen Li, Jiajie Xie, Xinran Long, Linger Qian, Jiayi Wang, Yanmin He, Hui Cai, Yushan Zhang, Qiuqian Zhang, Shaopeng Pan, Shengbiao Hu.
      This study addresses the core challenge of Fusarium wilt control in agricultural production. We successfully reconstituted a functional heterologous type III secretion system (T3SS) from Photorhabdus luminescens in the biocontrol bacterium Pseudomonas protegens Pf-5, creating an engineered molecular syringe for targeted delivery of antifungal effectors. The system is activated under low-calcium conditions, achieved by cultivation in calcium-limited medium followed by EGTA-mediated chelation of residual Ca2+, enabling conditional secretion of effector proteins. By fusing the antifungal protein Bg9562 to the N-terminal secretion signal of the T3SS effector LopT and co-expressing it with the cognate chaperone SlcT, we obtained fluorescence-based evidence for T3SS-dependent delivery of Bg9562 into the hyphae of multiple Fusarium species. The engineered strain exhibited enhanced rhizosphere colonization, promoted plant growth and conferred improved protection against tomato Fusarium wilt, restoring plant height to levels approaching healthy controls. We further demonstrated the modularity of this platform by successfully transferring it into Pseudomonas koreensis D26, a strain known for its plant growth-promoting properties, indicating broad applicability across biocontrol-relevant pseudomonads. This work establishes a versatile T3SS-based delivery platform for precision biocontrol, offering a generalizable strategy for engineering beneficial rhizobacteria.
    Keywords:  Fusarium wilt; Pseudomonas protegens Pf‐5; antifungal effector; biological control; protein delivery; type III secretion system (T3SS)
    DOI:  https://doi.org/10.1111/1751-7915.70403
  43. Int Immunopharmacol. 2026 Jun 22. pii: S1567-5769(26)00885-4. [Epub ahead of print]185 117039
    The role of the mesenchymal stem cell therapy in bone regeneration of osteoporosis: clinical translation and limitations.
    Mustafa T Ardah, Waleed K Abdulsahib, Hasanain Amer Naji, M M Rekha, Pradeepta Sekhar Patro, Anima Nanda, Vipasha Sharma, Ashish Singh Chauhan, Zebiniso Alimova, Farzaneh Yazdi.
      Osteoporosis (OP) is a gradual metabolic bone disease characterized by decreased bone mass and degradation of bone microarchitecture. It affects hundreds of millions of people globally and places considerable pressure on healthcare systems. Current pharmacological treatments, such as bisphosphonates, selective estrogen receptor modulators, and anabolic agents, can reduce fracture risk; however, their prolonged use is limited by significant adverse effects, elevated treatment costs, and a lack of sustained disease remission. Their constraints have intensified interest in restorative approaches utilizing mesenchymal stem cells (MSCs). In the past 20 years, MSCs have emerged as attractive treatment options for OP due to their capacity to differentiate into osteoblasts, modulate immune responses, and exert paracrine effects. Bone marrow-MSCs are the best characterized; nevertheless, MSCs obtained from adipose tissue, umbilical cord, and dental pulp have distinct benefits. Preclinical data demonstrate that direct MSC transplantation enhances bone mineral density, promotes osteoblast production, and reestablishes the equilibrium of bone remodeling in many OP models, including Ovariectomy, glucocorticoid-induced OP, and diabetic OP. Nonetheless, significant obstacles persist: insufficient targeting of osteoporotic bone surfaces, suboptimal cell viability and integration, donor heterogeneity, and unresolved safety concerns. The discovery that the secretome and exosomes (EXOs) produced from MSCs recapitulate several therapeutic advantages of the original cells has initiated a transition toward cell-free methodologies. EXOs produced from MSCs include osteogenic microRNAs (including miR-150-3p and miR-21), inhibit NLRP3 inflammasome activation in osteoclasts, promote macrophage polarization toward an M2 phenotype via TRIM25/TREM1 signaling, and facilitate angiogenesis through the activation of the PI3K/Akt pathway. Furthermore, nanoparticle engineering and combinatorial medicines are advancing to enhance targeting and therapeutic efficacy.
    Keywords:  Bone regeneration; Exosomes; Nanoparticles; Osteoporosis; Stem cells; Treatment
    DOI:  https://doi.org/10.1016/j.intimp.2026.117039
  44. J Control Release. 2026 Jun 22. pii: S0168-3659(26)00525-0. [Epub ahead of print] 115122
    Engineered bacterial membrane vesicles as transdermal cancer vaccines.
    Jiayi Lu, Wenqian Zhao, Ming Shao, Jianjiang Chen, Yuchun Xu, Haoyuan Xu, Xiaoying Yan, Chenxi Yin, Yuxuan Ma, Wenzhuo Yu, He Zhao, Zhuang Liu.
      Transdermal vaccines, leveraging the abundant antigen-presenting cells (APCs) resident in the skin to elicit antigen-specific immune responses, have progressed rapidly in recent years. However, successful transdermal vaccines still require effective transdermal delivery systems with potent immune adjuvant functions. Herein, we discovered that bacterial membrane vesicles (BMVs) with unique transdermal penetration behaviors and inherent immune-stimulating abilities could act as a nanoscale platform to engineer transdermal vaccines. In our system, BMVs produced from VNP20009 exhibited superior skin penetration compared to mammalian cell-derived membrane vesicles (CMVs) owing to their marked advantage in paracellular transport. Cholesterol-modified antigenic peptides are then incorporated into the lipid bilayer of BMVs to form a transdermal nanoscale vaccine, in which BMVs serve simultaneously as a transdermal carrier and an adjuvant. Notably, such BMV-based vaccine stimulated dendritic cell (DC) maturation and facilitate antigen cross-presentation, thereby promoting antigen-specific T-cell immunity. After topical application, tumor-antigen-loaded BMVs trigger robust anti-tumor immune responses and achieve efficient protective effects against melanoma tumors. This work highlights the potential of BMVs as a simple yet robust platform to develop transdermal vaccines.
    Keywords:  Bacterial membrane vesicles; Cancer vaccine; Transdermal delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115122
  45. iScience. 2026 Jul 17. 29(7): 116331
    Exosomes: A new frontier in the treatment of neurological diseases.
    Xin Li, Hong Chen, Peixin Xu, Xin Guo, Jing Gao, Dongmei Yao, Yurong Wang, Tong Wang, Bingchun Liu, Jianlong Yuan.
      Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.
    Keywords:  Biological sciences; Drug delivery system; Health sciences; Internal medicine; Medical manufactured object; Medical specialty; Medicine; Natural sciences; Neurology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.116331
  46. Pharmacol Res. 2026 Jun 22. pii: S1043-6618(26)00231-8. [Epub ahead of print]230 108316
    Chimeric antigen receptor-T cell therapy-induced cardiotoxicity: Pathophysiological mechanisms and pharmacological intervention strategies.
    Linhao Xu, Hongjie Wu, Chenfeng Wu, Yizhou Xu.
      Chimeric antigen receptor (CAR)-T cell therapy has emerged as a revolutionary treatment for hematologic malignancies and solid tumors. Multiple approved products and ongoing clinical trials have demonstrated its remarkable antitumor efficacy. However, its clinical application is severely limited by prominent cardiotoxicity, which is closely associated with high morbidity and mortality, posing an urgent clinical challenge. This review systematically elucidates the pathophysiological mechanisms underlying CAR-T cell therapy-induced cardiotoxicity, which can be primarily categorized into acute and long-term adverse effects. Acute cardiotoxicity is driven by cytokine release syndrome (CRS) through macrophage and monocyte activation, endothelial dysfunction, and subsequent myocardial injury, leading to hypotension, reduced left ventricular ejection fraction, and cardiac arrhythmias. Long-term cardiotoxicity is mainly caused by B-cell aplasia-induced immune deficiency and secondary hemophagocytic lymphohistiocytosis, which trigger infectious complications, myocardial ischemia, and apoptosis. We have further summarized clinical pharmacological interventions for such cardiotoxicity, including interleukin (IL)-6 receptor antagonists (tocilizumab), interferon-γ inhibitors (emapalumab), and Janus kinase inhibitors (ruxolitinib). However, none of these drugs can completely alleviate CRS or CAR-T cell therapy-induced cardiotoxicity in all patients. Preclinical agents targeting inflammatory cytokines (IL-1β, tumor necrosis factor-α) and signaling pathways have shown efficacy in ameliorating cardiotoxicity in various animal models. These findings provide novel directions and drug candidates for the treatment of CAR-T cell therapy-induced myocardial toxicity. This review provides a comprehensive theoretical basis for optimizing cardiovascular safety management and developing novel targeted interventions for CAR-T cell therapy.
    Keywords:  CAR-T cell; Cardiotoxicity; Cytokine release syndrome; IL-1β; Myocardial ischemia; Tumor therapy
    DOI:  https://doi.org/10.1016/j.phrs.2026.108316
  47. J Cancer. 2026 ;17(6): 1206-1219
    Exosomes in Cancer Biology: Emerging Biomarkers and Therapeutic Targets.
    Marriam Ahmed, Chieh-Wei Chang, Sundas Ijaz, Abdul Qadeer, Khalid J Alzahrani, Khalaf F Alsharif, Fuad M Alzahrani, Abdulwahab Abuderman, Chien-Chin Chen, Shahid Hussain.
      Exosomes are small extracellular vesicles (EVs) that play an important role in intercellular communication among multiple cell types. In recent years, they have emerged as a novel and promising class of cancer biomarkers, offering significant potential to increase diagnostic and therapeutic strategies. These bilayer nano-vesicles are actively secreted by living cells into various biological fluids and carry a diverse cargo of proteins, nucleic acids, and other biomolecules that reflect the physiological and pathological state of their cells of origin. The molecular composition of exosomes mirrors the dynamic processes and unique cargo of molecular and genetic data, reflecting the complex activities within cancer cells, making them a promising alternative for cancer detection and treatment monitoring. Although the mechanisms underlying exosome biogenesis, secretion, and cargo selection in cancer remain incompletely understood, growing evidence highlights their importance in tumor progression and therapeutic response. Exosomal proteins have gained considerable attention as potential therapeutic targets. These proteins can regulate immune responses, reshape the tumor microenvironment, and influence cancer cell proliferation and survival. Consequently, targeting exosome-associated proteins represents a promising strategy for developing innovative anticancer therapies. Advances in exosomal protein analysis have provided a promising approach for unraveling the complex molecular networks underlying cancer biology. A wide range of analytical techniques is available to identify and quantify exosomal proteins, enabling characterization of cancer-specific molecular signatures. As an expanding field in cancer research, exosomes have the potential to revolutionize both therapies and diagnostics. By deciphering the diverse molecular and functional cargos of exosomes, exosomes offer new insights that may lead to more precise, effective, and personalized approaches to cancer management.
    Keywords:  angiogenesis; annexins; biomarker; cell-to-cell communication; microvesicles
    DOI:  https://doi.org/10.7150/jca.132498
  48. Gels. 2026 Jun 02. pii: 492. [Epub ahead of print]12(6):
    Mussel Adhesive Protein/Hyaluronic Acid Hydrogels for EGF Delivery and MRSA-Infected Diabetic Wound Repair.
    Rong Tian, Han Yi, Jiaoyang Liu, Tong Wang, Tianyue Jiang, Song Qin.
      Diabetic foot ulceration is a severe and common chronic complication of diabetes, accompanied by excessive reactive oxygen species (ROS) accumulation, persistent bacterial infection, prolonged inflammation, and insufficient angiogenesis. Traditional single-function wound dressings fail to simultaneously resolve these pathological barriers, leading to unsatisfactory healing outcomes. In this study, we developed a multifunctional composite hydrogel (E/MGel) by introducing mussel adhesive protein (MAP) into methacrylated hyaluronic acid (mHA) to construct an antibacterial and antioxidant delivery system, which was further loaded with epidermal growth factor (EGF) to promote angiogenesis. The as-prepared E/MGel exhibited a uniform porous structure, favorable rheology, high swelling ratio, and sustained protein release behavior. In vitro results demonstrated that E/MGel exerted potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E.coli), high ROS scavenging efficiency, good cytocompatibility, and remarkable pro-angiogenic effect on endothelial cells. In a mouse model of diabetic MRSA-infected full-thickness skin defect, E/MGel significantly accelerated wound closure, reduced bacterial burden, downregulated pro-inflammatory cytokines, promoted collagen deposition, and enhanced neovascularization. Meanwhile, no obvious systemic toxicity was observed. Taken together, this multifunctional hydrogel integrates antibacterial, antioxidant, and pro-angiogenic capacities to break the pathological vicious cycle of diabetic wounds, providing a promising and safe strategy for the clinical treatment of diabetic infected wounds.
    Keywords:  antibacterial; antioxidant; diabetic wound healing; hydrogel dressing; mussel adhesive protein
    DOI:  https://doi.org/10.3390/gels12060492
  49. Sheng Wu Gong Cheng Xue Bao. 2026 Jun 25. pii: 1000-3061(2026)06-2626-18. [Epub ahead of print]42(6): 2626-2643
    [Functional characteristics of the SACE_2701-2702 transport system in Saccharopolyspora erythraea and its impact on erythromycin biosynthesis].
    Ziwei Lv, Yikai Ding, Nuo Li, Xueru Feng, Meng Wang, Guangrong Zhao, Yue Zhang.
      For antibiotic-producing microorganisms, enhancing product efflux not only alleviates the toxic effects of antibiotics on the cell factory but also represents a powerful metabolic engineering strategy for increasing yields. This study aims to elucidate the molecular mechanism of the erythromycin efflux transporter system in Saccharopolyspora erythraea, and to explore engineering modification strategies for enhancing erythromycin production by strengthening the efflux capacity. In this study, we targeted the ABC transport system SACE_2701-2702, which is responsible for erythromycin export in Saccharopolyspora erythraea. Structural analysis confirmed that SACE_2701-2702 was a canonical type-I ABC transporter, with the transmembrane protein SACE_2702 being enriched in the membrane fraction. SACE_2701-2702 overexpression in both the low-producing wild-type strain NRRL23338 and the high-yield industrial strain Ser0 generated recombinants Se-2702 and S0-2702, respectively. After seven days of shake-flask fermentation, Se-2702 achieved an erythromycin titer of 31.2 mg/L, which represented a 168.0% increase compared with that of the control strain, with a 24.4% rise in the efflux ratio. Strain S0-2702 produced 926.9 mg/L erythromycin, showing a 15.6% increase. Overexpression of the transport system markedly improved tolerance to elevated erythromycin concentrations and conferred a late-fermentation growth advantage. These results demonstrate that targeted enhancement of SACE_2701-2702-mediated erythromycin efflux can effectively relieve product toxicity across different genetic backgrounds and consistently boosts erythromycin production, providing a general strategy for the rational metabolic engineering of erythromycin-producing strains.
    Keywords:  Saccharopolyspora erythraea; erythromycin; gene overexpression; tolerance; transporter
    DOI:  https://doi.org/10.13345/j.cjb.260007
  50. Microorganisms. 2026 Jun 21. pii: 1375. [Epub ahead of print]14(6):
    Chlorogenic Acid Ameliorates CVB3-Induced Viral Myocarditis by Suppressing Viral Replication and ZBP1-Mediated PANoptosis.
    Junbo Huang, Qing Song, Yanjun Di, Hao Wu, Zhiyun Cheng, Haoyi Zhan, Kaiyuan Huang, Yachen Wang, Lijuan Xie, Jieqing Liu, Lei Tong.
      Viral myocarditis (VMC), predominantly driven by Coxsackievirus B3 (CVB3) infection and the resultant excessive immune response, lacks effective treatments and specific antiviral drugs in clinical practice. Chlorogenic acid (CGA) has been proven to have significant antiviral and anti-inflammatory properties. This study evaluated the potential and mechanism of action of CGA against CVB3-induced viral myocarditis. Our research results showed that CGA significantly alleviated myocardial tissue damage in vivo. This protective effect was accompanied by effective inhibition of myocardial inflammatory responses and viral replication. Further in vitro experiments confirmed that CGA significantly inhibited the replication of CVB3 in a dose-dependent manner, and its inhibitory effect mainly targeted the replication stage of the viral life cycle. Mechanistically, CGA treatment correlates with reduced ZBP1 expression and accelerated ZBP1 degradation involving the ubiquitin-proteasome pathway, accompanied by suppressed activation of PANoptosis markers. These findings suggest that CGA alleviates CVB3-induced myocarditis through concerted antiviral and anti-inflammatory effects, with ZBP1-mediated PANoptosis as a potential contributing mechanism.
    Keywords:  PANoptosis; Z-DNA-binding protein 1; antiviral; chlorogenic acid; coxsackievirus B3
    DOI:  https://doi.org/10.3390/microorganisms14061375
  51. Int Dent J. 2026 Jun 22. pii: S0020-6539(26)00281-9. [Epub ahead of print]76(4): 109688
    The Efficacy of Mesenchymal Stem Cell-Based Therapy for Sjögren's Syndrome: A Systematic Review and Meta-Analysis of Preclinical Studies.
    Xinyue Yang, Cheng Shi, Zhuoyang Wu, Jiahao Hu, Aokang Yao, Sheng Luo, Bo Fu, Yaqiong Yu.
       BACKGROUND: Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily characterized by xerostomia, often accompanied by xerophthalmia, cutaneous dryness, arthralgia, and stiffness. Mesenchymal stem cell (MSC)-based therapies have shown promising immunomodulatory potential in autoimmune diseases, yet their efficacy in SjS remains uncertain. Before advancing to clinical application, a systematic evaluation of preclinical evidence is essential to clarify their therapeutic impact and experimental consistency.
    METHODS: This systematic review and meta-analysis were registered in PROSPERO (CRD42023471348) and conducted in accordance with PRISMA guidelines. Comprehensive searches were performed in PubMed, Embase, Scopus, Cochrane Library, and Web of Science up to 1 May 2025. Random-effects meta-analyses were conducted to assess changes in salivary flow rate (SFR), inflammatory infiltration, and cytokine expression.
    RESULTS: A total of 25 studies met the inclusion criteria. Pooled analyses demonstrated that MSCs, MSC-derived exosomes, and MSC-conditioned medium significantly improved stimulated SFR (standardized mean difference = 3.19, 95% confidence interval 2.50-3.88, P < .001) and reduced inflammatory infiltration (standardized mean difference = -2.04, 95% confidence interval -2.66 to -1.43, P < .001). MSC-based therapies decreased serum levels of proinflammatory cytokines (interleukin-6 [IL-6] and interferon-gamma) and increased IL-10. Exploration of heterogeneity indicated that MSC type and dosage influenced SFR outcomes, MSC intervention type affected inflammatory infiltration and serum IL-6 levels, and MSC dosage influenced serum IL-10 levels.
    CONCLUSION: MSC-based therapies show potential for treating SjS in animal models, improving salivary secretion, reducing inflammation, and modulating immune cytokines. Substantial heterogeneity across studies highlights the need for standardized protocols regarding MSC source, dosage, and treatment duration before clinical translation.
    Keywords:  Conditioned medium; Exosomes; Immunomodulation; Mesenchymal stem cells; Meta-analysis; Sjögren’s syndrome
    DOI:  https://doi.org/10.1016/j.identj.2026.109688
  52. bioRxiv. 2026 Jun 08. pii: 2026.06.03.730028. [Epub ahead of print]
    Miniaturized subcutaneous cellular implants for sustained therapeutic protein delivery in resource-limited settings.
    Minseok Lee, Bo Wang, Kecheng Wang, Kento Okada, James Arthur Flanders, Alexander Barutis, Juan M Melero-Martin, Minglin Ma.
      Cell encapsulation offers a promising strategy for sustained therapeutic protein delivery, obviating the need for repeated injections. Among potential implantation sites, the subcutaneous space is particularly attractive for its accessibility and amenability to minimally invasive procedures. However, performance of subcutaneous devices reported to date has been limited due to various challenges including foreign body response (FBR) and inadequate mass transfer. Moreover, typical encapsulation devices require surgeries for implantation and retrieval, limiting their potential use in resource-limited settings. Here we present a miniaturized cell encapsulation platform comprising cells engineered to produce therapeutic proteins and an FBR-mitigating zwitterionic polyurethane nanofibrous membrane, in a thin cylindrical form factor compatible with applicator-based minimally invasive implantation and retrieval. Clonal mesenchymal stromal cells engineered to produce PGT121, a broadly neutralizing anti-HIV-1 antibody, were encapsulated and inserted subcutaneously, achieving long-term cell survival and sustained serum PGT121 concentrations for up to 36 weeks across multiple murine models. Cell-loaded devices retained therapeutic function after cryopreservation, supporting their potential use as an off-the-shelf product that can be centrally manufactured and implanted on-site without specialized infrastructure. The custom-designed applicator-based implantation and minimally invasive retrieval procedures were demonstrated in a more clinically relevant minipig model. These mini-"cellular factories" represent a translatable strategy for sustained delivery of biologic drugs in resource-limited settings.
    One Sentence Summary: An insertable and retrievable mini cellular construct enables sustained protein delivery, supporting its potential use in resource-limited settings.
    DOI:  https://doi.org/10.64898/2026.06.03.730028
  53. Neural Regen Res. 2026 Jun 20.
    Circulating exosomes convey the cognitive benefits of Tai Chi: The role of miR-625-5p in prefrontal remodeling and therapeutic potential.
    Jingfang Zhu, Li Huang, Sinuo Wang, Jiahui Gao, Lei Yang, Miaoran Lin, Chuyi Ma, Xiaolong Yin, Shengxiang Liang, Zhizhen Liu, Jia Huang, Ying Xu, Cong Chen, Yuwei Ye, Minguang Yang, Tiecheng Wu, Jia Lin, Zhifu Wang, Weilin Liu, Jing Tao, Lidian Chen.
      Long-term regular exercise is effective against age-related cognitive decline. However, the mechanisms through which mind-body exercises such as Tai Chi produce these effects, and the involvement of exosome-mediated signaling between the periphery and the brain, are unknown. For this 1:1 matched observational study, cognitively normal participants aged 60 to 75 years, with a male-to-female ratio of 2:3, were recruited into the long-term regular Tai Chi group (n = 50) and long-term irregular exercise group (n = 50). N-back task functional magnetic resonance imaging revealed that the long-term regular Tai Chi group showed a better working memory performance than the long-term irregular exercise group. Moreover, the long-term regular Tai Chi group showed altered activation in the superior frontal gyrus and pre/postcentral gyri. By integrating microRNA sequencing and proteomic profiling of serum exosomes, we identified miR-625-5p as a significant differential factor targeting CALM1 and VDAC2, whose expression levels negatively correlated with 1-back task accuracy. To investigate causality, serum-derived exosomes from both groups were delivered intravenously to SAMP8 mice. Exosomes from the Tai Chi group improved working memory deficits and resulted in an increase in prefrontal dendritic spine density, while down-regulating miR-625-5p and up-regulating the synaptic plasticity-related proteins calmodulin 1 and voltage-dependent anion channel 2 in the prefrontal cortex. Collectively, our findings suggest that long-term Tai Chi exercise may improve cognitive function by remodeling circulating exosome cargo. The key mediator, miR-625-5p, may act via the calmodulin 1/voltage-dependent anion channel 2 pathway to orchestrate prefrontal synaptic remodeling. Exosomes derived from Tai Chi practitioners may be a potential therapy for age-related cognitive decline.
    Keywords:  CALM1; SAMP8 mice; Tai Chi; VDAC2; circulating exosome; elderly; functional magnetic resonance imaging; miR-625-5p; prefrontal plasticity; working memory
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01364
  54. J Nanobiotechnology. 2026 Jun 26.
    Rational design of an optimized ferritin nanoparticle vaccine targeting both SARS-CoV-2 and MERS-CoV.
    Yaoming Liu, Haiyue Rao, Nana Wang, Xiaoqing Liu, Tao Chen, Bin Zhang, Jintao Lai, Jianyu Shan, Shiqi Xiao, Haojie Peng, Yiqiang Zhu, Taizhen Liang, Sen Liu, Meilin Hu, Lixiang Xie, Guochang Qiu, Xiaobo Li, Yaxin Li, Xiancai Ma.
       BACKGROUND: Coronaviruses including SARS-CoV-2 and MERS-CoV remain threats to global health. Ferritin nanoparticle-based vaccines are promising platforms for coronaviral multivalent antigen display. However, their development is often constrained by limited stability and homogeneity, which hinders scale-up manufacturing and long-term storage.
    RESULTS: Here, we employed artificial intelligence (AI)-guided structural modeling and optimization to introduce disulfide bonds into Helicobacter pylori ferritin (HPF). Cryo-EM at 2.2 Å confirmed the formation of inter-subunit disulfide bonds in the most promising variant HPF (I69C), resulting in a more homogeneous nanoparticle with enhanced thermal and pH stability, as well as improved solubility in physiological conditions. We utilized the ST003/SC003 molecular glue system to covalently conjugate receptor-binding domains (RBDs) of both SARS-CoV-2 and MERS-CoV, either as a mixture of individual RBD-HPF (I69C) particles or as a dimeric RBD displayed on a single HPF (I69C). Both bivalent nanoparticle vaccines elicited significantly higher titers of RBD-specific antibodies and neutralizing antibodies compared to monomeric and dimeric vaccines. Vaccination also increased frequencies of antigen-specific B cells and polyfunctional CD4+ and CD8+ T cells. No vaccine-related systemic abnormalities were observed. In both hACE2 and hDPP4 transgenic mice, two doses of bivalent nanoparticle vaccines provided protection against authentic SARS-CoV-2 and MERS-CoV challenges.
    CONCLUSIONS: Our study demonstrated that rationally engineered HPF (I69C) produced highly stable and efficiently functionalized nanoparticle vaccines capable of eliciting potent humoral and cellular immune responses against both SARS-CoV-2 and MERS-CoV infection, thereby supporting the further development of bivalent nanoparticle vaccine platforms.
    Keywords:  Coronaviruses; Disulfide bond; Ferritin; Nanoparticle vaccine
    DOI:  https://doi.org/10.1186/s12951-026-04738-y
  55. Tissue Cell. 2026 Jun 18. pii: S0040-8166(26)00399-X. [Epub ahead of print]103 103705
    Engineering immuno-smart bone scaffolds: Macrophage-centric strategies in 3D-printed tissue regeneration.
    Xiangqi Hui, Dongyu Shang, Shengji Li, Xianyu Meng.
      Large-scale bone defects resulting from trauma, infection, or tumor resection pose a formidable clinical challenge, with traditional grafting approaches limited by donor availability and potential immune complications. While synthetic biomaterials offer alternatives, their clinical efficacy critically depends on their interactions with the host immune system, particularly macrophages. This review explores the emerging paradigm of "immuno-smart" 3D-printed scaffolds that harness macrophage plasticity to enhance bone regeneration. Analysis is focused on the mechanisms by which macrophages orchestrate the transition from inflammation to healing via dynamic M1-to-M2 polarization, thereby directly influencing osteogenesis, angiogenesis, and tissue remodeling. Current evidence indicates that 3D-printed scaffolds can be engineered to modulate macrophage behavior through multiple strategies: controlled release of bioactive ions (e.g., Mg²⁺, Sr²⁺, and Cu²⁺), incorporation of immunomodulatory molecules, optimization of physical properties such as piezoelectricity, photothermal responsiveness, and precise architectural design. These approaches, which regulate the macrophage-mesenchymal stem cell axis to create pro-regenerative microenvironments, are critically evaluated. Despite promising preclinical outcomes, clinical translation remains challenging due to an incomplete understanding of spatiotemporal immune dynamics, insufficient long-term safety data, and a lack of standardized evaluation protocols. Ultimately, this review provides a comprehensive framework for developing next-generation immunomodulatory bone scaffolds, highlighting the integration of materials science, immunology, and regenerative medicine. We conclude that personalized, closed-loop systems capable of real-time immune modulation represent the future of bone tissue engineering, marking a shift from passive structural support to active biological orchestration.
    Keywords:  3D-Printed; Bone regeneration; Macrophages; Tissue Regeneration
    DOI:  https://doi.org/10.1016/j.tice.2026.103705
  56. Materials (Basel). 2026 Jun 14. pii: 2569. [Epub ahead of print]19(12):
    Multi-Scale Bionic Materials: Interfacial Design, Effective Fabrication and Functional Application.
    Haoqi Yang.
      Bionic materials represent an important frontier in modern materials science, where structural motifs, interfacial mechanisms, and functional strategies derived from natural systems are translated into engineered materials with enhanced performance [...].
    DOI:  https://doi.org/10.3390/ma19122569
  57. Biomedicines. 2026 Jun 03. pii: 1276. [Epub ahead of print]14(6):
    In Vivo mRNA-Lipid Nanoparticle CAR-T Cell Engineering: Advances, Challenges, and Clinical Translation.
    Vipin K Yadav, Priyanka Yadav, Sreevidya Mallappa, Praveen Neeli.
      Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of hematologic malignancies, yet its broader application, particularly in solid tumors, remains constrained by high cost, labor-intensive manufacturing, limited production capacity, and variable clinical performance, as well as barriers such as poor trafficking, antigen heterogeneity, and an immunosuppressive tumor microenvironment. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly within the patient, offers a paradigm shift by eliminating the need for ex vivo cell processing and complex logistical infrastructure. Among emerging approaches, messenger RNA (mRNA)-loaded lipid nanoparticles (LNPs) have emerged as a promising and clinically tractable platform for in vivo CAR-T cell generation, enabling direct reprogramming of T lymphocytes within the patient and thereby circumventing the need for leukapheresis, viral vector production, and prolonged ex vivo culture, effectively transforming the patient into their own cell therapy factory. This review synthesizes advances in mRNA-LNP-mediated in vivo CAR-T cell generation, encompassing ionizable lipid chemistry and emerging T cell-targeted delivery strategies, including surface functionalization approaches. We discuss the implications of transient CAR expression for immune activation, safety, and therapeutic durability, alongside CAR design optimization through co-stimulatory domains and safety switches. Preclinical evidence from murine tumor models and non-human primates is integrated with current regulatory considerations, and key barriers to clinical translation are highlighted. Collectively, progress in nucleic acid delivery, synthetic immunology, and precision medicine positions in vivo mRNA-CAR-T therapy as a promising modality for oncology and beyond.
    Keywords:  CAR-T cell therapy; adoptive immunotherapy; gene delivery; in vivo reprogramming; lipid nanoparticles; mRNA delivery
    DOI:  https://doi.org/10.3390/biomedicines14061276
  58. Tissue Cell. 2026 Jun 16. pii: S0040-8166(26)00395-2. [Epub ahead of print]103 103701
    Enhanced repair of type 2 diabetic wounds using combined hyperbaric oxygen and M2 macrophage-derived exosomes: An experimental rat model.
    Safa H Qahl, Ruba S Bakheet, Nahlah M Ghouth, Aishah E Albalawi, Fahad Eid Albalawi, Sameerh Alsahafi, Aaishah M H Kaabi, Zuhair M Mohammedsaleh, Yasmeen A Albalawi, Hailah M Almohaimeed, Sawsan Abd Ellatif, Mona H Soliman.
      Diabetic wounds exhibit delayed healing due to impaired angiogenesis, excessive inflammation, oxidative stress, and insufficient extracellular matrix regeneration. Hyperbaric oxygen therapy (HBO) and M2 macrophage-derived exosomes (M2-Exosome) have each emerged as promising therapeutic strategies that enhance wound repair through complementary mechanisms. This study aimed to evaluate the individual and combined effects of HBO and M2-Exosome on wound closure dynamics, histological regeneration, oxidative status, biomechanical recovery, and gene expression in type 2 diabetic rats. Full-thickness excisional wounds were created in streptozotocin-induced diabetic rats and treated with HBO, exosomes, or a combination of both. Wound closure rate was assessed on days 7 and 14, followed by histological evaluation of angiogenesis and fibroblast proliferation, Masson's trichrome staining for collagen deposition, biomechanical tensile testing, oxidative stress biomarker analysis (CAT, SOD, GSH, MDA), and qRT-PCR quantification of TGF-β, VEGF, TNF-α, and IL-1β expression. Both HBO and exosome treatments significantly accelerated wound closure compared with untreated wounds, while the combined HBO + Exosome therapy produced the highest rate of wound contraction at both time points. Histological results demonstrated enhanced angiogenesis, increased fibroblast density, and markedly improved collagen organization in all treated groups, with the combined treatment consistently showing the greatest regenerative response. Biomechanical testing further confirmed superior tensile strength and structural recovery in the HBO + Exosome group. Antioxidant capacity (CAT, SOD, GSH) increased significantly in all treated wounds, accompanied by reduced MDA levels, indicating attenuation of oxidative damage, particularly under combined therapy. Gene expression analysis revealed upregulation of TGF-β and VEGF and downregulation of TNF-α and IL-1β, with the strongest modulation observed in the HBO + Exosome group. In conclusion, HBO and exosome therapies each exert beneficial effects on diabetic wound healing; however, their combined application generates a synergistic enhancement across cellular, molecular, and biomechanical parameters, representing a promising therapeutic approach for improving diabetic wound repair.
    Keywords:  Angiogenesis; Diabetic wound healing; Exosomes; Hyperbaric oxygen therapy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tice.2026.103701
  59. J Funct Biomater. 2026 Jun 22. pii: 308. [Epub ahead of print]17(6):
    Zinc-Doped Calcium Phosphate Nanoagonists Amplifies cGAS-STING Signaling for Boosting Pyroptosis-Induced Cancer Immunotherapy.
    Bangliu Yang, Xinyu Li, Mingyue Zhang, Shiyao Guo, Xueqian Wang, Peiran Chen, Dongqin Yu, Chao Qi, Kaiyong Cai.
      The combination of chemotherapy and immunotherapy represents a promising approach that leverages their complementary benefits. However, the side effects resulting from off-target effects and the low efficiency of immune activation remain a significant concern. Herein, we developed a zinc-doped calcium phosphate (ZCP) nanocarrier for the delivery of the chemotherapeutic drug doxorubicin (DOX). By further encapsulating whole proteins from 4T1 breast cancer cells, we constructed a novel nanodrug delivery system named ZCPDM. This system enables specific targeting of tumor cells and undergoes intracellular degradation to release DOX, Zn2+, and Ca2+. As a chemotherapeutic agent, DOX induces apoptosis while significantly elevating intracellular reactive oxygen species (ROS), thereby enhancing cytotoxicity. This leads to DNA damage and the release of chromosomal fragments. These DNA fragments, together with Zn2+, activate the cGAS-STING signaling pathway and trigger pyroptosis, which promotes more efficient recognition and clearance of tumor cells by the immune system. Through these dual mechanisms, ZCPDM effectively combines chemotherapy and immunotherapy. The anti-tumor efficacy and underlying mechanisms were validated at the cellular level. Furthermore, studies in tumor-bearing mice demonstrated its robust anti-tumor performance and ability to suppress tumor recurrence, along with good biosafety. This targeted drug delivery system achieves safe and synergistic chemo-immunotherapy through homologous targeting-mediated pyroptosis and activation of the cGAS-STING pathway, offering a novel and promising strategy for cancer treatment.
    Keywords:  cGAS-STING; calcium phosphate; drug delivery; immunotherapy; pyroptosis
    DOI:  https://doi.org/10.3390/jfb17060308
  60. J Control Release. 2026 Jun 23. pii: S0168-3659(26)00524-9. [Epub ahead of print] 115121
    Engineered responsive-hydrogels drive cGAS-STING pathway activation for cancer immunotherapy.
    Chaopeng Shi, Shuang Liang, Kongshuo Ma, Kaiqing Yun, Wenyuan Ma, Zhaohui Wang.
      The cGAS-STING pathway holds considerable promise for cancer immunotherapy, yet its clinical translation is generally constrained by a narrow therapeutic window and the risk of systemic inflammation, making precision activation a central challenge. Engineered hydrogels provide a compelling strategy by serving as injectable, tissue-adherent depots that enable prolonged retention and programmable release within the tumor microenvironment. This review first outlines the immunological rationale and therapeutic window for cGAS-STING activation, then surveys hydrogel engineering strategies, including cargo loading, affinity-based retention, and stimuli-responsive release to effectively couple release kinetics with spatiotemporal immune activation profiles. We further examine hydrogel-enabled combinational regimens, emphasizing temporal programming and staged activation. While hydrogel platforms are well-positioned to bridge the gap between spatiotemporally controlled release and immune microenvironment remodeling, additional technological refinement, manufacturing-ready "minimalist intelligence" and accelerated translational and regulatory alignment are essential to realize their full clinical potential.
    Keywords:  Cancer immunotherapy; Drug delivery; Hydrogels; Spatiotemporal control; cGAS-STING
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115121
  61. Acta Biomater. 2026 Jun 25. pii: S1742-7061(26)00419-8. [Epub ahead of print]
    Acid-responsive bone-targeting nanoplatform enables spatiotemporal control of osteogenesis and angiogenesis for osteoporosis rescue.
    Yingqi Liu, Jie He, Xiaojing Zhang, Tao Zhang, Xinwei Fu, Jie Wang, Yue He, Huarui Shen, Ting Li, Shiyan Fu, Yuhui Hao, Yuejun Kang.
      Osteoporosis (OP) poses a significant challenge in regenerative medicine due to the lack of therapeutic strategies that can intelligently respond to the local pathological microenvironment for precise intervention. To address this issue, we developed a multifunction-integrated acid-responsive bone-affinitive nanoplatform (Asp6-PSO@MSNs, APS-M) for spatiotemporally coordinated bone regeneration. Hollow mesoporous silica nanoparticles (MSNs) were engineered to encapsulate the osteogenic bioactive Psoralen (PSO), surface-gated by a bone-targeting peptide (Asp6). This sophisticated design serves a dual function: the Asp6 gatekeeper ensures spatial accumulation at hydroxyapatite-rich lesion sites and remains closed at physiological pH, while the acidic microenvironment of osteoclasts triggers "temporal" gate opening for on-demand drug release. Mechanistically, transcriptomics and molecular assays unveiled a dual-mode therapeutic mechanism: the nanoplatform not only ensures high intracellular PSO concentration but also provides bioactive silicon ions from carrier degradation, which collectively robustly activate the PI3K-Akt signaling axis. This activation orchestrates a regenerative microenvironment by coupling osteogenesis (via RUNX2 stabilization) with angiogenesis (via VEGF upregulation), significantly outperforming free drug administration. Consequently, APS-M effectively reversed bone loss, restored microarchitecture, and enhanced biomechanical strength in osteoporotic mice. This work presents a sophisticated "seek-and-treat" nanoplatform that harmonizes the intrinsic bioactivity of silicate materials with targeted pharmacotherapy, offering an effective solution for precision osteoporosis management. STATEMENT OF SIGNIFICANCE: Herein, we report the rational design and synthesis of a new class of acid-responsive nanoreactors by integrating hollow mesoporous silica nanoparticles (MSNs) with surface-adaptive bone-targeting peptides (Asp6). Characterization studies demonstrated an optimal construct (APS-M) with a sophisticated "gatekeeping" capability, showing robust stability at physiological pH and rapid responsiveness to the acidic osteoporotic microenvironment. This optimized nanocarrier was subsequently encapsulated with the osteogenic drug psoralen (PSO). The resulting APS-M system was adequately investigated and shown to effectively synergize osteogenesis and angiogenesis via the activation of the PI3K-Akt signaling pathway. Our work provides new insights into nanoreactor engineering strategies for precision osteoporosis management.
    Keywords:  Asp6; Bone-targeting; Mesoporous silica nanoparticles; Osteoporosis; Psoralen
    DOI:  https://doi.org/10.1016/j.actbio.2026.06.049
  62. Int J Biol Macromol. 2026 Jun 24. pii: S0141-8130(26)03115-6. [Epub ahead of print] 153188
    Aptamer-tagged exosome-coated Bismuth ferrite-mesoporous silica nanoparticle for chemoradiotherapy and CT/MR imaging of non-small cell lung cancer.
    Nasim Kavousi, Hosein Azimian, Mohammad Taghi Bahreyni Toossi, Sirous Nekooei, Mona Alibolandi.
      The combination of chemotherapy and radiation therapy (RT) can significantly enhance anticancer efficacy, and nanoparticle-based systems that function as both radiosensitizers and drug carriers offer a promising strategy for multimodal cancer treatment. Here, we developed a core-shell nanoplatform composed of a bismuth ferrite (BiFeO3, BFO) core and a mesoporous silica shell, loaded with doxorubicin (DOX) and coated with mesenchymal stem cell-derived exosomes to form a biomimetic construct (Exo-BFO-Si-DOX). The system was further functionalized with a mucin-1 (MUC-1) aptamer (Apt-Exo-BFO-Si-DOX) to enable targeted delivery to MUC-1-overexpressing cancer cells. The BFO core enhanced RT efficacy while enabling dual-modality magnetic resonance imaging (MRI) and computed tomography (CT). The nanoplatform exhibited high DOX encapsulation efficiency and suitable loading capacity, and the exosome coating provided controlled drug release under physiological conditions. In vitro experiments demonstrated strong chemoradiation efficacy and apoptosis induction in SK-MES-1 and A549 non-small cell lung cancer (NSCLC) cells, with apoptosis rates of 52.10% and 64.28%, respectively. Notably, Apt-Exo-BFO-Si-DOX exhibited enhanced cytotoxicity, apoptosis induction, and radiosensitization compared with Exo-BFO-Si-DOX. In vivo MRI and CT imaging of SK-MES-1 tumor-bearing nude mice confirmed efficient tumor accumulation at 6 h post-injection, with significantly higher uptake for the targeted platform compared to its non-targeted counterpart (CT: 52.50 vs. 43.50 HU; MRI: 50.60 vs. 64.50 signal intensity). Overall, these results indicate that Apt-Exo-BFO-Si-DOX is a promising multifunctional nanoplatform for synergistic chemoradiotherapy and dual MR/CT imaging of cancer.
    Keywords:  Bismuth ferrite; CT imaging; MUC1 aptamer; NSCLC; Radiosensitizer; Theranostic
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153188
  63. Biomolecules. 2026 Jun 18. pii: 906. [Epub ahead of print]16(6):
    Exosomal circ_0050688 Shapes a Chemoresistant Microenvironment by Driving Spatial Resistance Spreading in Glioblastoma via the MDM2 Pathway.
    Qiang Li, Jianglong Xu, Yuhao Zhang, Junbing Qian, Diana Bee-Lan Ong, Kein Seong Mun, Yiping Tang, Xiuchao Geng, Kean Chang Phang.
      Background: Acquired tolerance to temozolomide (TMZ) remains one of the main obstacles to enduring therapeutic success in glioblastoma (GBM). While tumor-derived extracellular vesicles are known to orchestrate therapy evasion by horizontally transferring molecules across the tumor microenvironment, the precise regulatory roles of specific exosomal circular RNAs (circRNAs) in establishing this refractory state require further elucidation. Methods: The expression of circ_0050688 in TMZ-resistant GBM clinical tissues and cell lines was evaluated. Exosomes derived from resistant cells were isolated and confirmed via transmission electron microscopy (TEM) and marker analysis. PKH67 fluorescent tracking was utilized to visually demonstrate exosome internalization by sensitive recipient cells. Biological functions, including the expression of the multidrug resistance protein P-glycoprotein (P-gp) and the proliferation marker Ki-67, were evaluated. The competing endogenous RNA mechanism was validated using RNA FISH, dual-luciferase reporters, and functional rescue experiments. In vivo efficacy was determined using subcutaneous xenograft mouse models. Results: Clinical and in vitro analyses revealed that circ_0050688 is upregulated in TMZ-refractory GBM, predicting adverse patient survival. Through PKH67-based tracing, we confirmed that resistant cells actively secrete circ_0050688-enriched exosomes, which are subsequently engulfed by drug-sensitive bystander cells. This vesicular transfer directly instigates a chemoresistant and highly proliferative phenotype, marked by elevated P-gp and Ki-67 levels. At the molecular level, circ_0050688 operates as a molecular decoy for miR-508-5p, thereby preventing the suppression of its downstream target, MDM2. Functionally, circ_0050688 depletion eradicated these aggressive traits and restored TMZ vulnerability across both cellular and murine xenograft models. Furthermore, rescue assays confirmed that this circ_0050688-driven chemoresistance is fundamentally dependent on the miR-508-5p/MDM2 signaling axis. Conclusions: Current data uncover an intercellular signaling network driven by vesicular circ_0050688, which functions as a mobile oncogene to reshape the TMZ-refractory microenvironment. Targeting this exosomal circ_0050688/miR-508-5p/MDM2 network to suppress P-gp and Ki-67 expression represents a highly promising therapeutic strategy for refractory GBM.
    Keywords:  MDM2; acquired chemoresistance; circ_0050688; exosomes; glioblastoma
    DOI:  https://doi.org/10.3390/biom16060906
  64. Stem Cells Dev. 2026 Jun 23. 15473287261456137
    Inflammatory Preconditioning Reprograms Mesenchymal Stromal Cell-Derived Extracellular Vesicles into Distinct Functional States for Immunomodulation and Wound Healing.
    Ramiro A Villarreal-Leal, Oscar S Velazquez, Beck Burgelin, Robin S Vander Pol, Corrine Ying Xuan Chua, R Steven Conlan, Richard H Finnell, Alessandro Grattoni, Bruna Corradetti.
      Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are emerging as potent cell-free mediators of tissue repair, whose composition and function can be tuned by the cellular microenvironment. Although inflammatory cues modulate mesenchymal stromal cell (MSC) behavior, how defined preconditioning strategies program extracellular vesicle (EV) functional outputs remains incompletely understood. Here, we systematically evaluated how priming bone marrow-derived MSCs with interferon-gamma/tumor necrosis factor-alpha (I/T) or lipopolysaccharide (LPS) generates EV populations with distinct immunomodulatory and regenerative properties. Using a murine full-thickness wound model, we performed an integrative analysis of biodistribution, immune response, and extracellular matrix (ECM) remodeling, complemented by single-cell, transcriptomic, and proteomic profiling. All EV populations were retained at the wound site following subcutaneous delivery and supported wound contraction; however, they drove distinct, treatment-specific repair trajectories. I/T-EVs promoted a coordinated regenerative response characterized by balanced macrophage (MΦ) activation, controlled immune modulation, and efficient resolution of inflammation, resulting in organized ECM remodeling. In contrast, LPS-EVs induced a more pro-inflammatory response, accelerating wound contraction and promoting compensatory matrix stiffening with reduced structural coordination. Control EVs primarily facilitated early immune resolution with limited induction of regenerative remodeling pathways. Proteomic profiling of EVs identified enrichment of proteins associated with insulin-like growth factor signaling, MΦ recruitment, and ECM remodeling, consistent with in vivo protein expression patterns and linking EV cargo to functional outcomes. These findings demonstrate that preconditioning does not uniformly enhance EV efficacy but instead selectively programs distinct MSC-EV functional states, establishing EV preconditioning as a tunable strategy for engineering cell-free therapeutics with predictable and context-specific therapeutic outcomes.
    Keywords:  extracellular vesicles; immunomodulation; mesenchymal stromal cells; preconditioning; secretome; wound healing
    DOI:  https://doi.org/10.1177/15473287261456137
  65. Vaccines (Basel). 2026 Jun 07. pii: 514. [Epub ahead of print]14(6):
    Towards an Original Anti-ASFV Vaccine: Cellular Immunity Induced by Extracellular Vesicles Engineered with ASFV Proteins.
    Francesco Manfredi, Flavia Ferrantelli, Chiara Chiozzini, Micaela Donnini, Patrizia Leone, Katherina Pugliese, Monica Cagiola, Cecilia Righi, Stefano Petrini, Monica Giammarioli, Francesco Feliziani, Maurizio Federico.
      Background/Objectives: African Swine Fever (ASF) represents one of the most serious threats to animal health and global food security. The causative agent of ASF is the African swine fever virus (ASFV), a DNA virus belonging to the Asfarviridae family. Here, we describe ex vivo results for an original anti-ASFV vaccine approach based on the cellular immune response induced by extracellular vesicles (EVs) engineered to express four ASFV proteins. EV engineering was achieved by expressing a DNA vector encoding a biologically inactive HIV-1 Nef protein (Nefmut), which exhibits unusually high efficiency of incorporation into EVs, even when fused to foreign proteins. Previous studies have demonstrated that intramuscular injection of Nefmut-based vectors leads to the engineering of Evs, spontaneously released by muscle cells, and induction of antigen-specific CD8+ T cell immunity. Methods: We designed DNA vectors expressing the fusion products between Nefmut and each of the four ASFV structural proteins p30, p54, pp62, and p72. Engineered EVs were molecularly characterized by Western blot and nanotrack analysis, and their potential immunogenicity was assessed by priming and cross-presentation assays. Results: We assessed that the four fusion proteins were successfully expressed in transfected mammalian cells, with the release of valuable amounts of engineered EVs. When immature swine dendritic cells were challenged with the engineered EVs and then co-cultivated with autologous peripheral blood lymphocytes in priming assays, lymphocyte subpopulations specifically reacting against each ASFV antigen were elicited, as detected by an IFN-γ ELISpot assay. In addition, we provide evidence that the Nefmut-based fusion products incorporated into the engineered EVs can be cross-presented by professional antigen-presenting cells, leading to cross-priming of autologous lymphocytes. Conclusions: These results represent the best premise to go forward with experiments examining immunogenicity and antiviral efficiency in pigs.
    Keywords:  African swine fever virus; HIV-1 Nef; cellular immunity; extracellular vesicles; vaccines
    DOI:  https://doi.org/10.3390/vaccines14060514
  66. Int J Biol Macromol. 2026 Jun 22. pii: S0141-8130(26)03031-X. [Epub ahead of print] 153104
    Dicliptera chinensis (L.) Juss. polysaccharide alleviates metabolic dysfunction-associated steatotic liver disease by regulating miR-3073b-5p/CAMKK2 via the gut microbiota-bile acid axis.
    Wenxiu Wang, Yongwang Wang, Houkang Cao, Riming Wei, Jianzhao Wu, Kai Guo, Shaowei Zheng, Guiying Lu, Ya Gao, Kefeng Zhang.
      Dicliptera chinensis (L.) Juss. is a herbaceous plant renowned for its anti-inflammatory and antioxidant properties. Previous studies have demonstrated that its polysaccharide (DCP) exerts hepatoprotective effects, yet the underlying mechanism by which DCP alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study investigated the hepatoprotective effects of DCP in high-glucose and high-fat (HHF) diet-induced MASLD mice and AML12 hepatocytes, with a focus on miRNA-mediated regulatory mechanisms. Small RNA sequencing revealed that miR-3073b-5p was significantly upregulated in MASLD. Dual-luciferase reporter assays verified the direct binding of miR-3073b-5p to the 3'UTR of CAMKK2, and RIP assays further confirmed their interaction under physiological conditions. In vivo, DCP administration significantly ameliorated hyperglycemia, dyslipidemia, hepatic steatosis, and oxidative injury. 16S rRNA sequencing and bile acid metabolomics analyses demonstrated that DCP effectively reshaped the gut microbiota composition and restored bile acid metabolic homeostasis. In vitro, DCP downregulated miR-3073b-5p expression, thereby relieving the suppression of CAMKK2, regulating the AMPK/mTOR/Nrf2 signaling axis, restoring autophagy, and counteracting ferroptosis. These findings indicate that DCP alleviates MASLD by regulating miR-3073b-5p/CAMKK2 via the gut microbiota-bile acid axis, positioning it as a promising natural polysaccharide for MASLD therapy and providing a novel molecular target for the targeted intervention of this disease.
    Keywords:  Dicliptera chinensis (L.) Juss. Polysaccharide; Gut microbiota-bile acid/miR-3073b-5p/CAMKK2; Metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153104
  67. Arterioscler Thromb Vasc Biol. 2026 Jun 25.
    NORAD Overexpression Enhances hiPSC-CM Regenerative Potency via PUM2/MASTL Signaling.
    Kanghui Huan, Yujian Jiang, Xin Xie, Weifeng Xu, Xiaolei Duan, Sai Yao, Yanli Cheng, Shaomeng Li, Yanfang Duan, Yingxin Yuan, Yeying Sun, Meng Zhao, Weihua Bian.
       BACKGROUND: The engraftment of induced cells from human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for myocardial infarction therapy is critically hindered by their low cell-cycle activity and survival rates. In this study, we explored the role of the long noncoding RNA activated by DNA damage (NORAD) in enhancing the cell-cycle activity and engraftment of hiPSC-CMs, providing new insights into myocardial repair.
    METHODS: hiPSC-CMs overexpressing NORAD were generated via lentiviral transduction using a cardiac-specific promoter, whereas NORAD knockdown was achieved by small interfering RNA transfection. The effects of NORAD on cell-cycle activity, nuclear DNA content, nuclear number, maturation, and apoptosis in hiPSC-CMs were examined in vitro using Western blot, reverse transcription quantitative polymerase chain reaction, immunofluorescence, and flow cytometry. In a murine myocardial infarction model, hiPSC-CMs overexpressing NORAD were transplanted into the infarcted myocardium. Engraftment, cell-cycle activity, and infarct size were evaluated by immunofluorescence, and cardiac function was assessed by echocardiography. Furthermore, the molecular mechanisms underlying NORAD-mediated regulation of hiPSC-CM cell-cycle activity were investigated, including its role in exosome-mediated paracrine effects on host cardiomyocytes.
    RESULTS: NORAD overexpression significantly increased the percentages of Ki67-positive, phosphorylated histone 3-positive, Aurora B-positive, and EdU-positive cells. It also increased the proportion of diploid nuclei and mononucleated cells, induced a trend toward a less mature state, and reduced apoptosis in hiPSC-CMs. Transplantation of hiPSC-CMs overexpressing NORAD improved myocardial repair, with greater cell-cycle activity of engrafted cells and endogenous cardiomyocytes in the myocardial infarction model. Mechanistically, NORAD exerted its effects by sequestering PUM2, an RNA-binding protein, thereby alleviating its translational repression of MASTL, a key regulator of mitotic progression. Moreover, exosomes secreted by hiPSC-CMs overexpressing NORAD promoted the cell-cycle activity of recipient cardiomyocytes, suggesting a possible paracrine contribution to myocardial repair.
    CONCLUSIONS: NORAD overexpression promoted cell-cycle progression via the PUM2/MASTL mRNA axis. Moreover, exosomes derived from these cells stimulated endogenous cardiomyocyte cell-cycle activity, contributing to myocardial repair. These findings underscore the therapeutic potential of NORAD-modulated hiPSC-CMs for promoting myocardial repair.
    Keywords:  apoptosis; exosomes; infarction; myocardial infarction; transfection
    DOI:  https://doi.org/10.1161/ATVBAHA.126.324431
  68. Angew Chem Int Ed Engl. 2026 Jun 23. e9402364
    Bifluorinated Motif-Tailored Hybrid Membranes for Ultra-Permeable CO2 Separation From Air Under High Humidity.
    Jinjin Liu, Bingjie Wang, Zhibin Wang, Yuxiu Sun, Zhengqing Zhang, Yi Yang, Zhihua Qiao, Benqiao He.
      Membrane-based direct air capture (m-DAC) offers an energy- efficient route to mitigate rising atmospheric CO2, but its practical deployment is hindered by low CO2 concentration and high humidity. Herein, we propose a "Sailing-with-Water" strategy that turns humidity from an obstacle into a mass-transfer driving force. The bifluorinated motifs are engineered by integrating fluorinated ionic liquid@UiO66 (IL@UiO) as porous fillers and a novel polymer, PIM-1DFBP, as the second fluorine source. The abundant fluorine sites within the membrane facilitate CO2 capture and enrichment from dilute streams via Lewis acid-base interactions. Notably, under high humidity conditions, the fluorine sites in the membrane form a hydrogen-bond network with water molecules, creating a polar microenvironment that further enhances CO2 affinity and builds ultrafast channels for CO2 permeation. The optimized membrane achieves a CO2 permeability of 12697.08 Barrer and CO2/N2 selectivity of 44.06 under 65% relative humidity, surpassing the 2019 Robeson upper bound. The membrane also exhibits 180-days stability, large-area defect-free fabrication, and process simulation shows that only 612.37 m2 is needed to reach 40% CO2 outlet concentration. This work provides a humidity-resistant paradigm for high-performance m-DAC.
    Keywords:  gas separation; high humidity; ionic liquid; membrane‐based direct air capture; metal‐organic framework
    DOI:  https://doi.org/10.1002/anie.9402364
  69. Drug Des Devel Ther. 2026 ;20 607020
    Nanocarrier-Mediated Delivery Systems of Phytochemicals to Enhance and Accelerate Diabetic Wound Healing Processes.
    Eko Sri Wahyuningsih, Muhaimin Muhaimin, Anis Yohana Chaerunisaa, Miski Aghnia Khairinisa.
      This review explores the mechanistic and translational potential of nanotechnology-based delivery systems for natural compounds in diabetic wound healing. Diabetic wounds present a persistent challenge due to impaired tissue regeneration and chronic inflammation. Phytochemicals such as flavonoids and polyphenols exhibit potent antioxidant, anti-inflammatory, and tissue-regenerative properties but are limited by low bioavailability and stability. Nanoparticle formulations-particularly silver nanoparticles (AgNPs) and chitosan-based nanoparticles (CNPs)-offer innovative solutions by enhancing stability, tissue penetration, and sustained release of these bioactives. Our analysis highlights how these nanocarriers facilitate targeted delivery, thereby amplifying antioxidant activity, antimicrobial effects, and tissue regeneration mechanisms critical for wound healing. The review underscores the mechanistic insights into how nanoparticle systems improve therapeutic efficacy and discusses their translational potential in clinical settings. Notably, AgNPs' antimicrobial properties and green synthesis, along with CNPs' biocompatibility and bioadhesive characteristics, position these nanomaterials as promising candidates for advancing diabetic wound care. This synthesis of current evidence emphasizes nanotechnology's role in overcoming the limitations of natural compounds and advancing sustainable, effective treatments for diabetic wounds.
    Keywords:  diabetic wound healing; nanoparticles; nanotechnology; phytochemicals; therapeutic efficacy
    DOI:  https://doi.org/10.2147/DDDT.S607020
  70. Curr Opin Microbiol. 2026 Jun 25. pii: S1369-5274(26)00079-2. [Epub ahead of print]92 102785
    Progress in engineered bacterial cancer therapies.
    Eva Pico-Sánchez, Luis Á Fernández.
      Engineered bacteria are emerging as powerful tools in the development of cancer therapies, driven by advances in synthetic biology and tumor immunology. These microbes preferentially colonize solid tumors, where they can deliver therapeutic agents directly to malignant cells and into the tumor microenvironment, inducing tumor cell death and activating robust anti-tumor immune responses. Current strategies include programming bacteria to secrete toxins, tumor-suppressor or pro-apoptotic proteins, and to mediate targeted intracellular delivery. Bacteria can also be engineered to sense tumor-specific metabolites and to adhere to tumor-associated cell surface antigens, further enhancing selectivity and safety. Engineered strains synergize with immunotherapies - including immune checkpoint inhibitors and chimeric antigen receptor-T cells - and can stimulate both innate and adaptive immune responses, even at distant metastatic sites. Here, we review recent progress in this field, with a focus on engineering strategies and their effectiveness in preclinical in vivo tumor models, and outline prospects for future developments and remaining challenges.
    DOI:  https://doi.org/10.1016/j.mib.2026.102785
  71. Metab Brain Dis. 2026 Jun 26. pii: 144. [Epub ahead of print]41(1):
    The gut microbial metabolite 3-indolepropionic acid as a functional neuroprotective agent against intracerebral hemorrhage: integrating epidemiological screening with in vivo validation.
    Shuai Han, Zirui Wang, Feng Guo, Qiuyue Zheng, Tianfeng Huang, Ju Gao.
      Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Emerging evidence highlights the diet-gut-brain axis in neurological outcomes, yet the specific metabolic mediators remain elusive. This study integrated epidemiological, genetic, and experimental approaches to investigate the potential neuroprotective role of gut-derived metabolites in ICH. Utilizing Global Burden of Disease data and Mendelian randomization analysis, we explored the associations between dietary habits and ICH, and investigated putative causal relationships between specific gut microbiota and disease risk. Subsequent network pharmacology analysis predicted that 3-indolepropionic acid (3-IPA) might exert neuroprotective effects primarily through anti-apoptotic pathways. To evaluate these findings in vivo, we established a mouse model of ICH. Administration of 3-IPA significantly ameliorated neurological deficits and improved cognitive memory in the Morris water maze test. Furthermore, immunofluorescence and Western blot analyses indicated that 3-IPA treatment was associated with the upregulation of the anti-apoptotic protein BCL2 and the reduction of pro-apoptotic markers in the peri-hematomal region. In conclusion, our multidisciplinary study outlines a potential biological pathway linking dietary patterns, gut microbial metabolism, and brain injury recovery. Our findings suggest that the gut microbial metabolite 3-IPA protects against ICH-induced secondary brain injury, potentially by attenuating neuronal apoptosis, highlighting it as a promising metabolic intervention target for ICH therapy.
    Keywords:  3-Indolepropionic acid; Gut microbiota; Intracerebral hemorrhage; Mendelian randomization; Neuroprotection
    DOI:  https://doi.org/10.1007/s11011-026-01912-x
  72. J Nanobiotechnology. 2026 Jun 26.
    Extracellular vesicle-mediated bidirectional communication between the brain and peripheral organs in Alzheimer's disease: evidence, mechanisms, and translational perspectives.
    Yuqing Liu, Zhongliu Yao, Lemei Zhu, Weijun Peng.
      Alzheimer's disease (AD) has traditionally been conceptualized as a brain-centered neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and progressive neuronal loss. However, accumulating evidence suggests that AD is also shaped by systemic disturbances and reciprocal communication between the central nervous system and peripheral organs. Extracellular vesicles (EVs), which transport proteins, lipids, metabolites, and nucleic acids across biological fluids and barriers, have emerged as plausible mediators of this inter-organ crosstalk. In this Review, current evidence for EV-mediated bidirectional communication between the brain and peripheral organs is synthesized, with particular attention to the liver-brain, heart-brain, gut-brain, lung-brain, bone-brain, and adipose-brain axes. The strength of evidence across these axes is compared, and the ways in which organ-derived EVs may influence neuroinflammation, neurovascular dysfunction, metabolic homeostasis, blood-brain barrier integrity, and Aβ/tau-related processes are discussed, while also considering how brain-derived EVs (BDEVs) may affect peripheral physiology. The translational potential of EVs as diagnostic biomarkers, therapeutic carriers, and candidate targets for systemic intervention in AD is further evaluated. Current evidence most strongly supports the gut-brain, liver-brain, and adipose-brain axes, whereas several other axes remain supported primarily by experimental models or engineered EV studies. Major barriers to progress include EV heterogeneity, limited source specificity, insufficient standardization of isolation and quantification workflows, and a continuing reliance on associative human data and preclinical models. Overall, EVs are best viewed as one candidate signaling layer within a broader systemic network linking peripheral physiology to brain pathology. Clarifying the magnitude, directionality, and causal significance of these interactions will require rigorous EV characterization, source-resolved in vivo trafficking studies, and longitudinal clinical investigation.
    Keywords:  Alzheimer’s disease; Biomarkers; Extracellular vesicles; Interorgan communication; Therapeutic targets
    DOI:  https://doi.org/10.1186/s12951-026-04705-7
  73. Stem Cell Res Ther. 2026 Jun 23.
    SIRT6 enhances the therapeutic potential of extracellular vesicles in mitigating osteoarthritis in rat models.
    Guihua Yang, Su Liu, Huitian Han, Xueyan Yang, Feng Li, Qiong Wu, Zhiyu Zhao, Fei Liu, Zhifa Zheng, Guangxi Gao, Wenjing Ma, Lina Zhao, Baohua Liu, Zhihong Wu.
       BACKGROUND: Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapeutic candidates for osteoarthritis (OA). Sirtuin 6 (SIRT6), a class III histone deacetylase, exerts protective effects by preventing cellular senescence, reducing inflammation, and promoting longevity. This study aims to generate immortalized hUCMSCs with SIRT6 and telomerase reverse transcriptase (TERT) overexpression and investigate the therapeutic potential of their secreted EVs (EVs@SIRT6) in OA.
    METHODS: hUCMSCs were genetically engineered using lentiviral transduction to overexpress SIRT6 and TERT, referred to as SIRT6/TERT-hUCMSCs. Natural EVs and EVs@SIRT6 were isolated via differential ultracentrifugation and characterized by morphology, size distribution, marker expression, and proteomic signature. Their effects on IL-1β stimulated chondrocytes were assessed in vitro, including cell viability, apoptosis, scratch closure, inflammatory cytokine secretion, and oxidative stress. Transcriptomic alterations were analyzed by RNA sequencing. Therapeutic efficacy in vivo was evaluated in a rat anterior cruciate ligament transection (ACLT) model via micro-computed tomography, histological analyses, and immunohistochemistry.
    RESULTS: SIRT6/TERT-hUCMSCs preserved mesenchymal identity, trilineage differentiation potential, and sustained proliferative capacity up to passage 60, accompanied by longer telomeres and reduced senescence compared to parental cells. EVs@SIRT6 maintained typical EV features but were enriched in SIRT6 protein and displayed a distinct proteomic signature, comprising 1,440 unique proteins associated with nuclear/chromatin repair. In vitro, EVs@SIRT6 more effectively enhanced chondrocyte viability and wound healing while reducing apoptosis compared with natural EVs. EVs@SIRT6 also markedly alleviated inflammatory response, promoted anabolism, suppressed catabolism, and mitigated oxidative stress in chondrocytes. The protective effects of EVs@SIRT6 on chondrocytes were associated with the suppression of the JAK-STAT signaling pathway. Studies in a rat ACLT model further confirmed that EVs@SIRT6 outperformed natural EVs in attenuating subchondral osteosclerosis, reducing osteophyte formation, and mitigating cartilage damage.
    CONCLUSIONS: Engineered EVs@SIRT6 outperform natural EVs in preserving chondrocytes homeostasis and reducing OA progression, establishing an efficient platform for preparing engineered EVs for clinical application.
    Keywords:  Extracellular vesicles; Mesenchymal stem cells; Osteoarthritis; SIRT6
    DOI:  https://doi.org/10.1186/s13287-026-05112-3
  74. Int J Mol Sci. 2026 Jun 08. pii: 5186. [Epub ahead of print]27(12):
    Technological Advances of Cryopreservation in Ovarian Tissue for Female Children: Exploring the Molecular Insights and Mechanisms.
    Hsin-Hung Wu.
      Ovarian tissue cryopreservation (OTC) has emerged as the only viable fertility preservation strategy for prepubertal girls and adolescent cancer patients facing gonadotoxic treatments. While OTC has transitioned from an experimental procedure to an established clinical practice, the functional longevity of transplanted grafts remains limited by massive follicle depletion. This review synthesizes recent technological advances in OTC for female children, with a particular focus on the underlying molecular mechanisms and innovative protective strategies. We systematically evaluate pre-cryopreservation assessments, surgical harvesting techniques such as medulla-sparing biopsies, and the comparative efficacy of slow freezing versus vitrification in preserving stromal and follicular integrity. Central to this discussion are the molecular drivers of post-transplantation injury, including ischemia-reperfusion-induced oxidative stress and the iatrogenic over-activation of the PI3K/Akt/mTOR signaling pathway, which leads to follicular "burnout." Furthermore, we explore targeted pharmacological interventions, such as the dual-drug application of VEGFA and rapamycin, alongside emerging bioengineering frontiers including decellularized extracellular matrix scaffolds and 3D-printed bioprosthetic ovaries. Clinical outcomes are also summarized, highlighting high rates of endocrine recovery (~95%) and promising live birth rates (~28%), predominantly through natural conception. By integrating deep molecular insights with advanced tissue engineering, this review provides a comprehensive framework for optimizing long-term fertility restoration and improving the quality of survivorship for young female cancer survivors.
    Keywords:  fertility preservation; follicle burnout; ischemia–reperfusion injury; molecular mechanisms; oncofertility; ovarian tissue cryopreservation; prepubertal girls; tissue engineering
    DOI:  https://doi.org/10.3390/ijms27125186
  75. Pharmaceutics. 2026 Jun 21. pii: 760. [Epub ahead of print]18(6):
    Engineered Lipid Nanoparticles with Promoted Endosomal Escape and R283S-Mediated Stimulator of Interferon Genes (STING) Activation for Pancreatic Cancer Immunotherapy.
    Sizhen Wang, Qiwei Tai, Kehui Wang, Jianyu Zheng, Beibei Guo, Feng Yang, Chen Wang.
      Background/Objectives: Lipid nanoparticles (LNPs) have emerged as crucial vehicles for messenger RNA (mRNA) applications in antitumor therapy. Combining LNPs with stimulator of interferon genes (STING) activation holds promise for treating "cold" tumors such as pancreatic cancer. However, two major challenges remain: inefficient mRNA escape from endosomes and STING pathway suppression in immunosuppressive tumor microenvironments. Methods: To improve endosomal escape, we developed a novel pH-responsive PEGylated lipid (Ben-mPEG2000) for mRNA-LNP preparation while using commercial Man-mPEG2000 for dendritic cell (DC)-targeted delivery of LNPs; to alleviate suppression of the STING pathway in the tumor microenvironment and activate immune responses, STING-R283S mRNA was encapsulated into LNPs, ultimately resulting in DC-targeted/pH-responsive LNPs loaded with STING-R283S mRNA for pancreatic cancer immunotherapy research. Results: After pH-responsive cleavage, Ben-mPEG2000 not only enhanced the positive charge of LNPs through the exposed protonated amino groups but also eliminated the PEG-induced steric hindrance effect. The combination of these two effects promoted membrane fusion between LNPs and the endosome, thereby enhancing mRNA translation. As a payload, STING-R283S could further amplify STING signaling in DCs without cytotoxicity to counteract immunosuppression in pancreatic cancer. Conclusions: This engineered LNP platform enhanced mRNA expression and STING activation in DCs, improving immunotherapy outcomes in pancreatic cancer.
    Keywords:  STING activation; endosomal escape; lipid nanoparticle; mRNA therapy; pancreatic cancer
    DOI:  https://doi.org/10.3390/pharmaceutics18060760
  76. Nat Prod Res. 2026 Jun 21. 1-7
    Bioactive protopanaxadiol-enriched rice (DJ-PPD) exerts potent anti-inflammatory and antioxidant effects via dual regulation of NF-κB/MAPK/Akt and NRF2/HO-1 signalling.
    Chaiwat Monmai, Aimee Carol Tangonan, Jin-Suk Kim, Eui-Shik Rha, So-Hyeon Baek.
      Protopanaxadiol (PPD) is a bioactive ginsenoside with significant anti-inflammatory potential; however, its low natural abundance and dependence on inefficient intestinal microbial bioconversion hinder pharmaceutical development. To overcome these supply and bioavailability constraints, we developed a metabolically engineered rice variety, DJ-PPD, capable of directly biosynthesizing the aglycone PPD. This study investigated the anti-inflammatory and antioxidant mechanisms of DJ-PPD extract in lipopolysaccharide (LPS)-stimulated BV2 cells. DJ-PPD treatment significantly reduced nitric oxide (NO) production, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and the expression of iNOS and COX-2. Its efficacy surpassed conventional ginseng extract and was comparable to synthetic PPD (S-PPD). Mechanistically, DJ-PPD inhibited NF-κB, MAPKs, and Akt phosphorylation while activating the NRF2/HO-1 antioxidant pathway. These findings demonstrate that DJ-PPD simultaneously inhibits pro-inflammatory cascades and reinforces intrinsic antioxidant defences. By effectively bypassing the need for gut microbiota metabolism, this genetically engineered rice represents a sustainable, bioavailable, and commercially viable multi-target therapeutic candidate for neuroinflammatory conditions.
    Keywords:  BV2 microglia; Panax ginseng; Protopanaxadiol; metabolic engineering; multi-target therapeutic; neuroinflammation
    DOI:  https://doi.org/10.1080/14786419.2026.2691377
  77. Cancers (Basel). 2026 Jun 10. pii: 1890. [Epub ahead of print]18(12):
    Effects of Combining Immune-Priming Sub-Lethal Low-Dose Radiation with 4-1BB Activation and Gal-3 Blockade in In Vitro and Preclinical Group-3 Medulloblastoma Models.
    Arabinda Das, Connor Stephenson, Daniel G McDonald, Julian E Bailes, David Cachia, Ramin Eskandari.
       BACKGROUND/OBJECTIVES: Pediatric group 3 (G3) medulloblastomas (MB) are therapy resistant and have a significantly worse prognosis than the other MB subtypes. Aggressive radiation/chemotherapy improves survival, but potential long-term comorbidities include neurocognitive deficits. In previous work, we demonstrated that low-dose X-ray radiation (LDXR) acts as an immunological adjuvant. Recent studies have demonstrated that galectin-3 (Gal-3) expression in MB tumors accelerates M2 macrophage infiltration and restricts T cell receptor (TCR)-mediated signaling. Immunotherapy with an agonistic anti-4-1BB monoclonal antibody (mAb) activates CD8+ T cells, promoting their survival and acquisition of potent cytolytic properties. Building on these findings, we hypothesized that immune priming via sublethal LDXR, combined with a Gal-3 inhibitor and an anti-4-1BB mAb, would boost anti-tumor effects, resulting in survival benefits.
    METHODS: We tested this hypothesis in vitro in co-cultures of human MB cells and in vivo, in an immunocompetent G3MB mouse model (MP1). Treatment effects were assessed using Western blot, flow cytometry, hematoxylin and eosin (H&E) staining, immunofluorescence imaging, and analysis of cytokine and chemokine expression.
    RESULTS: Our data demonstrated higher Gal-3 expression in MB patient-derived tumor tissue than in non-tumor tissue. LDXR modulated major histocompatibility complex molecules, and, combined with a Gal-3 inhibitor and an anti-4-1BB mAb, altered T-cell/tumor-cell interactions, enhanced T-cell-mediated MB cell death, and shifted cytokine production to drive microglial polarization toward the M1 subtype. Furthermore, H&E-stained tumor sections showed a ~70% reduction in tumor size compared with untreated controls.
    CONCLUSIONS: These preclinical findings suggest that combining immune priming with sublethal LDXR, Gal-3 inhibition, and 4-1BB activation may be an effective treatment strategy for G3MB.
    Keywords:  4-1BB activation; Gal-3 inhibitors; low-dose X-ray radiation (LDXR); medulloblastoma; preclinical model
    DOI:  https://doi.org/10.3390/cancers18121890
  78. Asian J Pharm Sci. 2026 Jun;21(3): 101170
    Multifunctional nanotherapeutics for targeted modulation of endoplasmic reticulum stress to potentiate cancer therapy.
    Shuang Tian, Jingying Wang, Yitong Yu, Yueyuan Liu, Yi Liu, Jiameng Li, Yanfei Shang, Yueyuan Zhao, Yu Zhang, Yan Fang, Kai Shi.
      Endoplasmic reticulum stress (ERS), arising from the disruption of proteostasis within the tumor microenvironment, represents a fundamental driver of tumorigenesis, immune evasion and resistance against conventional therapies. In recent years, the precise modulation of ERS through the application of nanotechnology has emerged as a promising strategy to enhance the efficacy of cancer immunotherapy. This review provides a comprehensive analysis of the molecular mechanisms underlying ERS and discusses how engineered nanotherapeutics can selectively target the endoplasmic reticulum through approaches such as ligand conjugation, peptide modification or membrane fusion to induce sustained ERS. These nanotherapeutics initiate ERS by mechanisms including calcium ion dysregulation, overproduction of reactive oxygen species and direct activation of unfolded protein response signaling pathways. Persistent ERS subsequently facilitates immunogenic cell death by promoting the release of damage-associated molecular patterns, which enhance the maturation of dendritic cell and promote the activation of cytotoxic T lymphocytes. Moreover, combining ER-targeted nanotherapeutics with established therapeutic modalities, such as photodynamic therapy, photothermal therapy and chemodynamic therapy, has demonstrated synergistic antitumor efficacy and improved immune responses. Despite these advances, several critical challenges remain, particularly in terms of delivery efficiency, targeting specificity and systemic biocompatibility. Future research should emphasize the integration of nanotechnology with systems immunology and cancer metabolism, as well as the incorporation of artificial intelligence and single-cell omics to optimize the design and translational potential of ER-targeted nanotherapeutics. Collectively, these interdisciplinary strategies offer considerable potential to overcome therapeutic resistance and to promote the advancement of precision oncology.
    Keywords:  Cancer immunotherapy; Combination therapy; Endoplasmic reticulum stress; Immunogenic cell death; Nanomaterials; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ajps.2026.101170
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