bims-engexo Biomed News
on Engineered exosomes
Issue of 2026–06–07
sixty-two papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur
  1. Exosomal immune decoy integrates cfDNA scavenging and mTOR inhibition for synergistic lupus nephritis therapy.
  2. Molecular mechanisms governing exosome biogenesis, engineering strategies, and emerging role as cell-free therapeutics.
  3. Specifically targeted engineered exosomes loaded with circAKR1A1 enhance tumorigenesis and metastasis in prostate cancer by activating the PI3K/Akt signalling pathway.
  4. Bone targeted microenvironment actuated engineered exosomes for precision therapy of IBD associated bone loss.
  5. Enhanced exosomes for fertility protection against chemotherapy-induced ovarian damage.
  6. CCR2-overexpressing mesenchymal stromal cell-derived extracellular vesicles loaded with MPA ameliorate lupus nephritis.
  7. Exosomes in Glioma: Integrating Molecular Mechanisms with Diagnostic and Therapeutic Potential.
  8. CCR2-Guided Treg Exosome-Gas6 Hybrid Synergistically Reprograms Macrophage Inflammation and Immune Tolerance in Gouty Arthritis.
  9. Preformulated, Shelf-Stable, Dendritic Cell-Targeting Nanogel mRNA Vaccine Delivery Platform.
  10. Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies.
  11. Engineered EV-mediated delivery of an anti-amyloid peptide provides neuroprotection in an in vitro Alzheimer's disease model.
  12. Autologous cell-derived exosomes as precision nanocarriers for enhanced targeted drug delivery and therapeutic efficacy in parental tumor cells.
  13. The potential of bioengineered exosomes in regenerative medicine: a next generation therapy.
  14. Understanding exosomes in regenerative dentistry.
  15. [Embryonic Stem Cell-Derived Mesenchymal Stromal Cell Exosomes Protect Against Radiation-Induced Lymphocyte Injury and Its Related Mechanisms].
  16. Lactate-Depleting Engineered Probiotics Remodel the Tumor Microenvironment and Enhance PD-1 Blockade.
  17. Targeted extracellular vesicle-photoimmunotherapy remodels stromal-immune microenvironment to boost chemo-immunotherapy in preclinical models.
  18. ssDNA Modification on Lipid Carriers Utilizing ssDNA-Conjugated Fusion Protein with Cholesterol-Binding Ability.
  19. An Engineered Microbial Nanohybrid for Enhanced Ferroptosis Immunotherapy via Hypoxia-Responsive Hydrogen Sulfide Generation and Mitophagy Inhibition.
  20. Constructing EGF mRNA-Enriched Extracellular Vesicles Based on the AAVS1 Safe Harbor Site to Promote Skin Wound Healing.
  21. Targeting NETosis in the Lung: Respiratory Delivery of Neutrophil-Specific NEBP-Liposomes for Enhanced Therapy of Acute Lung Injury.
  22. A design-optimized engineered bacterium for enhanced efficacy and safety in treating tyrosinemia type 1: a multi-species preclinical study.
  23. Nanoassemblies Remodeling Tumor-Derived Exosomes' Immunity Ameliorate Local and Peripheral Immunosuppression for Cancer Immunotherapy.
  24. Advanced strategies to enhance the safety, persistence, and efficacy of CAR-T cells in solid tumors.
  25. Postpartum Plasma-Derived Exosomes Confer Mitochondrial Stabilization and Neuroprotection against Ischemic Stroke.
  26. Lateral Orbital Rim Advancement and Balanced Orbital Decompression for Exorbitism Regression in Crouzon Syndrome.
  27. Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate-mediated macrophage reprogramming and protects against sepsis-triggered lung cell death.
  28. In vivo circRNA-engineered macrophages mediate localized MMP9 neutralization to rejuvenate aged bone.
  29. Dissecting Discoidin Domain Receptor 2 Dynamics in Fibrosis with a Programmable Collagen-Mimetic Probe.
  30. Trained immunity-primed DLL3-targeted CAR macrophages for the eradication of small cell lung cancer.
  31. Protective effects of human umbilical cord-derived exosomes on testicular ischemia-reperfusion injury: Comparison of local versus systemic administration.
  32. FGF9 attenuates osteoarthritis progression through the NRF2/GPX3 antioxidant axis.
  33. Biomarker-driven and AI-assisted nanomedicine for breast cancer: advancing precision drug delivery from bench to bedside.
  34. Targeting taurine metabolism via PROTAC-mediated SLC6A6 degradation potentiates photodynamic therapy and reverses immunosuppression in cholangiocarcinoma.
  35. Bioelectric signals promote diabetic bone regeneration through Piezo1-mediated activation of the efferocytic immune microenvironment.
  36. Transferring a microhaplotype-specific probabilistic genotyping model from targeted amplification to hybridization capture: A proof-of-concept study of a 100-locus panel for DNA mixtures.
  37. Chemo-physical loading of exosomes on porous titanium for improved soft tissue integration.
  38. Mesenchymal Stem Cell-Derived Exosomes: A Novel Frontier in Regenerative Medicine and Immunotherapy.
  39. Immunotoxin therapy: a promising frontier in targeted cancer treatment a review of clinical trials in hematological and solid tumors.
  40. A Novel Retinoid and Salicylic Acid Topical Treatment for Moderate-Severe Acne.
  41. Tailored Biomaterials Induce Tertiary Lymphoid Structures for Boosting Cancer Immunotherapy.
  42. Selective rewiring of Met4 ubiquitin regulation enhances S-adenosylmethionine accumulation in sake yeast.
  43. YBX1 takes actions on triggering M2-like polarization of macrophages and stabilizing CXCL8 mRNA to exhibit its metastatic potential in bladder cancer.
  44. Focused ultrasound as a therapeutic adjunct in pancreatic cancer: from thermal and mechanical effects to immune modulation.
  45. Trained immunity agonists given to neonatal mice fail to protect against leptospiral infection in adulthood and may cause adverse effects.
  46. Platelet-rich plasma cues program M2 macrophage-derived exosome mimetics to regenerate the tendon-bone interface.
  47. Ecology and engineering to modify the bile acid output of a defined microbial community.
  48. Modular Biosurface Engineering of Magnetotactic Bacteria for Multimodal Synergistic Cancer Therapy.
  49. Electrospinning-constructed polysaccharide-based multilayer nanofiber composite membrane for bridging hemostasis and tissue repair.
  50. Electrospun nanocomposite dressing integrating cerium dioxide and collagen accelerates pressure injury healing.
  51. Exosomal POSTN from cancer-associated fibroblasts drives progression of microinvasive lung adenocarcinoma: insights from single-cell and tissue exosome sequencing analysis.
  52. Exosomes-Transferred lncRNA H19 Reverses Osimertinib Resistance by Upregulating PTEN via Sponging miR-148-3p in Non-Small Cell Lung Cancer.
  53. Metabolically engineered probiotic OMVs as nanovaccine mediating sequential immunomodulation for chronic bone infection immunotherapy.
  54. Antitumor Immunity Mediated by Nanoreactors Based on Bacterial Membrane Vesicles.
  55. A Dual-Phase Exosomal Nanotherapy Enhances Continual Efferocytosis by Coordinating Checkpoint Inhibition and Metabolic Reprogramming in Atherosclerosis.
  56. A Prodrug Strategy to Conditionally Trap Therapeutic Payloads for Improved Tumor Retention.
  57. One-step cleavage and purification: a bifunctional IdeS-Protein A fusion protein for on-column generation of antibody fragments.
  58. Time-restricted feeding prior to Mycobacterium tuberculosis infection reduces tissue CD4+ T cells with limited impact on bacterial clearance.
  59. Combined application of the modified early warning score and the modified hematoma expansion prediction score for predicting hematoma expansion in intracerebral hemorrhage.
  60. ROS-pH Dual-Responsive Polydopamine Nanoparticles for Targeted Fasudil Delivery Ameliorate Multiple Pathologies in Diabetic Retinopathy.
  61. Targeted delivery of TGF-β inhibitor via LHRH-NanoTi reverses the NAT10/ac4C-mediated cisplatin-induced immunosuppressive tumor microenvironment in ovarian cancer.
  62. A Self-Cascading Immunomodulatory Hydrogel for Remodeling Infected Diabetic Wounds.
  1. Theranostics. 2026 ;16(12): 6763-6782
    Exosomal immune decoy integrates cfDNA scavenging and mTOR inhibition for synergistic lupus nephritis therapy.
    Mingxin Zhu, Qinyao Xu, Zhicheng Tang, Zexin Wang, Haofang Zhu, Lingyun Sun.
       Objective: Lupus nephritis (LN) treatment faces the challenge of balancing effective immunosuppression with systemic safety. To address this, we aimed to develop a biomimetic nanoplatform capable of simultaneously targeting multiple pathogenic pathways in LN, thereby achieving potent immunomodulation without broad toxicity.
    Methods: A "smart immune decoy" (RAPA@MEX-PL) was engineered by encapsulating rapamycin (RAPA) in mesenchymal stromal cell-derived exosomes (MEX) and coating the surface with a cationic polylysine (PLL) corona. The platform was designed to concurrently: (1) the polylysine corona potently scavenges cell-free DNA (cfDNA) to quench TLR9-mediated inflammation, (2) the MEX core mediates the repolarization of macrophages from an M1 to an M2 phenotype, and (3) localized RAPA release provides durable mTOR inhibition, synergistically rebalancing autoimmune responses. Renal targeting, immunomodulatory activity, and systemic safety were evaluated in lupus-prone mouse models.
    Results: In lupus-prone mice, RAPA@MEX-PL demonstrated precise accumulation in renal tissue, leading to a significant reduction in auto-antibody levels and resolution of glomerular inflammation. The platform concurrently addressed three key pathogenic pathways-cfDNA scavenging, macrophage repolarization and mTOR inhibition-resulting in synergistic rebalancing of autoimmune responses. Notably, it circumvented the metabolic side effects typically associated with systemic RAPA administration.
    Conclusions: The RAPA@MEX-PL nanoplatform represents a targeted and effective immunotherapeutic strategy for LN, capable of achieving sufficient immunosuppression without systemic toxicity. These findings emphasize its potential as a favorable candidate for the therapy for autoimmune diseases.
    Keywords:  cell-free DNA; engineered exosomes; lupus nephritis; polylysine; targeted delivery
    DOI:  https://doi.org/10.7150/thno.130906
  2. Mol Biol Rep. 2026 Jun 01. pii: 866. [Epub ahead of print]53(1):
    Molecular mechanisms governing exosome biogenesis, engineering strategies, and emerging role as cell-free therapeutics.
    Muhammad Hassan Raza, Javaria Ilyas, Kashf Shahid, Zania Urooj, Maria Tayyab Baig, Muhammad Shahid.
      Exosomes are nanosized extracellular vesicles that mediate intercellular communication by delivering functional cargo, including proteins, lipids, and regulatory nucleic acids. They overcome limitations of conventional cell-based therapies such as immune rejection, tumorigenicity, and poor engraftment, making them a promising tool for regenerative and precision medicine. Exosome engineering involves modifying exosomes through cargo enrichment, surface modification, hybrid vesicle design, and targeted delivery. It has revolutionized therapeutic strategies by enhancing tissue-specific targeting, stability in circulation, delivery efficiency of nucleic acids and drugs across biological barriers, and reducing off-target effects. These advances provide a clinically relevant platform for personalized treatments, offering safer and more efficient alternatives to traditional therapies. This review highlights the latest advances in exosome biology, including their biogenesis, cargo sorting, and engineering strategies for targeted delivery. Additionally, key therapeutic applications in regenerative and precision medicine are discussed, along with challenges in large-scale production, standardization, and clinical translation. This paper also highlights the transformative potential of exosome-based therapies and engineered platforms as next-generation, cell-free therapeutic strategies compared to conventional molecules such as liposomes.
    Keywords:  Biogenesis; Cargo loading; Exosome engineering; Exosomes; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s11033-026-12040-1
  3. Oncogene. 2026 May 30.
    Specifically targeted engineered exosomes loaded with circAKR1A1 enhance tumorigenesis and metastasis in prostate cancer by activating the PI3K/Akt signalling pathway.
    Shenglong Li, Yue Kang, Yujing Guan, Jiahang Li, Runze Jiang, Shouyi Zhang, Enduo Qiu, Tianfu Wang, Rui Liu, Shanlin Wang, Cong Ning, Xing Niu, Yuming Wang, Yu Zeng.
      Determining effective treatment strategies for prostate cancer patients with bone metastasis remains a difficult issue. Targeted engineered exosomes have the potential to deliver anticancer drugs to tumor sites in a highly efficient and precise manner while minimizing treatment-related side effects. Here, we assessed the function and value of targeted engineered exosomes loaded with circAKR1A1 (OE-circAKR1A1-exosomes) in bone metastatic prostate cancer cells. The function and underlying mechanism of OE-circAKR1A1-exosomes were investigated via in vivo and in vitro experiments. We observed a positive correlation between circAKR1A1 expression and prostate cancer metastasis and progression. Both in vivo and in vitro experiments confirmed that OE-circAKR1A1-exosomes specifically targeted prostate cancer cells in the bone microenvironment. This targeting mechanism activated the PI3K/Akt signalling pathway, thereby facilitating tumor invasion and metastasis. Collectively, our findings suggest that circAKR1A1 is a driver and treatment target for metastatic prostate cancer. Targeted delivery of therapeutic circRNAs via engineered exosomes represents a highly promising clinical therapeutic approach. The schematic diagram of this study E3 aptamer-modified engineered exosomes loaded with circAKR1A1 specifically target bone metastases in PCa, thereby activating the PI3K/Akt signalling pathway to facilitate tumor invasion and metastasis.
    DOI:  https://doi.org/10.1038/s41388-026-03833-6
  4. Bioact Mater. 2026 Oct;64 817-836
    Bone targeted microenvironment actuated engineered exosomes for precision therapy of IBD associated bone loss.
    Jiang Liu, Cong Wang, Taojin Feng, Siyu Chen, Siliang Ge, Yue Zhao, Ming Chen, Zhongqi Wang, Weier Bao, Pincong Fu, Zhichao Wang, Simiao Kang, Pengbin Yin, Ying Tian, Yi Li, Haile Pan.
      Systemic bone loss is a frequent extraintestinal complication of inflammatory bowel disease (IBD) and can continue even when intestinal inflammation is clinically controlled. The steps linking gut inflammation to bone deterioration at distant sites are not fully defined. We found that interleukin-18 (IL-18) links intestinal inflammation to bone loss. In the gut, IL-18 supports mucosal repair and barrier maintenance. When circulating IL-18 remains elevated, it accumulates in bone-associated niches, shifts bone remodeling, and ultimately leads to bone loss. While IL-18 is a protective factor essential for intestinal repair and barrier homeostasis, its sustained systemic elevation leads to pathological accumulation in bone-associated niches, driving aberrant bone remodeling and bone loss. To address this challenge, we developed ExoBIP, a bone-targeted and microenvironment-actuated engineered exosome system. This platform enables site-specific IL-18 neutralization within inflamed bone tissues while preserving the physiological function of IL-18 in the gut. ExoBIP integrates the intrinsic pro-osteogenic properties of bone marrow mesenchymal stem cell derived exosomes with spatiotemporally controlled cytokine blockade, thereby simultaneously suppressing inflammation-driven bone resorption and supporting bone regeneration. In a chronic IBD-associated bone loss model, ExoBIP effectively restores bone mass, improves trabecular microarchitecture, and single-cell RNA sequencing showed that ExoBIP restores the marrow niche by increasing osteogenic cells and reducing inflammatory, cytotoxic CD8+ T cell programs. Collectively, this work establishes IL-18 as an actionable driver of IBD-induced bone loss and introduces a precision nanotherapeutic strategy for treating inflammation-induced skeletal complications, highlighting a generalizable paradigm for distal organ protection in chronic inflammatory diseases.
    Keywords:  Engineered exosomes; Exosome-based drug delivery; Inflammatory bone loss; Inflammatory bowel disease; Interleukin-18 (IL-18)
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.034
  5. NPJ Regen Med. 2026 Jun 04.
    Enhanced exosomes for fertility protection against chemotherapy-induced ovarian damage.
    Mohammad Mousaei Ghasroldasht, Hang-Soo Park, Farzana Liakath Ali, Jin Seok, Analea Beckman, Samar Alkhrait, Mervat M Omran, Hiba Alkelani, Nina Hafner, Hyunho Kim, Ayman Al-Hendy.
      Exosome-based therapies are emerging as promising tools in regenerative medicine and tissue protection. In this study, we engineered exosomes by mimicking paracrine signaling between umbilical cord-derived mesenchymal stem cells (UC-MSCs) and granulosa cells to mitigate chemotherapy-induced ovarian toxicity. Enhanced exosomes were evaluated in vitro, in vivo, and ex vivo using human granulosa cells, cyclophosphamide-treated mice, and cultured ovarian tissues from humans and rats. Enhanced exosomes demonstrated protective effects compared with chemotherapy-only controls. Molecular analyses revealed increased pro-proliferative and anti-apoptotic gene expression and reduced apoptotic markers following treatment. In vivo, enhanced exosome administration was associated with 70% higher primordial follicle counts and a two-fold increase in combined primordial and primary follicles relative to CTX controls. Primary follicle numbers were markedly elevated ( > 20-fold vs CTX). In breeding studies, pup numbers increased from 1 in CTX-treated mice to 7 in enhanced exosome-treated mice in the first mating, and pregnancies were observed in later breeding rounds only in the enhanced group. Enhanced exosomes also modulated ATP-binding cassette transporter expression. In human ovarian tissue ex vivo, treatment resulted in a two-fold increase in AMHR2 expression. These findings support engineered exosomes as a potential platform for oncofertility preservation and mitigation of chemotherapy-associated gonadotoxicity.
    DOI:  https://doi.org/10.1038/s41536-026-00477-8
  6. J Nanobiotechnology. 2026 Jun 02.
    CCR2-overexpressing mesenchymal stromal cell-derived extracellular vesicles loaded with MPA ameliorate lupus nephritis.
    Yang Hang, Jinghan Yang, Xiaoquan Wei, Xiaojing Li, Min Xu, Yuxuan Chen, Weiwei Chen, Genhong Yao, Xiaojun Tang, Xiaojuan Han, Min Nie, Lingyun Sun.
      Lupus nephritis (LN) is a common renal complication of systemic lupus erythematosus, and its severity is closely correlated with disease prognosis. Conventional therapy for LN faces challenges including multiple side-effects caused by systemic administration and low drug delivery efficiency due to lack of organ targeting. Herein, we designed a renal-targeted delivery platform based on C-C Motif Chemokine Receptor 2 (CCR2)-C-C Motif Chemokine ligand 2 chemotaxis, constructed by engineering CCR2-overexpressing mesenchymal stromal cell-derived EVs loaded with mycophenolic acid (MPA)-encapsulated MSNs (MPA@CMSNs). In LN models, MPA@CMSNs enabled efficient delivery of MPA into renal region and significantly alleviated kidney inflammation. Mechanistically, MPA@CMSNs effectively inhibited the proliferation and differentiation of proinflammatory immune cells, while concurrently suppressing the Dectin3/NF-κB signaling pathway in macrophages to remodel and optimize the renal immune microenvironment. Collectively, our findings present an efficient renal-targeted strategy with profound therapeutic efficacy against LN, offering a promising approach for targeted disease treatment.
    Keywords:  CCR2; Extracellular vesicles; Lupus nephritis; Mesenchymal stromal cell; Mycophenolic acid
    DOI:  https://doi.org/10.1186/s12951-026-04583-z
  7. Small. 2026 May 30. e73721
    Exosomes in Glioma: Integrating Molecular Mechanisms with Diagnostic and Therapeutic Potential.
    Yantong Liu, Yingdi Nie, Hao Zhang, Wantao Wu, Nan Zhang, Zhiwei Xia, Jianping Wen, Peng Luo, Quan Cheng.
      Glioma, a lethal intracranial malignancy with limited therapeutic options, represents one of oncology's most persistent challenges. Entering a new era of molecular oncology, exosomes-nanoscale extracellular vesicles-have emerged as master regulators of intercellular communication, dynamically sculpting the glioma tumor microenvironment (TME) and orchestrating hallmarks of malignancy, including immune evasion, angiogenesis, and therapeutic resistance. These versatile vesicles transport bioactive cargo (e.g., miRNAs, lncRNAs, proteins) to reprogram stromal, neuronal, and immune cells, creating a permissive niche for tumor progression. Recent breakthroughs now position exosomes at the forefront of translational medicine, serving dual roles as minimally invasive biomarkers and engineered nanovectors for precision therapy. This review systematically deciphers how exosomes fuel glioma pathogenesis-from driving macrophage polarization and T-cell suppression to facilitating blood-brain barrier disruption and chemoresistance. Beyond mechanistic insights, we spotlight pioneering strategies harnessing exosomes for drug delivery, immunotherapy, and nanotechnology-driven interventions. By bridging foundational discoveries with clinical applications, this work heralds a new era in glioma management, where exosome-based tools promise to revolutionize personalized diagnosis, prognostication, and therapeutic innovation.
    Keywords:  exosome; glioma; precision medicine; tumor microenvironment
    DOI:  https://doi.org/10.1002/smll.73721
  8. Adv Healthc Mater. 2026 Jun 01. e71311
    CCR2-Guided Treg Exosome-Gas6 Hybrid Synergistically Reprograms Macrophage Inflammation and Immune Tolerance in Gouty Arthritis.
    Sang Lin, Yilan Liu, Yingzi Zhou, Jing Zhang, Wenjing Ye, Jixin Zhong, Yu Xue, Fangfang Chen.
      Gouty arthritis (GA) is a recurrent inflammatory joint disease initiated by monosodium urate (MSU) crystal deposition and driven by progressive immune dysregulation. The collapse of immune tolerance, together with persistent synovial inflammation and pathogenic cytokine imbalances, jointly exacerbates joint injury. Here, we design a bioresponsive therapeutic platform composed of regulatory T cell (Treg)-derived exosomes co-loaded with growth arrest-specific protein 6 (Gas6), engineered to preferentially home to inflamed joints via CCR2-guided chemotactic targeting. The two components of the hybrid-Gas6 and Treg exosomes-exert both independent and synergistic immunomodulatory effects. By mitigating inflammation and reprogramming the tissue environment toward a tolerogenic state, the system bridges innate and adaptive immunity to restore overall immune function. In an MSU-induced murine GA model, this therapy not only alleviates key clinical symptoms, but also promotes the expansion of regulatory T cells and suppresses TH17 responses, leading to restoration of a more tolerogenic immune balance. Together, our study presents a cell-free, CCR2-guided immunoengineering approach that achieves targeted delivery and coordinated immune reprogramming, offering a promising strategy for treating GA and other disorders associated with immune imbalance.
    Keywords:  Gas6; adaptive immune tolerance; gouty arthritis; macrophage; regulatory T cell exosomes
    DOI:  https://doi.org/10.1002/adhm.71311
  9. Bioconjug Chem. 2026 Jun 01.
    Preformulated, Shelf-Stable, Dendritic Cell-Targeting Nanogel mRNA Vaccine Delivery Platform.
    Amy E Laturski, Verónica Durán, Bruce T Schaar, Maria T Dulay, Shirit Einav, Joseph M DeSimone.
      Current mRNA-based vaccine platforms are limited by complex fabrication, stringent cold-chain dependence, and off-target in vivo delivery, restricting their global accessibility and targeting precision. Here we show a modular mRNA delivery platform; our approach integrates inverse microemulsion-derived polymeric nanogels with adsorption-based mRNA loading and the capability for ligand-directed targeting to develop targeted reductively cleavable acrylate-based inverse microemulsion nanogels (TRAINs). By decoupling nanoparticle fabrication from mRNA loading, preformed TRAINs can be stockpiled and later combined with newly designed mRNA, enabling a plug-and-play strategy for rapid adaptation to emerging pathogens, which is particularly advantageous for pandemic preparedness. This architecture supports efficient mRNA association and robust cellular uptake and translation in HEK293T cells. TRAIN also enables postsynthetic surface functionalization; as a proof of concept, CD206-targeted TRAINs promoted selective delivery to antigen-presenting cells (APCs), producing sustained and localized protein expression in BALB/c mice and preferential mRNA delivery to myeloid APCs in heterogeneous human peripheral blood mononuclear cells. Together, these results demonstrate TRAINs as a surface-customizable, adsorption-based mRNA delivery platform with potential for APC-targeted vaccination and rapid, adaptable vaccine deployment.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.6c00069
  10. Front Immunol. 2026 ;17 1808474
    Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies.
    Ran Pan, Yiyi Sun, Lu Chen, Jianping Pan, Junping Guo.
      Sepsis-associated acute lung injury (S-ALI) remains a life-threatening condition with high mortality and limited therapeutic options. Macrophages, as key sentinels of innate immunity, exhibit remarkable heterogeneity and functional plasticity. These properties are fundamentally driven by metabolic reprogramming, which tailors their effector functions to specific microenvironmental demands. Beyond the traditional M1/M2 binary classification, macrophage activation is now appreciated as a continuous functional spectrum. Pro-inflammatory macrophages preferentially utilize aerobic glycolysis and the pentose phosphate pathway, coupled with suppressed oxidative phosphorylation (OXPHOS), whereas reparative macrophages rely predominantly on OXPHOS and fatty acid oxidation (FAO). Key glycolytic enzymes such as PFKFB3 and PKM2, the transcriptional regulator HIF-1α, and TCA cycle intermediates including succinate and itaconate serve as critical metabolic checkpoints governing macrophage inflammatory responses. During S-ALI, the metabolic landscape undergoes dynamic temporal shifts: the early hyperinflammatory phase is characterized by enhanced glycolysis, while the late immunosuppressive phase exhibits impaired OXPHOS and FAO. This review synthesizes recent advances in understanding how metabolic reprogramming orchestrates macrophage polarization during S-ALI, encompassing glycolysis, the TCA cycle, FAO, and amino acid metabolism. Natural compounds, pharmacological inhibitors, and innovative delivery platforms have shown promise in reprogramming macrophage metabolism to restore immune homeostasis. Notable examples include aerosolized CRISPR/Cas9 nanotherapeutics, biomimetic nanoplatforms, pH-responsive nanoparticles, and engineered exosomes. However, challenges such as broad cytotoxicity, limited macrophage selectivity, incomplete pharmacokinetic characterization, and the timing of intervention in the evolving septic milieu must be addressed. Future strategies should focus on developing cell-type-restricted delivery systems, validating targets in human-relevant models, and designing phase-specific interventions tailored to the metabolic trajectory of S-ALI.
    Keywords:  Acute lung injury; macrophage; metabolic reprogramming; sepsis; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2026.1808474
  11. Int J Pharm. 2026 Jun 01. pii: S0378-5173(26)00491-6. [Epub ahead of print]700 127043
    Engineered EV-mediated delivery of an anti-amyloid peptide provides neuroprotection in an in vitro Alzheimer's disease model.
    Varsha Birendra Singh, Sharad Gupta, Raja Natesan Sella.
      Alzheimer's disease is driven in part by amyloid-β (Aβ) aggregation, oxidative stress, and progressive neuronal dysfunction. Despite various attempts, therapeutic translation remains limited by inefficient delivery of bioactive molecules to neuronal cells. This study presents a surface-engineered extracellular vesicle (EV) platform designed for targeted peptide delivery, assessing its neuroprotective efficacy in an in vitro model of Alzheimer's disease. EVs were obtained from NIH/3T3 cells expressing Lamp2b-RVG and were surface-modified with the β-sheet breaker peptide H102 through CP05-CD63 affinity binding. ATR-FTIR, SERS Raman spectroscopy, high-resolution transmission electron microscopy, nanoparticle tracking analysis, zeta potential measurements, and EV marker profiling demonstrated successful peptide conjugation and vesicle integrity. Aggregated Aβ25-35 was utilized to assess neuronal toxicity in NGF-differentiated PC-12 cells. Peptide-modified EV demonstrated effective, time-dependent cellular uptake and significantly improved cell viability while decreasing membrane damage and intracellular reactive oxygen species levels in comparison to Aβ-treated controls. Treatment with Peptide-modified EV normalized the expression of key genes associated with Alzheimer's, such as APP, Bax, Sirt1, and Stat1, suggesting a coordinated modulation of amyloidogenic, apoptotic, oxidative, and inflammatory pathways. The results indicate that surface-engineered EVs facilitate efficient neuronal delivery of therapeutic peptides and offer multi-level cytoprotection against Aβ-induced neurotoxicity. This study emphasizes the capability of peptide-decorated EV as a multifunctional nanocarrier system for the treatment of Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Engineered extracellular vesicles; Neuroprotection; Peptide therapeutics; Surface modification; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127043
  12. J Microencapsul. 2026 Jun 01. 1-15
    Autologous cell-derived exosomes as precision nanocarriers for enhanced targeted drug delivery and therapeutic efficacy in parental tumor cells.
    Tianzhi Yang, Spencer Canham, Elise Kaserman, Mansi More, Shuhua Bai.
      Exosomes are emerging as biologically derived nanocarriers for targeted drug delivery. In this study, we compared autologous and heterologous exosomes for delivery of chemotherapeutic agents and ICAM-1 siRNA in lung adenocarcinoma (A549) and brain endothelial (bEND.3) cells. Fluorescence imaging and flow cytometry showed significantly greater uptake of autologous exosomes in parental cells (p < 0.05). Doxorubicin-loaded autologous exosomes reduced A549 viability to 40.5 ± 2.0% at 200 µg/mL, compared to 64.5 ± 8.1% with heterologous exosomes, with similar trends for methotrexate and paclitaxel. Optimised exosome-Lipofectamine-siRNA formulations achieved 49.0 ± 7.2% ICAM-1 knockdown, outperforming controls. Both exosome types were nanosized (34.5 ± 1.0 nm and 72.1 ± 3.3 nm) and expressed CD63, CD81, ALIX, and TSG101. Proteomic analysis revealed a shared core proteome with distinct cell-specific signatures. These findings highlight the superior delivery efficiency of autologous exosomes as precision nanocarriers.
    Keywords:  A549 cells; Autologous exosomes; ICAM-1 siRNA; bEND.3 cells; nanocarriers; targeted drug delivery
    DOI:  https://doi.org/10.1080/02652048.2026.2676311
  13. Hum Cell. 2026 Jun 05. pii: 86. [Epub ahead of print]39(6):
    The potential of bioengineered exosomes in regenerative medicine: a next generation therapy.
    Shiwani Kumari, Anjali Agnihotri, Arpit Sharma, Shweta Dongre, Ashwani Tiwari, Naveen Soni, Bhawana Bissa.
      The limitations of conventional drug delivery systems and synthetic nanocarriers have spurred the search for advanced therapeutic platforms in regenerative medicine. Bioengineered exosomes/sEV, natural extracellular vesicles with inherent biocompatibility and targeting capabilities, have emerged as a groundbreaking solution. This review explores the fabrication of these nanovesicles as precision drug delivery vehicles through strategies such as parent-cell modification, direct cargo loading (via sonication, electroporation, and extrusion), and surface functionalization. Critically, the synergy between exosomes and biomaterial scaffolds-including natural and synthetic polymers, hydrogels, and metallic implants-is highlighted as a transformative approach to overcome challenges of rapid clearance and off-target delivery, enabling localized, sustained release at injury sites. We detail their profound regenerative efficacy in healing chronic wounds by modulating inflammation and promoting angiogenesis, in repairing bone defects via osteogenic signaling activation, and in treating complex neurological and cardiovascular diseases by crossing biological barriers like the blood-brain barrier. Despite the promising preclinical outcomes summarized herein, significant hurdles in scalable production, standardization, and clinical translation remain. Addressing these challenges is essential to fully harness the potential of this cell-free therapy. Ultimately, bioengineered exosomes represent a versatile and powerful frontier in regenerative medicine, offering a targeted, efficient, and potentially transformative approach for tissue repair and the treatment of degenerative diseases.
    Keywords:  Biomaterials; Cell-free therapy; Exosome-based therapeutics; Exosomes/sEV; Regenerative medicine; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s13577-026-01400-5
  14. Periodontol 2000. 2026 Jun 01.
    Understanding exosomes in regenerative dentistry.
    Paras Ahmad, Anton Sculean, Richard J Miron.
       BACKGROUND: Regenerative dentistry is shifting from cell-based strategies to cell-free biologics capable of orchestrating intricate tissue repair. Exosomes, nanosized extracellular vesicles carrying bioactive molecular payloads, have emerged as central modulators of intercellular communication. This review aimed to offer a comprehensive synthesis of exosome-based regenerative processes across oral and craniomaxillofacial (CMF) tissues.
    METHODS: A structured literature review was performed utilizing PubMed, Scopus, and Web of Science databases without time restriction. Eligible studies included in vitro, in vivo, and clinical investigations assessing exosome-based mechanisms, molecular signaling pathways, and bioengineering approaches in regenerative dentistry.
    RESULTS: Exosomes derived from stem cells, immune cells, and dental tissues showed multifaceted regenerative impacts across periodontal, endodontic, orthodontic, and CMF applications. Mechanistically, exosomes mediated osteogenesis, angiogenesis, immune regulation, oxidative stress, and stem cell recruitment through central pathways, such as the PI3K/AKT, MAPK/ERK, Wnt/β-catenin, TGF-β/BMP, and NF-κB. They enhanced macrophage polarization toward anti-inflammatory phenotypes, restored osteoclast-osteoblast homeostasis, enhanced angiogenesis, and preserved mitochondrial homeostasis. In regenerative endodontics, exosomes enhanced cell viability, decreased apoptosis, and improved odontogenic differentiation and neurovascular coupling. In orthodontic and CMF regeneration, they coordinated mechanotransduction, osteogenesis, and angiogenesis. Bioengineering approaches, such as scaffold-mediated platforms, preconditioning, and genetic modification, further improved exosome stability, targeting, and treatment efficacy.
    CONCLUSION: Exosomes represent a versatile and robust cell-free treatment approach capable of orchestrating intricate oral tissue regeneration. Despite promising preclinical evidence, challenges associated with standardization, scalability, and clinical validation must be addressed to allow translation in routine dental practice.
    Keywords:  bone regeneration; extracellular vesicles; stem cells; tissue engineering
    DOI:  https://doi.org/10.1111/prd.70054
  15. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2026 Apr;34(2): 559-567
    [Embryonic Stem Cell-Derived Mesenchymal Stromal Cell Exosomes Protect Against Radiation-Induced Lymphocyte Injury and Its Related Mechanisms].
    Jia-Xin Chen, Zhi-Qing Liu, Yang-Yang Lei, Dong-Mei Wang, Tie-Qiang Liu, Hai-Long Zhuo, Chang-Lin Yu, Hui-Sheng Ai, Kai-Xun Hu, Bo Cai, Mei Guo, Yi Wang.
       OBJECTIVE: To explore the repair effect and its related mechanism of exosomes derived from embryonic stem cell-induced mesenchymal stromal cells (ESC-MSC) on radiation-induced lymphocyte damage.
    METHODS: A culture system for differentiating embryonic stem cells (ESC) into ESC-MSC was established, with the induced cells identified by flow cytometry and morphological methods. ESC-MSC-derived exosomes (ESC-MSC-Exo) were isolated and purified, followed by identification via electron microscopy, nanoparticle tracking analysis (NTA), and Western blot. Then they were compared with human bone marrow mesenchymal stromal cell-derived exosomes (BM MSC-Exo) to observe their similarities and differences. Lymphocytes from healthy human were isolated and irradiated with 4 Gy 60Co γ-rays, then they were co-cultured with ESC-MSC-Exo or BM MSC-Exo for 48 hours. Apoptosis, DNA fragmentation, reactive oxygen species (ROS) production, and mitochondrial membrane potential changes were detected to compare the therapeutic efficacy differences between the two types of exosomes and explore the repair effect and related mechanism of ESC-MSC-Exo on radiation-induced lymphocyte damage.
    RESULTS: Flow cytometry and morphological identification confirmed that ESC-MSC expressed mesenchymal stromal cell (MSC) surface markers and exhibited a spindle-shaped morphology. Electron microscopy observation showed ESC-MSC-Exo was cup-shaped or hemispherical with a concave side. Western blot verified the presence of exosomal marker proteins (TSG101, CD63, CD81), and NTA revealed uniform particle size with a peak of 153.6 nm. ESC-MSC-Exo alleviated radiation-induced lymphocyte apoptosis and DNA fragmentation, reduced ROS production, and improved radiation-induced mitochondrial membrane potential depolarization.
    CONCLUSION: ESC-MSC-Exo can mitigate radiation-induced oxidative stress and reduce apoptosis in lymphocytes.
    Keywords:  embryonic stem cell; mesenchymal stromal cell; exosome; radiation injury; oxidative stress
    DOI:  https://doi.org/10.19746/j.cnki.issn1009-2137.2026.02.039
  16. Adv Healthc Mater. 2026 Jun 01. e71316
    Lactate-Depleting Engineered Probiotics Remodel the Tumor Microenvironment and Enhance PD-1 Blockade.
    Jing Zhang, Qiushuang Zhang, Yuhan Liu, Yicong Dai, Xucong Teng, Jinghong Li.
      High lactate concentrations in the tumor microenvironment (TME) suppress antitumoral immunity. Although modulating intratumoral lactate is a promising strategy, tumor-targeted interventions remain limited. Here, we developed an engineered probiotic, Lac-EcN, capable of targeted lactate consumption within the TME. Lac-EcN reduces intratumoral lactate levels by over 60% and alleviates tumor acidosis, accompanied by reversal of aberrant NFAT1 nuclear translocation in Tregs and restoration of effector molecule production by cytotoxic T cells. In B16-F10 melanoma and MC-38 colorectal carcinoma models, Lac-EcN combined with anti-PD-1 improves tumor inhibition and extends survival. These results position engineered probiotics as a platform for targeted metabolic intervention in the TME, integrating metabolic reprogramming with immune checkpoint blockade.
    Keywords:  cancer immunotherapy; engineered probiotics; lactate metabolism, PD‐1 blockade; tumor microenvironment
    DOI:  https://doi.org/10.1002/adhm.71316
  17. Cell Rep Med. 2026 Jun 03. pii: S2666-3791(26)00260-0. [Epub ahead of print] 102843
    Targeted extracellular vesicle-photoimmunotherapy remodels stromal-immune microenvironment to boost chemo-immunotherapy in preclinical models.
    Chengming Qu, Jie Liu, Jinpeng Cen, Ming Tian, Yibo Chai, Peng Xia, Runhua Zhou, Jingbo Ma, Huifang Wang, Haitao Yuan, Felix Rückert, Ji Li, Bo He, Zhiyong Yang, Rui Hou, Zhijie Li, Jigang Wang, Yufeng Yuan.
      Solid tumors, especially pancreatic ductal adenocarcinomas (PDACs), activate quiescent fibroblasts into cancer-associated fibroblasts (CAFs) that generate dense desmoplastic stroma. This barrier restricts drug penetration and immune infiltration, promoting tumor progression. Here, we engineer Midkine (MDK)-targeting nanobody-functionalized extracellular vesicles (D4-EV) as a precision photoimmunotherapy platform. These vesicles selectively accumulate in the tumor microenvironment through MDK overexpression. Loaded with chlorin e6 (Ce6), Ce6@D4-EV induces immunogenic cell death upon light irradiation, triggering dsDNA release and cGAS-STING activation in tumor-associated macrophages. Concurrently, it reprograms CAFs, reduces extracellular matrix deposition, improves vascular perfusion, and alleviates hypoxia. This stromal-immune remodeling substantially enhances the therapeutic efficacy of immune checkpoint blockade, adoptive T cell therapy, and chemotherapy, leading to prolonged survival in multiple MDK-positive preclinical tumor models. The platform provides a promising strategy to overcome stromal barriers in desmoplastic tumors.
    Keywords:  Midkine; cGAS-STING; engineered exosomes; nanobody; pancreatic ductal adenocarcinoma; photoimmunotherapy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102843
  18. Bioconjug Chem. 2026 Jun 02.
    ssDNA Modification on Lipid Carriers Utilizing ssDNA-Conjugated Fusion Protein with Cholesterol-Binding Ability.
    Kei Nishida, Nami Oba, Eiry Kobatake, Masayasu Mie.
      Lipid carriers, such as liposomes and exosomes, are nanoscale vesicular structures composed of phospholipids, glycolipids, membrane proteins, and cholesterol, which have been widely investigated as drug- and nucleic-acid-delivery systems. Functionalization of lipid carrier surfaces with ligand molecules is an effective approach for the targeted delivery of lipid carriers to specific tissues and cells. In this regard, the use of DNA modification represents a rational and promising approach as DNA aptamers exhibit high affinity and specificity for target molecules and offer several advantages over conventional ligands. The current strategies for modifying lipid carriers with DNA remain suboptimal, leaving room for further improvement. In this study, we aimed to modify lipid carriers with single-stranded (ss)DNA-conjugated fusion proteins that have cholesterol-binding abilities. The fusion protein (Rep-ALOD4) was composed of a replication initiator protein derived from porcine circovirus type 2 (Rep), which acted as an ssDNA-conjugating domain, and domain 4 of anthrolysin O (ALOD4), which acted as a cholesterol-binding domain. As Rep-ALOD4 can bind to cholesterol in lipid membranes under mild conditions, ssDNA-conjugated Rep-ALOD4 achieved ssDNA modification on liposome carriers containing more than 30 wt % cholesterol. Furthermore, cell-selective targeting using DNA aptamer- and ssDNA-modified liposomes and exosomes was successful because of the functional applicability of ssDNA-displaying Rep-ALOD4. Thus, the DNA modification platform of Rep-ALOD4 has the potential to substantially advance targeted drug delivery using lipid carriers.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.6c00186
  19. ACS Nano. 2026 Jun 05.
    An Engineered Microbial Nanohybrid for Enhanced Ferroptosis Immunotherapy via Hypoxia-Responsive Hydrogen Sulfide Generation and Mitophagy Inhibition.
    Yuewei Li, Shujing Xu, Guocheng Wang, Zhangzhi Song, Shuqi Zhang, Xinyu Dai, Sheng Wang.
      Ferroptosis immunotherapy holds promise but suffers from insufficient activation of antitumor immunity. Here, we developed an engineered microbial nanohybrid for enhanced ferroptosis immunotherapy via hypoxia-triggered hydrogen sulfide (H2S) generation and activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. The engineered microbial nanohybrid could locally produce H2S in the hypoxic tumor microenvironment, damaging mitochondria and inhibiting catalase. Concurrently, surface-conjugated ferrocene potently catalyzed the Fenton reaction to convert hydrogen peroxide into hydroxyl radicals, leading to ferroptosis and the release of mitochondrial DNA (mtDNA). Furthermore, the loaded Mdivi-1 acts as a critical molecular brake on cellular self-repair, overcoming the mitophagic clearance of damaged mitochondria. This intervention locks in mitochondrial damage, thereby promoting the sustained accumulation of cytosolic mtDNA and potently activating the cGAS-STING pathway. The enhanced ferroptosis immunotherapy by the engineered microbial nanohybrid was confirmed in a 4T1 murine mammary carcinoma model. Therefore, this study provides a promising strategy for precise and potent antitumor immunotherapy.
    Keywords:  cGAS-STING pathway; engineered bacteria; ferroptosis; hydrogen sulfide; synergistic therapy
    DOI:  https://doi.org/10.1021/acsnano.6c06383
  20. Adv Healthc Mater. 2026 Jun 02. e04092
    Constructing EGF mRNA-Enriched Extracellular Vesicles Based on the AAVS1 Safe Harbor Site to Promote Skin Wound Healing.
    Peifen Gao, Wanyun Feng, Xian Zhao, Jiuheng Shen, Xudong Wang, Xue Wu, Wantong Zhou, Yinan Wang, Junge Chen, Wenlin An.
      Skin wound healing is a complex biological process that requires the coordinated regulation of cell proliferation, migration, and extracellular matrix (ECM) remodeling. Epidermal growth factor (EGF) plays a key role in this process, but its clinical application is limited by its rapid degradation at the wound site. Extracellular vesicles (EVs), as natural nanocarriers, can protect nucleic acids from degradation and enhance their bioavailability. In this study, using CRISPR/Cas9 technology, we site-specifically integrated the EGF gene carrying the TPA signal peptide into the AAVS1 safe harbor site of 293F cells, generating a cell line that stably secretes EVs enriched in EGF mRNA. Characterization and in vitro and in vivo functional evaluation of these engineered EVs (293F-EGF-EV) demonstrated that they significantly promoted fibroblast proliferation and migration and inhibited excessive collagen production. In a rat skin defect model, 293F-EGF-EV promoted wound recovery. High-concentration 293F-EGF-EV focused on "high-quality repair," such as promoting angiogenesis, hair follicle regeneration, and epidermal structural remodeling. Low-concentration 293F-EGF-EV favored "high-efficiency closure", such as reducing scar area. This study offers new insights into skin wound treatment.
    Keywords:  3D culture; Engineered extracellular vesicles; Monoclonal cell lines; Skin repair
    DOI:  https://doi.org/10.1002/adhm.202504092
  21. Mol Pharm. 2026 Jun 04.
    Targeting NETosis in the Lung: Respiratory Delivery of Neutrophil-Specific NEBP-Liposomes for Enhanced Therapy of Acute Lung Injury.
    Xin Liu, Yun Liu, Wuqi Guo, Xinghua Li, Yiran Han, Qiang Huo, Yang Liu, Yimin Niu.
      The activation, adhesion, and migration of neutrophils are one of the main reasons for the progression of acute lung injury (ALI) and a new therapeutic target for ALI. Although respiratory administration for ALI has the characteristics of targeted drug delivery, some issues, such as the drug's short residence time in the lungs, rapid clearance rate, and lack of specificity for neutrophils, make it difficult to maintain an effective drug concentration. Here, we designed and evaluated a neutrophil-targeting peptide NEBP-modified andrographolide liposome (N-Lip@A) that can be administered via the respiratory tract to inhibit the formation of neutrophil extracellular traps, aiming to provide a rapid, efficient, and precise intervention strategy for ALI. N-Lip@A liposomes were synthesized by the traditional thin-film hydration method. Cell immunofluorescence and scanning electron microscopy observations indicated that N-Lip@A could reduce the formation of neutrophil extracellular traps (NETs). Quantitative analysis using the PicoGreen assay showed that the release of double-stranded DNA (dsDNA) in the N-Lip@A group was reduced to 57.9% compared with the untreated PMA group, and its effect was superior to that of the nontargeted liposome formulation (Lip@A). SYTOX staining, CCK8 assay, and Calcein-AM/PI staining results demonstrated that N-Lip@A could reduce the death of PMA-stimulated neutrophils. Besides, compared with the untreated group, the supernatant from neutrophils pretreated with N-Lip@A increased the survival rate of alveolar epithelial MLE-12 cells. In a lipopolysaccharide-induced murine model of ALI, compared with the nontargeted Lip@A group or the untreated group, the pathological lung injury score decreased to 52.6% and 31.6%, respectively. Significant disease remission, including reduced pulmonary edema, restored integrity of the blood-air barrier, and improved alveolar architecture were also demonstrated through EB staining analysis, lung wet-to-dry weight ratio determination, and HE staining analysis. Collectively, N-Lip@A enables precise delivery of AGL to activated neutrophils via NEBP-mediated targeting, effectively inhibiting NETs formation and mitigating ALI-associated pathological damage. This strategy provides an expandable targeted drug delivery platform for the treatment of various acute or chronic pulmonary inflammatory diseases driven mainly by neutrophils.
    Keywords:  acute lung injury; andrographolide; drug delivery system; neutrophil extracellular traps; targeted liposomes
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.6c00094
  22. Mol Ther. 2026 Jun 01. pii: S1525-0016(26)00468-5. [Epub ahead of print]
    A design-optimized engineered bacterium for enhanced efficacy and safety in treating tyrosinemia type 1: a multi-species preclinical study.
    Peng Gu, Yunfei Zhao, Jiajia Hu, Yuguang Tian, Lingyan Zhao, Jingjing Ren, Qin Yang, Jiaxin Li, Wenhao He, Jiayin Guo, Peng Chen.
      Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with nitisinone (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including FAH-/- mice, FAH-/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH-/- mice, including neonatal death, acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH-/- rabbit model. Moreover, e-EcN-HT administration led to the rapid metabolism of orally administered 13C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well-tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.05.024
  23. ACS Nano. 2026 Jun 06.
    Nanoassemblies Remodeling Tumor-Derived Exosomes' Immunity Ameliorate Local and Peripheral Immunosuppression for Cancer Immunotherapy.
    Laozhi Xie, Fenfen Ma, Chengjie Qiu, Shiqiang Tong, Jianing Gong, Xiaoying Xie, Lechen Li, Jun Chen, Yukun Huang, Sijian Pan.
      Current immunotherapies primarily focus on intratumoral immune suppression, with limited consideration of peripheral immune exhaustion, resulting in suboptimal clinical outcomes. Tumor-derived exosomes (TEXs) play a crucial role in both intratumoral immune suppression and peripheral immune exhaustion, making them an attractive target for cancer immunotherapy. In this study, we developed an optimized TEXs modulation strategy to enhance cancer immunotherapy by reprogramming the immune-promoting phenotype of TEXs and boosting their secretion. We designed a TEXs-tuning nanoassembly (TEXT) coloaded with biguanides and photosensitizers. The nanoassembly leverages hyaluronic acid for targeted accumulation at tumor sites. Biguanides inhibit the AMPK/Yap pathway in tumor cells, thereby reprogramming the tumor metabolic landscape and remodeling TEXs to an immune-promoting phenotype. Photodynamic therapy (PDT) is employed to boost the release of immune-promoting TEXs. Through the reprogramming of TEXs' phenotype and enhancement of their release, TEXT effectively alleviates immune exhaustion in peripheral tissues and reverses intratumoral immune suppression. TEXT effectively overcame both local and peripheral immunosuppression and demonstrated robust inhibition of primary and metastatic tumors as a monotherapy. Our findings highlight TEXT as an effective TEXs modulator, showcasing exosome regulation as a highly efficient and low-toxicity approach to combat cancer immune evasion. Overall, this strategy achieves a functional shift of TEXs from immunosuppressive factors to therapeutic synergists, establishing a paradigm of proactive immune modulation in cancer immunotherapy.
    Keywords:  cancer immunotherapy; nano assembly; photodynamic therapy; systemic immune activation; tumor-derived exosomes
    DOI:  https://doi.org/10.1021/acsnano.6c03357
  24. Front Immunol. 2026 ;17 1813730
    Advanced strategies to enhance the safety, persistence, and efficacy of CAR-T cells in solid tumors.
    Iqra Ajmal, Bingtan Du, Na Huang, Qianying Huang, Dan Jiang, Muhammad Asad Farooq, Guangxian Xu.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic cancers but encounters challenges, including severe treatment-related toxicities, a highly suppressive tumor microenvironment (TME), limited long-term persistence, and poor trafficking/infiltration into solid tumors. This review outlines recent genetic engineering strategies to address these issues and enhance the safety, durability, and efficacy of CAR-T cell therapy. To reduce cytokine release syndrome and neurotoxicity, methods such as affinity-tuned and humanized scFvs, hinge/TM optimization, and ITAM calibration have been developed, along with programmable "switch-off" and "switch-on" systems that include suicide genes, antibody-bridging switches, and optogenetic or hypoxia-gated circuits. TME remodeling strategies utilize nanomaterials for targeted cytokine delivery, cell-surface "backpack" systems, and engineered oncolytic viruses that release cytokines or checkpoint-blocking agents. For durability and resistance to exhaustion, precise genome engineering techniques, including CRISPR-based editing and multiplexed shRNA platforms, were employed to target inhibitory receptors and exhaustion-driving transcriptional programs. Additionally, chemokine-receptor engineering and local biomaterial-based delivery systems are discussed as ways to enhance CAR-T trafficking and intratumoral persistence. These innovations collectively point toward integrated, patient-specific CAR-T platforms that incorporate safety controls, metabolic and transcriptional flexibility, and enhanced trafficking through the TME to broaden clinical use.
    Keywords:  CAR-T cell therapy; chemokine trafficking; chimeric antigen receptor-T cells; cytokine release syndrome; genome engineering; immune checkpoint regulation; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1813730
  25. Res Sq. 2026 May 27. pii: rs.3.rs-9573067. [Epub ahead of print]
    Postpartum Plasma-Derived Exosomes Confer Mitochondrial Stabilization and Neuroprotection against Ischemic Stroke.
    Xiaoyun Sun, Lijun Xu, Majesty Greer, Elijah McMillan, Oiva Arvola, Pervez Sultan, Kazuo Ando, Jiong-Jin Min, Vishal Chavda, Julian Wolf, Vinit Mahajan, Brendan Carvalho, Creed M Stary.
      Background The molecular mechanisms governing adaptive neuroprotection during the postpartum period remain unknown. We hypothesized that circulating exosomes contain bioactive cargo (such as Hsp20) that confer neuroprotection against ischemic injury during the postpartum period. Methods Exosomes were isolated from plasma of postpartum female mice (ppExos) and control female mice, and from serial blood samples obtained from healthy human volunteers during pregnancy (3rd trimester) and again on postpartum day 2. Exosomal size and protein markers were confirmed via nanoparticle tracking analysis and Western blotting. Neuroprotection with exosome treatment was assessed in vitro using mouse neuronal and astrocyte cultures and human retinal pigment cell line subjected to simulated ischemia. I n vivo neuroprotection was assessed using transient middle cerebral artery occlusion (MCAO) in young adult and aged mice. Mitochondrial integrity and reactive oxygen species (ROS) production were evaluated by live cell imaging. In vivo neuroprotection was evaluated by assessing infarct volume and neurobehavioral scores. Changes in mitochondrial dynamics were measured by immunofluorescence and Western blot. Human exosomes were sent for proteomic assessment (SomaScan™) followed by differential expression analysis (R software v4). Protein quantification was validated by immunoblot. Results ppExos significantly reduced infarct volumes and improved neurological deficits post-MCAO in both young and aged female mice. In vitro , ppExos reduced ROS generation in all cell types after simulated ischemia and reduced mitochondrial fragmentation in astrocytes. Mitochondrial fusion proteins Mfn2 and Opa1 proteins were elevated in maternal postpartum brains, and preserved in both astrocyte and neuronal cell cultures after in vitro ischemia with ppExo treatment. Proteomics revealed significant upregulation of heat shock protein 20 (Hsp20) in human ppExos, while Western blot validated elevated Hsp20 in both human and mouse ppExos. Simulated ischemia significantly reduced Hsp20 in astrocyte and neuronal cultures which was reversed by treatment with ppExos. In conclusion, ppExos represent a previously unrecognized, naturally optimized neuroprotective agent that enhances mitochondrial resilience and antioxidant defenses associated with enhanced Hsp20 expression. These findings establish a novel platform for sex-informed, cell-free therapies in ischemic cerebrovascular accidents.
    DOI:  https://doi.org/10.21203/rs.3.rs-9573067/v1
  26. Int J Oral Maxillofac Surg. 2026 May 30. pii: S0901-5027(26)00173-6. [Epub ahead of print]
    Lateral Orbital Rim Advancement and Balanced Orbital Decompression for Exorbitism Regression in Crouzon Syndrome.
    W Qian, L Fang, Y Li, H Zhou.
      Crouzon syndrome is a syndromic craniosynostosis characterized by brachycephaly, midfacial hypoplasia, exorbitism, and malocclusion. Although current treatments can effectively address these deformities, they generally involve extensive staged procedures associated with prolonged treatment duration and substantial financial cost. For postpubescent and adult patients with relatively mild manifestations whose primary concern is noticeable exorbitism, less invasive options are limited. We describe a minimally invasive technique termed lateral orbital rim advancement combined with balanced orbital decompression (LORA-BOD), designed to improve exorbitism and periorbital contour. Three patients treated with this technique showed measurable reductions in globe protrusion, with no complications observed during follow-up. Mean reductions were 7.25 ± 1.97 mm on Hertel exophthalmometry, and 3.62 ± 1.65 mm or 4.29 ± 2.41 mm on computed tomography, measured as the distance from corneal apex to the interzygomatic line and orbitale, respectively. Exotropia also improved postoperatively, contributing to enhanced function and appearance. Overall, this technique demonstrates favorable efficacy in reducing exorbitism in Crouzon syndrome and may serve as a targeted adjunctive option for patients with localized periorbital concerns.
    Keywords:  Craniofacial Dysostosis; Crouzon syndrome; Decompression; Orbit; Osteotomy; Proptosis
    DOI:  https://doi.org/10.1016/j.ijom.2026.04.019
  27. Cell Death Discov. 2026 May 30.
    Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate-mediated macrophage reprogramming and protects against sepsis-triggered lung cell death.
    ZuoJun Huang, Jialin Zhong, Li Zhang, Xianggui Huang, Shanshan Liang, Youfeng Zhu, Rui Zhang, Hongzhi He, Chengcheng Xu, Wang Chen, Jing Wang, Xiaolong Wu, Yumin Liang, Jian Zou, Shuyao Zhang.
      Excessive inflammation and metabolic dysregulation fuel alveolar cell death in sepsis-induced lung injury, yet effective molecular interventions are lacking. We identify citrate lyase beta-like (CLYBL) as a previously unrecognized metabolic driver of macrophage-mediated tissue damage. In a murine cecal ligation and puncture model, CLYBL was strongly upregulated in lung tissue and peritoneal macrophages. To therapeutically target this pathway, we engineered platelet-derived extracellular vesicle-coated poly(lactic-co-glycolic acid) nanoparticles (PEVs@PLGA) encapsulating CLYBL-specific small interfering RNA. This platelet-mimetic system enabled efficient, biocompatible delivery of siRNA and robust CLYBL knockdown both in vitro and in vivo. CLYBL silencing triggered accumulation of the anti-inflammatory metabolite itaconate, limited M1 macrophage polarization, and preserved alveolar epithelial integrity, thereby reducing cell death and improving pulmonary repair. Transcriptomic analysis revealed broad immunometabolic remodeling consistent with enhanced resolution of inflammation. Biosafety evaluation confirmed negligible systemic toxicity. These findings uncover CLYBL as a critical metabolic checkpoint linking macrophage activation to alveolar cell death and highlight platelet-mimetic siRNA nanoparticles as a potent therapeutic strategy. Our work provides a mechanistic and translational framework for targeting macrophage immunometabolism to prevent fatal organ damage during sepsis.PEVs@PLGA@si-CLYBL promote itaconate accumulation, induce immune cell functional remodeling, and facilitate lung epithelial repair, offering a novel therapeutic approach for sepsis-induced lung injury (Created with BioRender.com).
    DOI:  https://doi.org/10.1038/s41420-026-03119-6
  28. Bioact Mater. 2026 Oct;64 701-715
    In vivo circRNA-engineered macrophages mediate localized MMP9 neutralization to rejuvenate aged bone.
    Daoyu Zhu, Shifeng Ling, Haoyu Fang, Qianhao Yang, Yawei Du, Wenguo Cui, Yixuan Chen.
      Aging causes osteoporosis, delayed fracture repair, and osteoarthritis, but mechanisms and therapies remain unclear. Transcriptomics of serum and bone from older patients showed marked MMP9 upregulation, highlighting systemic MMP9 neutralization as a potential immunotherapy. Here, we developed an in vivo circRNA-based antibody-engineering strategy that specifically targets macrophages, converting them into biofactories for anti-MMP9 antibodies. Central to this therapy is an apoptosis-mimicking lipid nanoparticle incorporating phosphatidylserine with an optimized formulation (aMMP9-LNP), which enhances macrophage-specific recognition and endocytosis. Leveraging inflammation-guided chemotaxis, this approach enables systemic, targeted MMP9 neutralization. In aged mice, systemic aMMP9-LNP reduced stem cell senescence, boosted osteogenesis, accelerated fracture repair, and mitigated cartilage degeneration. Mechanistically, MMP9 blockade dampened senescence-associated secretory phenotype, restored osteoblast-osteoclast balance, and lowered p21/MMP3. Biodistribution confirmed bone-targeted delivery with preserved tissue homeostasis, supporting translational potential. Collectively, our results identify MMP9 as a key effector and advance an in vivo mRNA immunotherapy for skeletal aging.
    Keywords:  Antibody biosynthesis; Degenerative bone disease; MMP-9; Macrophages; circRNA
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.030
  29. ACS Nano. 2026 Jun 05.
    Dissecting Discoidin Domain Receptor 2 Dynamics in Fibrosis with a Programmable Collagen-Mimetic Probe.
    Yinghua Liu, Xufei Wang, Xiaotong Ma, Lu Huang, Penghui Yang, Tao Li, Wenjun Wu, Daoning Zhou, Jin Su, Yang Li.
      Collagen receptors orchestrate vital extracellular matrix signaling, yet the inability to distinguish functional receptor activation from mere expression in real-time has obscured our understanding of fibrotic progression. Here, we develop a fluorescent triple-helical collagen-mimetic peptide (CMP) probe, [GVMGFO]3, designed to selectively target the ligand-engaging conformation of Discoidin Domain Receptor 2 (DDR2)─the sole receptor tyrosine kinase family that signals collagen. In pulmonary fibrosis, this probe identifies active fibrotic niches in vivo and directly tethers to disease-driving activated fibroblasts to enable precise ex vivo mapping, all without perturbing baseline signaling. Utilizing this tool, we decipher the long-standing mystery of DDR2's characteristically slow, hours-long activation kinetics. We reveal that while monomeric collagen engagement fails to override constitutive DDR2 internalization, supramolecular fibrillar collagen provides a multivalent physical anchor that arrests DDR2 trafficking at the cell-matrix interface to sustain receptor clustering and phosphorylation. To recapitulate this biophysical requirement, we engineered Zn2+-coordinated supramolecular assemblies of a histidine-modified CMP, [H-GVMGFO-H]3, triggering rapid DDR2 activation within minutes. Our work transforms CMPs from structural models of collagen into programmable chemical tools for dissecting the spatiotemporal dynamics of collagen-receptor interplay, offering a platform for imaging and modulating fibrotic disease.
    Keywords:  cell-collagen signaling; fibrillar activation; live-cell imaging; precision-cut lung slices; pulmonary fibrosis imaging; targeted cellular profiling
    DOI:  https://doi.org/10.1021/acsnano.6c04093
  30. J Adv Res. 2026 Jun 01. pii: S2090-1232(26)00443-1. [Epub ahead of print]
    Trained immunity-primed DLL3-targeted CAR macrophages for the eradication of small cell lung cancer.
    Hangjie Ying, Yazhou Wang, Na Li, Wenshuo Ma, Xin Shou, Zhiyun Liu, Changjiang Chen, Zhenzhen Dong, Hung-Wing Li, Junfeng Zhang, Ying Jin, Sergei Krasny, Liyun Shi.
       BACKGROUND: Small cell lung cancer (SCLC) is highly malignant with limited treatment options. Chimeric antigen receptor macrophages (CAR-Ms) show potential for solid tumor therapy due to their phagocytic activity, tissue penetration, and immunomodulatory functions, but their application in SCLC remains unexplored. Delta-like ligand 3 (DLL3), a SCLC-specific membrane antigen, represents a promising therapeutic target. Here, we developed a DLL3-targeted CAR-M therapy and an enhanced strategy for SCLC immunotherapy.
    METHODS: DLL3-specific CAR-Ms were generated by introducing a CAR construct (DLL3-ScFv-CD8-CD3ζ) into murine and human macrophages via lentiviral transduction. A β-glucan (BG)-based training protocol was established to enhance CAR-M functionality. Phagocytic and cytotoxic activities were evaluated by flow cytometry and bioluminescence assays, and in vivo antitumor efficacy was assessed in immunodeficient and immunocompetent mouse models.
    RESULTS: Engineered CAR-Ms exhibited potent phagocytic and cytotoxic activity against DLL3-positive cells and effectively infiltrated and eliminated tumor spheroids in 3D culture systems. Intravenously administered CAR-Ms suppressed DLL3-positive lung cancer growth in both immunodeficient and immunocompetent models without discernible toxicity. Importantly, BG training enhanced CAR-M functionality by conferring sustained anti-tumor immunity, amplifying inflammatory and interferon pathway activation, and remodeling the tumor microenvironment through epigenetic and metabolic reprogramming. These findings establish BG-trained, DLL3-targeting CAR-Ms as a promising therapeutic approach for SCLC.
    CONCLUSION: Anti-DLL3 CAR-Ms demonstrate significant potential for solid tumor treatment and may offer a viable clinical strategy for SCLC in the future.
    Keywords:  Chimeric antigen receptor; Delta-like protein 3; Macrophage; Small cell lung cancer; Trained immunity
    DOI:  https://doi.org/10.1016/j.jare.2026.05.047
  31. Tissue Cell. 2026 May 29. pii: S0040-8166(26)00335-6. [Epub ahead of print]103 103642
    Protective effects of human umbilical cord-derived exosomes on testicular ischemia-reperfusion injury: Comparison of local versus systemic administration.
    Funda Elumar, Elif Ünlü, Kamuran Çelik, Özlem Özmen, İbrahim Halil Yıldırım, Ali Erol.
      Testicular torsion (TT) is a urological emergency characterized by twisting of the spermatic cord, resulting in ischemia and rapid testicular damage. This study aimed to evaluate the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cell exosomes (hUC-MSC-Exos) administered via local and systemic routes in a rat model of TT-induced ischemia-reperfusion (IR) injury. Twenty-one male rats subjected to right testicular torsion (720° counterclockwise rotation) for 90 min, followed by surgical detorsion. Animals were randomly divided into three groups (n = 7 each): Group I (control) received 0.5 mL intraperitoneal saline; Group II received 0.2 mL exosomes (2 × 10⁸ particles) via intratesticular injection; and Group III received 0.5 mL exosomes (5 × 10⁸ particles) intraperitoneally. Histopathological evaluation, immunohistochemical analysis of caspase-3, endothelial nitric oxide synthase (eNOS), and tumor necrosis factor-alpha (TNF-α), as well as measurements of serum testosterone and C-reactive protein levels were performed. TT resulted in significant histopathological alterations, including seminiferous tubular degeneration, necrosis, and inflammatory cell infiltration, accompanied by increased expression of caspase-3, eNOS, and TNF-α (p < 0.001). Both local and systemic exosome treatments were associated with attenuation attenuation of these changes (p < 0.001). Intratesticular administration showed greater preservation of seminiferous tubule architecture, lower immunohistochemical expression of the evaluated markers, and improved spermatogenic activity compared with systemic administration (p < 0.001). No significant differences were observed in serum testosterone or C-reactive protein levels among the groups (p > 0.05), suggesting limited sensitivity of these systemic markers in acute testicular IR injury. Overall, hUC-MSC-Exos were associated with improved histopathological and immunohistochemical outcomes at the tissue level, with intratesticular administration showing a greater effect. However, given that the present study is based on histopathological and immunohistochemical analyses, no definitive conclusions can be drawn regarding the underlying molecular mechanisms. Further studies incorporating detailed molecular and functional analyses are required to clarify these effects.
    Keywords:  Apoptosis; Exosome; Ischemia-reperfusion; Rat model; Spermatogenesis; Testicular Torsion
    DOI:  https://doi.org/10.1016/j.tice.2026.103642
  32. Bone Joint Res. 2026 Jun 03. 15(6): 632-646
    FGF9 attenuates osteoarthritis progression through the NRF2/GPX3 antioxidant axis.
    Yuan-Shun Lo, Tsung-Ming Chen, Teng-Le Huang, Yu-Chia Liu, Chu-Han Chang, Chia-Yang Chen, Hung-Lun Hsieh, Chun-Hao Tsai, Yi-Xue Yeow, Chia-Jou Wang, Ya-Huey Chen.
       Aims: Osteoarthritis (OA), a prevalent age-related joint disease affecting over 250 million people globally, currently lacks effective disease-modifying treatments. Fibroblast growth factor 9 (FGF9) has shown cartilage-protective effects in post-traumatic OA models, but its role in chondrocyte degeneration and OA pathogenesis remains unclear. This study investigates FGF9's function in human and murine chondrocytes and its therapeutic potential for OA.
    Methods: Gene expression profiling was performed on primary chondrocytes from OA patients and normal controls. Senescence and reactive oxygen species (ROS) levels were assessed by β-galactosidase staining and flow cytometry. FGF9 function was evaluated through short hairpin RNA (shRNA)-mediated knockdown and treatment with FGF9-conditioned media (CM). The impact of FGF9-enriched exosomes on chondrocyte senescence was also examined in vitro. In vivo effects were tested using adenovirus-delivered FGF9 in a destabilization of the medial meniscus (DMM)-induced OA mouse model.
    Results: FGF9 expression was significantly downregulated in OA chondrocytes (n = 195) compared to normal (n = 71). FGF9 knockdown elevated ROS levels and senescence via suppression of the NRF2/GPX3 antioxidant axis, while FGF9 promoted chondrogenesis in mesenchymal stem cells. Intra-articular FGF9 gene therapy reduced OA progression in DMM mice. Additionally, FGF9-enriched exosomes reduced senescence in primary chondrocytes in vitro.
    Conclusion: FGF9 alleviates OA progression by activating the NRF2/GPX3 pathway, reducing ROS and chondrocyte senescence. These findings support the therapeutic potential of FGF9 and FGF9-enriched exosomes in OA treatment.
    DOI:  https://doi.org/10.1302/2046-3758.156.BJR-2025-0365.R1
  33. Expert Opin Drug Deliv. 2026 Jun 05. 1-31
    Biomarker-driven and AI-assisted nanomedicine for breast cancer: advancing precision drug delivery from bench to bedside.
    Jaleh Barar, Rais Ansari, Yadollah Omidi.
       INTRODUCTION: Breast cancer remains the most prevalent malignancy among women worldwide, with its pronounced molecular heterogeneity demanding therapeutic strategies that transcend conventional systemic chemotherapy toward tumor-selective, molecularly precise interventions. The convergence of biomarker science, engineered nanomedicine, and artificial intelligence (AI) offers a transformative framework for realizing this goal.
    AREAS COVERED: This review examines how molecular biomarkers (e.g. mucin glycoproteins, human epidermal growth factor receptor 2 (HER2), circulating tumor cells, and circulating tumor DNA) serve dual roles as diagnostic identifiers and active targeting ligands directing engineered nanocarriers. We critically evaluate biomarker-guided nanoplatforms (liposomal, polymeric, metallic, and protein-based architectures), stimuli-responsive drug release strategies, and AI-driven microfluidic manufacturing for scalable, good manufacturing practice-compliant nanoparticle production. Literature was retrieved from PubMed/MEDLINE, Scopus, and Web of Science (2000-2026), supplemented by ClinicalTrials.gov data.
    EXPERT OPINION: Near-term clinical impact is most realistically achieved through AI-assisted biomarker interpretation and multi-analyte liquid biopsy integration rather than novel nanoformulations, whose translational attrition remains high. Bridging the bench-to-bedside gap requires prospective biomarker-stratified clinical trials, co-developed companion diagnostics, and federated AI architectures as advances that will progressively replace static histological subtype classification with a continuously updated, molecularly individualized treatment paradigm for breast cancer.
    Keywords:  Artificial intelligence; biomarkers; breast cancer; drug delivery; nanomedicine; precision medicine; targeted therapy; theranostics
    DOI:  https://doi.org/10.1080/17425247.2026.2680061
  34. J Nanobiotechnology. 2026 Jun 02.
    Targeting taurine metabolism via PROTAC-mediated SLC6A6 degradation potentiates photodynamic therapy and reverses immunosuppression in cholangiocarcinoma.
    Jingjin Zhu, Tianhao Zou, Weimin Wang, Jianjun Xu, Xuan Li, Lei Liu, Bohan Yang, Zifang Song, Yang Gao.
       BACKGROUND: Photodynamic therapy (PDT) is a promising treatment for cholangiocarcinoma (CCA), but its efficacy is limited by robust tumor antioxidant defenses and immunosuppressive microenvironment. Disrupting the expression of SLC6A6, a taurine transporter critical for redox homeostasis, represents a promising strategy for sensitizing CCA cells to PDT by disrupting taurine-mediated antioxidant protection.
    METHODS: A first-in-class antibody-based PROTAC (AbTAC) specifically targeting SLC6A6 degradation was developed, followed by the engineering of biomimetic, ROS-responsive nanoparticles cloaked with CCA cell membranes (CM-TAC@Ce@PEG) for tumor-targeted co-delivery of the AbTAC and the photosensitizer chlorin e6 (Ce6). Comprehensive nanoparticle characterization covered size, drug loading, spectral properties, ROS production, and drug release kinetics. And the CM-TAC@Ce@PEG was evaluated for targeted fluorescence imaging and therapeutic efficacy in vitro and in vivo, with further investigation of its synergy with anti-PD-1 immunotherapy.
    RESULTS: Preclinical studies demonstrated that light-induced ROS triggers nanoparticle depolymerization. SLC6A6 degradation depletes taurine in tumor cells, disrupting antioxidant defenses and inducing ferroptosis. Crucially, CM-TAC@Ce@PEG simultaneously induces tumor cells to secrete colony-stimulating factor 2 (CSF2), driving M1 macrophage polarization and restoring CD8⁺ T cell cytotoxicity. This dual action powerfully activates innate and adaptive immunity, significantly inhibiting CCA growth. Furthermore, as a combination therapy with anti-PD-1 immunotherapy, CM-TAC@Ce@PEG markedly enhances therapeutic efficacy and effectively prevents tumor recurrence.
    CONCLUSION: This work unveils an integrated strategy that integrating PDT with metabolic reprogramming and immune activation. Targeting SLC6A6-mediated redox dysregulation not only overcomes PDT resistance but also synergizes with immune checkpoint blockade, establishing a promising therapeutic strategy for CCA.
    Keywords:  Cholangiocarcinoma; Ferroptosis; Nanoparticles; PROTACs; Photodynamic therapy; Solute carrier
    DOI:  https://doi.org/10.1186/s12951-026-04592-y
  35. Bioact Mater. 2026 Oct;64 716-730
    Bioelectric signals promote diabetic bone regeneration through Piezo1-mediated activation of the efferocytic immune microenvironment.
    Dilixiati Duolikun, Lei Zhang, Tianlong Wang, Xinhui Wu, Xuran Guo, Waheed Muhammad Zeeshan, Zhiqing Liu, Haijun Zhang, Jinhui Zhao, Longpo Zheng.
      Defective macrophage efferocytosis sustains inflammation and compromises bone repair in diabetic defects, yet strategies that restore efferocytic immune homeostasis remain limited. Here, we engineered an ultrasound-responsive piezoelectric hydrogel (Gel BC@ZnO) by incorporating zinc oxide (ZnO) nanoparticles into a bacterial cellulose (BC)-reinforced gelatin methacryloyl (GelMA) network to provide localized bioelectric cues. Gel BC@ZnO exhibited good cytocompatibility, structural stability, and robust ultrasound-triggered piezoelectric output. Under diabetic-mimicking conditions, ultrasound activation generated bioelectric signals that engaged Piezo1, induced Piezo1-dependent Ca2+ influx, and rescued macrophage efferocytosis. This efferocytic reactivation attenuated ROS accumulation, shifted macrophages toward a pro-regenerative phenotype, enhanced osteogenic differentiation, and suppressed osteoclast genesis, thereby restoring bone-remodeling homeostasis. In a diabetic femoral condyle defect model, Gel BC@ZnO combined with ultrasound accelerated bone repair, increased local Piezo1 expression, promoted collagen deposition and osteogenic marker expression, and rebuilt a favorable immune microenvironment. These results define a bioelectric signal-Piezo1-Ca2+-efferocytosis axis for diabetic bone regeneration and establish a non-invasive, ultrasound-controllable immunomodulatory strategy for compromised bone repair.
    Keywords:  Diabetic bone regeneration; Efferocytic immune microenvironment; Macrophage; Piezo1; Piezoelectric hydrogel
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.037
  36. Forensic Sci Int Genet. 2026 Jun 02. pii: S1872-4973(26)00130-4. [Epub ahead of print]86 103549
    Transferring a microhaplotype-specific probabilistic genotyping model from targeted amplification to hybridization capture: A proof-of-concept study of a 100-locus panel for DNA mixtures.
    Chun Yang, Yueyan Cao, Yuting Wang, Yuhan Hu, Tingyun Hou, Haoyu Wang, Tiantian Shan, Qiang Zhu, Ji Zhang.
      Probabilistic genotyping (PG) has become the standard framework for evaluating forensic DNA mixtures, yet most implementations were developed for STR data and PCR-based enrichment. Microhaplotypes (MHs) provide high allele diversity without stutter and are attractive for mixture deconvolution, particularly when combined with hybridization capture for degraded or limited DNA. Here, we developed a 100-locus hybridization capture MH panel and assessed its performance for mixture interpretation using two continuous PG models: (i) a MH-specific Truncated Gaussian (TG) model previously developed by our group for targeted amplification MH-MPS data, and (ii) the gamma-based model implemented in EuroForMix (EFM). Panel performance was first examined using sensitivity (0.5, 0.125, and 0.0625 ng; triplicates) and repeatability/consistency (10 individuals, 0.5 ng; duplicates) experiments. We then analyzed two- and three-person mixtures with increasing mixture imbalance (2-person: 1:1-1:40; 3-person: 1:1.5:3-1:4:20; triplicates). Across all mixtures, true contributors yielded likelihood ratios (LRs) > 1 under both models, with all tested non-contributors yielding LRs < 1. For two-person mixtures, major-contributor deconvolution accuracy approached 100%, whereas minor-contributor accuracy peaked at 83% (1:5) and declined with increasingly imbalanced mixtures. In three-person mixtures, minor-contributor accuracy depended strongly on relative proportions among contributors and showed non-monotonic trends. Overall, the TG model produced higher LRs and improved deconvolution for minor contributors compared with EFM, supporting transferability of the TG framework from targeted amplification to hybridization capture MH-MPS data. These results provide a preliminary practical foundation for probabilistic interpretation of hybridization capture microhaplotypes in forensic mixtures.
    Keywords:  DNA mixtures; Hybridization capture; Massively parallel sequencing; Microhaplotypes; Probabilistic genotyping
    DOI:  https://doi.org/10.1016/j.fsigen.2026.103549
  37. Nanomedicine. 2026 Jun 02. pii: S1549-9634(26)00068-7. [Epub ahead of print]75 102967
    Chemo-physical loading of exosomes on porous titanium for improved soft tissue integration.
    Dan Zou, Fanfan Dai, Xue Zhou, Ping Yang, Lang Jiang, Li Li.
      Establishing a durable soft tissue seal around dental implants is critical for preventing peri-implantitis, yet efficient loading of exosomes onto titanium surfaces remains challenging. Here, a dual-functional coating was developed on anodized porous titanium combining stem cell-derived exosomes with cefotaxime sodium via a chemo-physical loading strategy. Porous titanium surfaces exhibited 27% of pores equal/larger than 150 nm at 150 V along with enhanced hydrophilicity. Exosomes loaded via chemo-physical approach achieved the highest loading (30.8 μg/cm2), 2.6-fold higher than chemical grafting alone, while preserving bioactivity. In vitro, porous titanium and exosome-modified surfaces promoted epithelial cell adhesion and induced spindle-shaped fibroblast morphology. In vivo subcutaneous implantation demonstrated good biocompatibility across all groups, as evidenced by absence of necrosis or abscess, and comparable fibrous capsule thickness (~150 μm). No adverse tissue reactions were observed for any of the tested surfaces. These findings demonstrate that chemo-physical loading on optimized porous titanium enables stable, high-capacity exosome immobilization. The resulting dual-functional coating simultaneously promotes soft tissue cell responses and provides antibacterial protection, offering a promising strategy for supporting the tissue healing around dental implants.
    Keywords:  Biotin-avidin-system; Dental implant; Exosome; Porous structure; Soft tissue seal
    DOI:  https://doi.org/10.1016/j.nano.2026.102967
  38. Curr Stem Cell Res Ther. 2026 May 20.
    Mesenchymal Stem Cell-Derived Exosomes: A Novel Frontier in Regenerative Medicine and Immunotherapy.
    Sami G Almalki.
      Mesenchymal stem cells (MSCs) are a heterogeneous cell population that can be isolated from various tissues, including adipose tissue and bone marrow. Their ease of isolation and robust ex vivo expansion make MSCs an attractive candidate for regenerative and therapeutic applications, particularly in tissue repair and angiogenesis. Increasing evidence indicates that the therapeutic effects of MSCs are largely mediated through the secretion of extracellular vesicles, especially mesenchymal stem cell-derived exosomes (MSC-Exos). These exosomes contain diverse bioactive molecules, including proteins, nucleic acids, and lipids, which contribute to their regenerative, immunomodulatory, and therapeutic potential. Preclinical studies have demonstrated that MSC-Exos promote tissue repair, regulate immune responses, and alleviate pathological conditions associated with cardiovascular diseases, neurological disorders, musculoskeletal injuries, and immune-mediated diseases. The outcomes of these studies suggest that MSC-Exos represent a promising and effective therapeutic modality for a broad range of diseases. Compared with conventional MSC-based therapies, MSCExos offer several advantages, including reduced immunogenicity, lower tumorigenic risk, improved stability, and easier storage and handling, making them particularly suitable for clinical translation. This review provides a comprehensive overview of the current clinical and translational landscape of MSC-Exos therapy, highlighting their therapeutic applications, underlying mechanisms, and key challenges that must be addressed to facilitate successful clinical implementation. Collectively, the emerging evidence underscores the potential of MSC-Exos to advance regenerative medicine and suggests that exosome-based therapies may represent a transformative approach for the treatment of diverse human diseases.
    Keywords:  Exosomes; MSCExos therapy.; Mesenchymal stem cells; clinical application; immune system; surface markers; therapeutics
    DOI:  https://doi.org/10.2174/011574888X442232260516190904
  39. Cancer Treat Res Commun. 2026 May 23. pii: S2468-2942(26)00168-1. [Epub ahead of print]48 101257
    Immunotoxin therapy: a promising frontier in targeted cancer treatment a review of clinical trials in hematological and solid tumors.
    Arash Abdi, Hamid Sedighian, Zoleikha Goleij, Mahdi Fasihi-Ramandi, Reza Kachuei, Abbas Ali Imani Fooladi.
       BACKGROUND AND OBJECTIVE: Background and objective: Cancer is a leading cause of death worldwide, creating a major socioeconomic burden. Despite advances in conventional therapies, mortality remains high, highlighting the need for more effective, targeted treatments. This review critically examines immunotoxin therapy as a promising approach, focusing on its evolution from experimental agents to clinical development, including design, mechanisms of action, and therapeutic potential.
    METHODS: We conducted a structured review of immunotoxins currently under clinical investigation for both hematological and solid malignancies. The analysis compares different immunotoxin constructs, their targeted antigens, and outcomes from recent and ongoing clinical trials.
    RESULTS: Immunotoxins, engineered by fusing a targeting moiety (e.g., an antibody fragment) with a potent protein toxin, have shown significant efficacy, particularly in hematological tumors. The review details key immunotoxins in the clinical pipeline, discussing their successes, such as high response rates in certain leukemias and lymphomas, as well as the critical challenges they face. These challenges include immunogenicity, off-target toxicity, and the development of drug resistance, which have limited their efficacy in solid tumors.
    CONCLUSION: Immunotoxins represent a powerful class of targeted anticancer agents. While obstacles remain, ongoing innovations in protein engineering to reduce immunogenicity and improve tumor penetration are poised to enhance their clinical utility. With continued advancement, immunotoxins are expected to play an increasingly vital role in the future of precision cancer therapy.
    Keywords:  Antibody-drug conjugates; Bacterial toxins; Cancer therapy; Clinical trials; FDA-approved therapies; Immunotoxins; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101257
  40. J Drugs Dermatol. 2026 Jun 01. 25(6): 558-561
    A Novel Retinoid and Salicylic Acid Topical Treatment for Moderate-Severe Acne.
    Sidney B Hornby, Yen H Ly, Zaidal A Obagi, Zein E Obagi, Connie C Stahl, Frederick W Woodin.
       BACKGROUND: Advances in biotechnology have enabled highly effective, site-specific topical therapies for skin disease. Particle-based delivery systems can be engineered with tailored physicochemical properties and surface modifications to optimize controlled drug release and skin targeting, potentially improving acne treatment outcomes.
    OBJECTIVE: To evaluate the effectiveness and tolerability of a retinol plus site-specific salicylic acid-targeted bio-delivery system in 40 Fitzpatrick skin type I-VI patients with moderate-to-severe acne over 12 weeks.
    RESULTS: Significant improvements were observed across multiple efficacy measures, including expert grading, microbiome analysis, visual imaging, and patient self-assessments. Investigator grading demonstrated a 27.8% reduction in inflamed pustules at 2 weeks and a 68.6% reduction at 12 weeks. Acne nodules improved by 61.1% at 2 weeks, with a 92.2% reduction by week 12. Post-inflammatory hyperpigmentation improved significantly beginning at week 2, with an overall 32.3% improvement at week 12. Microbiome analysis showed a 52% reduction in Cutibacterium acnes levels by week 12. Expert grading revealed no erythema by week 12 and no edema throughout the study period. Patients also reported no significant itching, burning, tingling, or stinging sensations during treatment.
    CONCLUSION: Combination therapy with site-specific acne medication and retinol produced significant clinical improvement in acne and post-inflammatory hyperpigmentation while demonstrating excellent tolerability over 12 weeks. &nbsp.
    DOI:  https://doi.org/10.36849/JDD.9390
  41. ACS Nano. 2026 Jun 05.
    Tailored Biomaterials Induce Tertiary Lymphoid Structures for Boosting Cancer Immunotherapy.
    Xiao-He Wang, Ze-Yu Huang, Zhi-Jun Sun, Shu-Jin Li.
      A central obstacle in cancer immunotherapy is the "cold" tumor, characterized by limited immune infiltration, which renders it largely unresponsive to treatment. Tertiary lymphoid structures (TLS), functioning as ectopic immune niches, can convert these cold tumors into "hot" ones by supporting antigen presentation, lymphocyte activation, and coordinated immune responses. Therefore, strategies to induce TLS formation hold significant therapeutic promise. Recent studies have explored a range of biomaterial systems designed to orchestrate the formation of TLS within the tumor microenvironment. This encompasses synthetic biomaterial platforms (nanocarriers, stimulus-responsive hydrogels, programmable 3D scaffolds, and mesoporous materials), natural and bioderived systems (organoids and exosomes), as well as emerging bioactive entities (engineered immune cells, oncolytic viruses, and bacteria). This review outlines the cellular composition, maturation process, and immunological functions of TLS, highlights diverse biomaterial platforms facilitating TLS formation, and summarizes translational challenges, including biosafety, standardization, and scalability. Inducible TLS (iTLS) provide a potent means to remodel the tumor immune microenvironment, offering exciting opportunities for advanced cancer immunotherapy.
    Keywords:  TLS maturation; artificial tertiary lymphoid structures; biomaterials; cancer immunotherapy; immune checkpoint blockade; immune microenvironment modulation; spatiotemporal delivery; tertiary lymphoid structures
    DOI:  https://doi.org/10.1021/acsnano.6c05908
  42. J Biosci Bioeng. 2026 Jun 03. pii: S1389-1723(26)00191-X. [Epub ahead of print]
    Selective rewiring of Met4 ubiquitin regulation enhances S-adenosylmethionine accumulation in sake yeast.
    Shogo Kakoi, Akira Nishimura, Hiroyuki Senjyu, Takuya Asai, Takahiro Akashi.
      S-Adenosylmethionine (SAM) is a central sulfur-containing metabolite that serves as a universal methyl-group donor and a high-value molecule for food and pharmaceutical applications. In Saccharomyces cerevisiae, sulfate assimilation into methionine and SAM is coordinately governed by the transcription factor Met4, whose activity is controlled by Met30-dependent ubiquitination. This feedback represses sulfur-metabolic gene expression under methionine-replete conditions and limits metabolic input into the methionine-SAM branch. While metabolic engineering has often targeted individual enzymatic steps to enhance SAM accumulation, direct tuning of this transcriptional hub remains underexplored. Here, we engineered a sake yeast strain expressing a Met4 K163RΔInh variant combining a Lys163-to-Arg substitution with deletion of the Met30-interacting inhibitory region. The engineered Met4 remained predominantly nuclear during methionine supplementation and maintained elevated expression of sulfur-assimilation genes under methionine-replete conditions. Metabolite profiling under methionine supplementation revealed increased abundance of methionine/SAM-cycle-related metabolites relative to the control strain, consistent with enhanced output into the methionine/SAM-linked branch. Even in nutrient-rich medium, the Met4 K163RΔInh strain expanded the intracellular SAM pool compared with the parental strain. Together, selective rewiring of Met4 ubiquitin control provides a transcription-factor-centric route to construct SAM-accumulating sake yeast strains and complements enzyme-level pathway engineering for sulfur-derived metabolite production.
    Keywords:  S-Adenosylmethionine; Sake yeast; Sulfur metabolism; Transcription factor engineering; Yeast metabolic engineering
    DOI:  https://doi.org/10.1016/j.jbiosc.2026.05.003
  43. Int Immunopharmacol. 2026 Jun 01. pii: S1567-5769(26)00757-5. [Epub ahead of print]184 116911
    YBX1 takes actions on triggering M2-like polarization of macrophages and stabilizing CXCL8 mRNA to exhibit its metastatic potential in bladder cancer.
    Huihui Yang, Chuanchi Zhou, Zheng Zhou, Fan Zhang, Liang Tong.
       BACKGROUND: Patients diagnosed with bladder cancer (BCa) with lymph node (LN) metastasis face a grim prognosis with limited treatment options. We examined the relationship between Y-box binding protein 1 (YBX1) and tumor-associated macrophages (TAMs) concerning LN metastasis in BCa.
    METHODS: Popliteal lymphatic metastasis model was constructed in Balb/c mice. Histological examinations were conducted using hematoxylin and eosin (HE) and Immunohistochemical staining. Flow cytometry detected M1/M2 polarization markers. Immunofluorescence staining tested distribution of interleukin enhancer binding factor 3 (ILF3) and YBX1 and macrophage markers. Transwell and tube formation assays assessed migration and angiogenesis. Enzyme-linked immunosorbent assay (ELISA) measured C-X-C motif chemokine ligand 8 (CXCL8), transforming growth factor beta (TGF-β), vascular endothelial growth factor A (VEGFA) and macrophage markers. Levels of mRNA and protein were measured by RT-qPCR and Western blot. Subcellular localization of ILF3 and CXCL8 was detected utilizing fluorescence in situ hybridization (FISH) assay. Exosomes derived from BCa cells were isolated and identified. RNA immunoprecipitation (RIP) and Co-immunoprecipitation (Co-IP) validated molecular interactions.
    RESULTS: Knockdown of YBX1 in BCa cells suppressed lymphangiogenesis in vitro and in vivo and reduced M2 macrophage polarization. CXCL8 levels, elevated in BCa patients, were positively correlated with YBX1 and M2 macrophage infiltration, and this elevation was reduced upon YBX1 knockdown. BCa cell-derived exosomes containing YBX1 were internalized by macrophages, where they were crucial for inducing M2-like polarization and promoting CXCL8 expression, ultimately stimulating angiogenesis and lymphangiogenesis. Mechanistically, YBX1 interacted with ILF3 to stabilize CXCL8 mRNA.
    CONCLUSION: By inducing macrophage M2-like polarization, YBX1 promoted lymphangiogenesis and lymphatic metastasis in BCa, which may provide novel clinical markers for LN metastatic BCa.
    Keywords:  Bladder cancer; CXCL8; Exosome; ILF3; Lymphangiogenesis; M2-like polarization of macrophages; YBX1
    DOI:  https://doi.org/10.1016/j.intimp.2026.116911
  44. Ultrasonography. 2026 May;45(3): 195-204
    Focused ultrasound as a therapeutic adjunct in pancreatic cancer: from thermal and mechanical effects to immune modulation.
    Jae Young Lee, Cyril Lafon, Petros Mouratidis, Timothy Bullock, Joan Vidal-Jove, Jessica Gannon, Eli Vlaisavljevich, Holger Grüll, Tim Meakem, Chrit Moonen.
      Pancreatic cancer remains highly lethal, with only limited improvements achieved with surgery, chemotherapy, radiotherapy, or immunotherapy. Focused ultrasound (FUS) offers complementary, noninvasive therapeutic modalities-including thermal ablation, non-ablative mechanical stimulation, and histotripsy-that can debulk tumors, palliate pain, enhance drug delivery through modulation of the dense stromal environment, and stimulate antitumor immunity. Extracorporeal high-intensity focused ultrasound is clinically feasible, while endoscopic and intraoperative approaches aim to overcome anatomical constraints. Preclinical studies demonstrate cavitation-mediated increases in tissue permeability and immune activation, and early clinical trials combining FUS with chemotherapy have reported encouraging signals in response rates and survival outcomes. Ongoing investigations are evaluating synergistic effects with immunotherapies and targeted drug delivery strategies. Key challenges-including the deep anatomical location of the pancreas, its fibrotic microenvironment, and the low immunogenicity of pancreatic tumors-necessitate the standardization of treatment parameters and improvements in image guidance. Overall, FUS represents a promising adjunct within multidisciplinary pancreatic cancer care.
    Keywords:  Drug delivery; Focused ultrasound; HIFU; Histotripsy; Immunotherapy; Pancreatic cancer
    DOI:  https://doi.org/10.14366/usg.25199
  45. Innate Immun. 2026 Jan-Dec;32:32 17534259261455983
    Trained immunity agonists given to neonatal mice fail to protect against leptospiral infection in adulthood and may cause adverse effects.
    Mégane Fernandez, Frédérique Vernel-Pauillac, Tiffany Pezier, Sonia Lacroix-Lamandé, Catherine Werts.
      Background and ObjectivesTrained immunity (TI) refers to a non-specific, long-lasting protective immune response that occurs following initial stimulation of the immune system and thought to be largely mediated by functional reprogramming of myeloid cells. TI has been demonstrated in BCG-vaccinated infants and can be induced in human cells and adult mice via agonists of pattern recognition receptors (PRR), such as β-glucan or MDP (a muropeptide that activates NOD2). However, its induction in neonates remains poorly understood. Previously, we demonstrated that the synthetic TLR2-NOD2 dual agonist CL429 enhances antimicrobial functions in adult mice and protects against subsequent infection with Leptospira interrogans, a zoonotic pathogen. We also demonstrated the immediate protective benefits of NOD2 stimulation in neonates against Cryptosporidium, a zoonotic pathogen that affects young animals in livestock herds. However, whether NOD2 agonists can induce TI in neonates and protect them at adulthood is unknown.Methods and ResultsHere, we investigated whether exposure of neonatal mice to PRR agonists (CL429, MDP or β-glucan), administered intraperitoneally at one week interval at 7/14 or 14/21 days of age, could enhance inflammatory cytokines production after ex vivo restimulation and confer long-term protection into adulthood. Surprisingly, none of the treatments enhanced ex vivo cytokine responses in adulthood after restimulation, nor did they confer protection against experimental leptospirosis. Instead, MDP-treated neonates exhibited 50% mortality following adult infection, revealing an unexpected detrimental effect.ConclusionThese findings demonstrate that these PRR agonists fail to induce protective TI against Leptospira when administered to neonatal mice, challenging assumptions derived from adult models. Furthermore, our study reveals the risks of administering immunostimulants during the early stages of life, and highlights unanticipated and potentially harmful, PRR- and age-specific mechanisms of immune system modulation.
    Keywords:  NOD2; leptospirosis; macrophages; neonatal mice; trained immunity
    DOI:  https://doi.org/10.1177/17534259261455983
  46. J Nanobiotechnology. 2026 Jun 02.
    Platelet-rich plasma cues program M2 macrophage-derived exosome mimetics to regenerate the tendon-bone interface.
    Chihao Lin, Hongyi Jiang, Linjie Chen, Liang Zhu, Yuhan Wang, Hanting Shen, Zhongnan Lin, Junfeng Shi, Jilong Wang, Junjie Deng, Xiaoyun Pan.
      Surgical repair of rotator cuff injuries is frequently complicated by high retear rates, driven by persistent inflammation and inadequate tissue regeneration. Exosomes derived from M2 macrophages represent a promising therapeutic avenue due to their innate immunomodulatory and regenerative properties. However, their clinical application is hindered by low yields and complex purification processes. In this study, we employed an extrusion technique to isolate exosome mimetics from platelet-rich plasma (PRP) pretreated M2 macrophages. These engineered vesicles, termed PRP-M2-EM, acquired additional bioactive factors from PRP, which significantly enhanced their pro-angiogenic and immunoregulatory functions compared to standard M2-EM. This biomimetic engineering strategy successfully transposes the therapeutic benefits of PRP into a stable, nanoscale delivery system, overcoming the limitations of PRP's short half-life and high production costs. Mechanistically, we identified the enrichment of miR-21a-5p within PRP-M2-EM as a primary driver of their superior efficacy. Further mechanistic investigation revealed that the high expression of miR-21a-5p in PRP-M2-EM targets and inhibits the tissue inhibitor of metalloproteinase 3 (TIMP3) gene, facilitating a regenerative environment. In conclusion, our study introduces engineered PRP-M2-EM as a potential therapeutic strategy. This approach promotes rotator cuff regeneration through enhanced angiogenesis and immunomodulation, with the miR-21a-5p/TIMP3 axis potentially contributing to these effects.
    Keywords:  Exosome mimetics; M2 macrophages; Platelet-rich plasma; Rotator cuff injury; Tendon-bone interface healing
    DOI:  https://doi.org/10.1186/s12951-026-04626-5
  47. bioRxiv. 2026 May 25. pii: 2026.05.23.727444. [Epub ahead of print]
    Ecology and engineering to modify the bile acid output of a defined microbial community.
    Xianfeng Zeng, Xiandong Meng, Allison M Weakley, Kelsey E Jarrett, Steven Higginbottom, Eugenell Mae Lopez, Ashley V Cabrera, Ira J Gray, Brian C DeFelice, Masahiko Terasaki, Rochelle Lai, Madelaine Brearley-Sholto, Aishan Zhao, Kerrigan R Hall, Mikhail Levia, Jeanette Arreola, Thomas Q de Aguiar Vallim, Michael A Fischbach.
      The bile acid pool, which is synthesized collaboratively by the host and its microbiome, impacts metabolism, immunity, and disease risk. Targeted microbiome interventions could in principle reshape the bile acid pool for therapeutic benefit, but practical strategies remain elusive. In the course of screening a complex defined community for metabolic phenotypes by dropping out individual strains, we observed that several of the single-strain dropout communities had markedly increased deoxycholic and lithocholic acid levels and a larger bile acid pool. In each of these communities, a second strain- Lactobacillus plantarum- had bloomed. The bile salt hydrolase activity of L. plantarum was necessary and sufficient to expand the size of the bile acid pool. An engineered community in which the bsh gene is overexpressed in multiple Lactobacillus strains confers on mice increased levels of secondary bile acid levels and a larger pool size. By overexpressing a different pair of bile acid metabolic genes in multiple strains of Lactobacillus -7α- and 7β-hydroxysteroid dehydrogenase-we changed the composition of the bile acid pool, enlarging it and redirecting it toward ursodeoxycholic acid. Together, these results demonstrate that fine details of the microbiome's strain composition can have a substantial effect on bile acid metabolism, and that rational manipulation of the microbiome can alter the size and composition of the bile acid pool.
    DOI:  https://doi.org/10.64898/2026.05.23.727444
  48. Chem Bio Eng. 2026 May 28. 3(5): 524-534
    Modular Biosurface Engineering of Magnetotactic Bacteria for Multimodal Synergistic Cancer Therapy.
    Qilong Li, Wangqing Li, Xuefei Sun, Feng Feng, Zhengdong Cheng, Wenchao Li, Li Yao, Xiuyu Wang.
      Bacterial-mediated cancer therapy shows therapeutic potential yet remains constrained by bioavailability and biosafety challenges. We introduce a scalable, modular biosurface-engineering platform for functionalizing wild-type magnetotactic bacteria (Magnetospirillum magneticum, AMB-1), enabling the integration of diverse materials, including small molecules, polymers, nanoparticles, and metal-organic frameworks. As a proof-of-concept, AMB-1@Fe3+-PDA (poly dopamine) exemplifies a bacteria-mediated therapeutic strategy that merges tumor-targeted delivery, immunosuppressive tumor microenvironment (TME) reprogramming, and innate immune activation with photothermal-chemodynamic therapy. The Fe3+-PDA coating counteracts deep-tissue immunosuppression and primes adaptive immunity, while AMB-1 enhances penetration into resistant TME niches. These mechanisms synergistically suppress aggressive 4T1 breast tumor progression, metastasis, and recurrence while establishing immunological memory. In murine models, two treatment cycles prolonged median survival from 45 to 67 days and elicited systemic antitumor immunity, including abscopal effects targeting untreated distant tumors. This platform establishes a bridge between materials science and synthetic biology, providing a generalizable blueprint for advancing the clinical translation of engineered bacterial therapies.
    Keywords:  Antitumor Immunity; Biosurface Engineering; Cancer Therapy; Magnetotactic Bacteria; Tumor Targeting
    DOI:  https://doi.org/10.1021/cbe.5c00177
  49. Carbohydr Polym. 2026 Aug 15. pii: S0144-8617(26)00472-8. [Epub ahead of print]386 125355
    Electrospinning-constructed polysaccharide-based multilayer nanofiber composite membrane for bridging hemostasis and tissue repair.
    Ruiyi Tan, Zhou Wen, Xinying He, Bitao Lu, Enling Hu, Ruiqi Xie, Guangqian Lan, Cuibin Guo, Chunzu Cheng, Bowen Cheng, Fei Lu.
      The persistent gap between hemostasis and tissue repair in wound care demands new biomaterials. To address this, we engineered an electrospun polysaccharide-based multilayer composite nanofiber membrane (MCNM) designed to transform early blood clots into bioactive, pro-regenerative interfaces. The MCNM integrates distinct carbohydrate polymer functionalities: a wound-contacting layer of pullulan/tannic acid/tranexamic acid nanofibers for hemostasis and fibrinolysis suppression; a polydopamine/CaCl2-modified cellulose acetate intermediate layer for platelet adhesion and fibrin nucleation; and a chitosan-composited cellulose spunlace backing for directional exudate management. When applied, this structure quickly concentrates blood to create a stable clot that acts as both hemostatic barrier and reservoir or regenerative factors. Proteomic analysis confirmed significant upregulation of extracellular matrix organization, focal adhesion, and actin cytoskeleton remodeling pathways within the clot microenvironment. In vivo, the MCNM accelerated wound closure, improved re-epithelialization and collagen deposition, and promoted anti-inflammatory macrophage polarization. This work establishes an example for leveraging polysaccharide-driven clot bioengineering to seamlessly bridge hemostasis and tissue regeneration in advanced wound care.
    Keywords:  Cellulose; Chitosan; Electrospinning; Polysaccharide composite membrane; Pullulan; Wound healing
    DOI:  https://doi.org/10.1016/j.carbpol.2026.125355
  50. iScience. 2026 Jun 19. 29(6): 116096
    Electrospun nanocomposite dressing integrating cerium dioxide and collagen accelerates pressure injury healing.
    Zhikang Mo, Jiani Wu, Huiyu Tan, Caiyan Qian, Yumei Zhong, Lu Zhang, Haibin Chen, Yue Tang.
      Pressure injuries (PIs) involve a pathological cycle of oxidative stress, inflammation, and impaired angiogenesis. To address this, we engineered an electrospun nanocomposite dressing-CePC-incorporating cerium dioxide nanoparticles into a polycaprolactone collagen matrix. This dressing could modulate the wound microenvironment. In vitro, it could scavenge reactive oxygen species, protect endothelial cells, enhance vascular endothelial growth factor (VEGF) expression, and reduce pro-inflammatory cytokines. In a murine PI model, the treatment accelerated wound closure, promoted granulation tissue formation and dermal regeneration, and improved functional angiogenesis. Mechanistically, the dressing shifted the macrophage phenotype from a pro-inflammatory to a pro-healing state. These findings demonstrate a strategy that combines nanomaterials and biomaterials to regulate inflammation and vascularization, providing a potential therapeutic approach for PI repair.
    Keywords:  bioengineering; biotechnology; materials science
    DOI:  https://doi.org/10.1016/j.isci.2026.116096
  51. Front Immunol. 2026 ;17 1767771
    Exosomal POSTN from cancer-associated fibroblasts drives progression of microinvasive lung adenocarcinoma: insights from single-cell and tissue exosome sequencing analysis.
    Jie Chen, Chenkang Zhou, Yixin Chen, Kate Huang, Yumin Wang, Junjun Wang.
       Background: Microinvasive adenocarcinoma (MIA) represents an early stage of lung adenocarcinoma (LUAD), yet how the tumor microenvironment (TME) and cancer-associated fibroblast (CAF)-derived exosomes contribute to its progression remains unclear. We aimed to define the cellular ecosystem of MIA and to clarify the role of periostin (POSTN) and POSTN+ CAF-derived exosomes in early LUAD progression.
    Methods: Single-cell RNA sequencing (scRNA-seq) and tissue-derived exosomal RNA sequencing were performed on four primary MIA lesions and matched adjacent lung tissues. Integrated analyses of scRNA-seq data, exosomal transcriptomes, the TCGA-LUAD cohort, and an independent LUAD tissue/serum cohort were used to characterize POSTN expression and to evaluate its prognostic and diagnostic relevance. Primary MIA-associated POSTN+ and POSTN- CAFs were isolated for exosome preparation, followed by co-culture experiments with LUAD cell lines and xenograft assays.
    Results: scRNA-seq identified a malignant Cancer-alveolar type II (Cancer-AT2) epithelial subset and multiple CAF subsets. Among these, POSTN+ CAFs were enriched in MIA tissues and showed enhanced crosstalk with Cancer-AT2 cells through extracellular matrix (ECM)-related ligand-receptor interactions. Tissue-derived exosomes contained 588 differentially expressed mRNAs, among which POSTN was markedly upregulated and showed the strongest association with fibroblast-related signatures. POSTN was predominantly expressed in fibroblasts across independent non-small cell lung cancer datasets and was elevated in LUAD tissues, tissue-derived exosomes, and serum exosomes, correlating with advanced stage, lymph node metastasis, and poor survival. Functionally, POSTN+ CAF-derived exosomes promoted LUAD cell proliferation, migration, invasion, colony formation, and xenograft growth.
    Conclusion: Exosomal POSTN derived from POSTN+ CAFs may represent an important stromal mediator of MIA/LUAD progression and a potential diagnostic and prognostic biomarker in early-stage LUAD.
    Keywords:  cancer-associated fibroblasts; exosomes; lung adenocarcinoma; microinvasive adenocarcinoma; postn
    DOI:  https://doi.org/10.3389/fimmu.2026.1767771
  52. Oncol Res. 2026 ;34(6): 28
    Exosomes-Transferred lncRNA H19 Reverses Osimertinib Resistance by Upregulating PTEN via Sponging miR-148-3p in Non-Small Cell Lung Cancer.
    Weixiang Song, Yanbo Zhang, Xubo Shen, Qin Yu, Yujin Liu, Yongchun Yu, Rui Chen.
      Objective: Osimertinib can selectively inhibit both epidermal growth factor receptor (EGFR) sensitizing and T790M gatekeeper mutations, and has shown remarkable therapeutic effects in patients with lung adenocarcinoma. However, almost all patients inevitably develop drug resistance. Herein, we sought to clarify the roles of exosomal lncRNA H19 in modulating osimertinib resistance, focusing on the PI3K-PTEN-Akt signaling axis. Methods: Functional assays, including cell viability assay, colony formation, cell apoptosis and xenograft mouse, employed in evaluate the effects of exosomal lncRNA H19 on cell growth and apoptosis. RNA quantitation and western blot were adopted to demonstrate the regulatory roles of exosomal lncRNA H19 in PI3K-PTEN-Akt signaling pathway. Immunofluorescence was applied to obverse the function and distribution of exosomes. Furthermore, dual-luciferase reporter analysis combined with RNA immunoprecipitation (RIP) was applied to verify the molecular interaction between lncRNA H19 and phosphatase and tensin homolog (PTEN). Results: LncRNA H19 exhibited obviously decreased expression in H1975R cells and their secreted exosomes. Overexpression of H19 enhances the cytotoxicity of osimertinib, inhibits the growth of H1975R cells, and promotes apoptosis. Conversely, H19 silencing promotes osimertinib resistance in H1975 cells and enhances the cell-resistant phenotype. Furthermore, exosome-transferred lncRNA H19 sponged miR-148-3p to augment PTEN expression, which in turn inactivated the PI3K-Akt signaling pathway and ultimately induced cell apoptosis. Conclusion: Exosome-encapsulated lncRNA H19 can be delivered to osimertinib-resistant H1975R cells, thereby reversing resistance through the miR-148-3p/PTEN/PI3K-Akt axis. Our results uncover a potential therapeutic approach to surmount osimertinib resistance in lung cancer.
    Keywords:  exosomes; lncRNA H19; non-small cell lung cancer; osimertinib; phosphatase and tensin homolog (PTEN)
    DOI:  https://doi.org/10.32604/or.2026.078665
  53. Cell Rep Med. 2026 Jun 02. pii: S2666-3791(26)00259-4. [Epub ahead of print] 102842
    Metabolically engineered probiotic OMVs as nanovaccine mediating sequential immunomodulation for chronic bone infection immunotherapy.
    Jie Lei, Bide Tong, Shihao Zhang, Zixuan Ou, Dingchao Zhu, Xingyu Zhou, Huaizhen Liang, Zhengdong Zhang, Lei Tan, Cao Yang, Xiaobo Feng.
      Chronic, drug-resistant bone infection caused by methicillin-resistant Staphylococcus aureus (MRSA) features an immunosuppressive niche enabling persistent infection and impaired bone healing. A specific treatment requires initial antibacterial immune activation against infection, followed by reshaping an anti-inflammatory microenvironment for later bone repair. Here, we screen Lactococcus lactis outer membrane vesicles (Lac-OMVs) with first-stage dendritic cell (DC) activation and later stage inflammatory macrophage repolarization potential. Mechanistically, enrichment of the nicotinamide metabolism pathway within Lac-OMVs is discovered, with nicotinamide adenine dinucleotide (NAD+) as a key anti-inflammatory mediator. NAD+-enriched Lac-OMVs (NAD+-Lac-OMVs) are thus metabolically engineered via targeted culture condition optimization, exerting biphasic immunomodulatory effects: (1) early-stage DC activation establishes robust humoral immunity, protecting against primary and recurrent MRSA challenge (99.35% and 98.07% bacterial clearance rates, respectively); and (2) later stage targeted NAD+ delivery reprograms inflammatory macrophages at the defect site, resolving inflammation and establishing a pro-osteogenic microenvironment (∼10 times higher bone-repair rate).
    Keywords:  NAD(+); OMVs; antibacterial nanovaccine; chronic bone infection; immune microenvironment regulation; nicotinamide adenine dinucleotide; probiotic outer membrane vesicles
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102842
  54. Mol Pharm. 2026 Jun 02.
    Antitumor Immunity Mediated by Nanoreactors Based on Bacterial Membrane Vesicles.
    Ruixin Zhang, Yue Sun, Fang Ding, Wenxuan Ju, Zhongren Chu, Ziwei Ren, Zhouyi He, Xiaobing Wang, Pan Wang.
      Traditional cancer vaccines are designed to elicit tumor-specific immune responses against preexisting or recurrent tumors and have been widely explored in oncology. However, their clinical translation has been hampered by persistent limitations such as suboptimal immunogenicity, complex manufacturing processes, and safety concerns, underscoring the need for multifunctional cancer vaccines that simultaneously achieve high potency and favorable tolerability. Here, we present a tumor vaccine platform based on engineered bacterial membrane vesicles (E-MVs) displaying the well-defined tumor-associated antigen MUC1 VNTR. This platform integrates antigen delivery with the intrinsic adjuvant properties of E-MV biological macromolecule, thereby enabling both therapeutic antitumor immunity and durable prophylactic protection. E-MVs derived from engineered Escherichia coli Rosetta (DE3) exhibit a spherical morphology with a size distribution of 100-200 nm. Following subcutaneous administration, E-MVs rapidly accumulate in draining lymph nodes and are efficiently internalized by dendritic cells, promoting antigen processing and cross-presentation to T cells. Functionally, E-MVs induce significant infiltration of CD8+ T cell into the tumor microenvironment and enhance IFN-γ production, resulting in potent tumor immune responses. This leads to suppressed tumor growth, prolonged survival, and effective prevention upon tumor challenge in both "cold tumor" (breast cancer) and "hot tumor" (melanoma) mouse models. Collectively, these results demonstrate that the E-MV-based vaccine is a versatile therapeutic and prophylactic platform, offering a simple, efficient, and clinically translatable strategy to induce durable antitumor immunity.
    Keywords:  E-MV; MV; antitumor effect; antitumor immunity; bacterial membrane vesicles
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01694
  55. Adv Sci (Weinh). 2026 Jun 04. e75941
    A Dual-Phase Exosomal Nanotherapy Enhances Continual Efferocytosis by Coordinating Checkpoint Inhibition and Metabolic Reprogramming in Atherosclerosis.
    Danwen Zheng, Shiteng Cai, Jinfeng Gao, Sheng Zhao, Bohan Wei, Xueyi Weng, Zhengmin Wang, Qiaozi Wang, Qiyu Li, Chengzhi Han, Weiyan Li, Yiwen Tan, Yuyuan Fu, Meng Ji, Zheyong Huang, Yanan Song, Juying Qian, Junbo Ge.
      Atherosclerosis is a chronic inflammatory disease characterized by defective efferocytosis, which contributes to necrotic core expansion and plaque instability. This dysfunction arises from two key barriers: first, impaired recognition of apoptotic cells due to activation of the CD47-SIRPα immune checkpoint; and second, insufficient metabolic processing of apoptotic cell-derived substrates, which limits the capacity for continual efferocytosis. Arg1-mediated arginine metabolism has emerged as a crucial pathway supporting this process. To address these limitations, we created Am@SExo, a dual-functional engineered exosome derived from macrophages that unites checkpoint inhibition with metabolic reprogramming. The vesicles overexpress SIRPα on its surface to competitively engage CD47 on apoptotic cells and relieve the inhibitory signal, facilitating initial binding and uptake. Subsequently, it delivers Arg1 mRNA to recipient macrophages, driving an arginine to putrescine program aligned with Rac1 and actin remodeling to sustain successive rounds of clearance. In ApoE-/- mice, systemic administration of Am@SExo significantly reduced necrotic core area, increased fibrous cap thickness, and enhanced features of plaque stability. Together, our findings demonstrate that Am@SExo as a single-platform, dual-phase modulator that restores macrophage continual efferocytosis, offering a promising strategy to resolve inflammation and stabilize atherosclerotic plaques.
    Keywords:  Arg1; SIRPa; efferocytosis; exosomes; metabolic reprogramming
    DOI:  https://doi.org/10.1002/advs.75941
  56. ACS Cent Sci. 2026 May 27. 12(5): 719-730
    A Prodrug Strategy to Conditionally Trap Therapeutic Payloads for Improved Tumor Retention.
    Deokhee Kang, Apurva Pandey, Garima Kumar, Abijeet Singh Mehta, Tyler C Detomasi, Dashiell Anderson, Conner Bardine, Garrison Asper, Junyang Qi, Isha Nadig, Yifan Cui, Fiona M Quimby, Jesse Ling, Youngho Seo, Bruce E Cohen, Mekhail Anwar, Michael J Evans, Charles S Craik.
      Altered extracellular proteolysis has been exploited to selectively activate therapeutics in diseases such as cancer; however, once activated, extracellular drugs can diffuse away, limiting efficacy. We address this challenge by coupling proteolytic activation with membrane tethering to retain drugs within diseased tissue. To accomplish this, we developed "restricted interaction peptides" (RIPs), a delivery platform that leverages elevated proteolytic activity to activate membrane-interacting peptides, localizing cargos near the site of proteolysis. We demonstrate that RIPs can deliver diverse therapeutic cargos, including cytotoxins and radioisotopes. As proof of concept, we engineered "FRIP," a RIP designed for cleavage by fibroblast activation protein (FAP), an endoprotease upregulated in solid tumors and fibrosis. Efficient P4-P4' substrate sequences were identified and incorporated into FRIPs. Cell-based studies showed that, upon activation, the peptide adhered to membranes rapidly internalized and successfully delivered therapeutic cargos. Consistent with this, FRIPs delivering MMAE inhibited proliferation in an FAP-dependent manner. Imaging studies confirmed tumor targeting with minimal uptake in normal tissues. Finally, FRIPs delivering MMAE or Cu-67 exhibited potent antitumor effects. These findings establish membrane tethering as a strategy to enhance drug retention.
    DOI:  https://doi.org/10.1021/acscentsci.6c00185
  57. MAbs. 2026 Dec;18(1): 2684388
    One-step cleavage and purification: a bifunctional IdeS-Protein A fusion protein for on-column generation of antibody fragments.
    Tongsheng Zhang, Huayuan Liao, Chun-Bo Teng, Chao Wang.
      Conventional production of antibody fragments (e.g. Fab/F(ab')2, VHH/(VHH)2) involves sequential enzymatic cleavage and multi-step purification to remove Fc domains and residual enzymes, a process that is laborious and inefficient for small-scale workflows. To address this, we engineered a bifunctional IdeS-Protein A (IPA) fusion protein, which combines the specific IgG-cleaving activity of IdeS with the Fc-binding capability of Protein A. In solution, this construct enabled simultaneous antibody cleavage and affinity-mediated removal of both the enzyme and Fc fragments in a single step. Furthermore, we immobilized the fusion protein on a chromatographic resin to create an integrated "on-column cleavage-purification" platform. This system allows antibody capture, in-situ cleavage, and direct collection of high-purity F(ab')2 fragments from the flow-through, while Fc fragments, uncleaved antibodies, and the enzyme are retained on the column. This work establishes a streamlined, one-step method for generating antibody fragments, offering a robust and automatable platform for research and preclinical applications.
    Keywords:  Antibody; F(ab′)2 fragments; IdeS; Protein A; antibody fragment; enzymatic cleavage; on-column generation
    DOI:  https://doi.org/10.1080/19420862.2026.2684388
  58. FEBS Open Bio. 2026 Jun 04.
    Time-restricted feeding prior to Mycobacterium tuberculosis infection reduces tissue CD4+ T cells with limited impact on bacterial clearance.
    Ashish Gupta, Nidhi Yadav, Subhasmita Das, R Rajendra Kumar Reddy, Nupur Sharma, Amol Ratnakar Suryawanshi, Jaswinder Singh Maras, Ranjan Kumar Nanda.
      The effects of time-restricted feeding (TRF) on immune responses during bacterial infection are not well-studied. Here, we subjected mice (6-8 weeks, male) to 8 h of TRF for 30 days and then infected them with a low dose of Mycobacterium tuberculosis (Mtb) H37Rv. During the first 15 days, TRF improved glucose tolerance with marginal weight loss. However, global serum and liver metabolomics alongside liver proteomics indicated that TRF perturbed fatty acid biosynthesis and degradation, steroid hormone biosynthesis, and tyrosine metabolism. Together, these results indicate that TRF potentially affected the distribution and functionality of host immune cells. TRF mice had similar mycobacterial burdens in lungs and spleen at 21 days postinfection but had significantly lower CD3+ T cells in bone marrow and CD4+ T cells in both bone marrow and lungs. Ultimately, we show that TRF induced changes in amino acid and lipid metabolism persist during Mtb infection.
    Keywords:  Mycobacterium tuberculosis; immunology; metabolomics; time‐restricted feeding
    DOI:  https://doi.org/10.1002/2211-5463.70263
  59. Sci Rep. 2026 May 30.
    Combined application of the modified early warning score and the modified hematoma expansion prediction score for predicting hematoma expansion in intracerebral hemorrhage.
    Tao Luo, Jie Peng, Ai Chen, Wei Xiong, Jianchao Xu, Caiyong Jiang, Kehan Li, Yuanshu Yang, Chunhong Li, Jun Su.
      This study aimed to evaluate the predictive value of the combined Modified Early Warning Score (MEWS) and Modified Hematoma Expansion Prediction (MHEP) score for hematoma expansion(HE)in patients with intracerebral hemorrhage (ICH). The goal was to provide an accurate and practical tool for risk assessment in this patient population. Clinical data from patients with ICH admitted to Nanchuan Hospital Affiliated to Chongqing Medical University between January 2024 and June 2025 were prospectively collected. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with HE. Subsequently, the predictive performance of the combined MEWS and MHEP scores (termed MEWS-MHEP) was evaluated using receiver operating characteristic (ROC) curve analysis. A total of 421 patients were enrolled and categorized into the hematoma expansion group (n = 58) and the non-hematoma expansion group (n = 363). Significant differences (P < 0.05) were observed in smoking history, alcohol consumption, hematoma location, hematoma volume, island sign, and Glasgow Coma Scale (GCS) score, indicating their association with HE. The MEWS showed a moderate correlation with HE (P = 0.004). Both the MHEP score and the combined MEWS-MHEP score were significantly higher in the HE group (P < 0.001). The MEWS-MHEP score yielded an AUC of 0.813, which was significantly higher than that of the MEWS alone (0.616) and the MHEP score alone (0.699) (P < 0.001), with an overall prediction accuracy of 80.76%.The MEWS-MHEP score outperforms either the MEWS or MHEP score alone in predicting HE in patients with ICH. Thus, it represents a reliable tool for emergency risk stratification and may aid in optimizing medical resource allocation.
    Keywords:  Hematoma expansion; Intracerebral hemorrhage; Modified Early Warning Score; Modified Hematoma Expansion Prediction Score; Predictive model
    DOI:  https://doi.org/10.1038/s41598-026-55173-w
  60. Int J Nanomedicine. 2026 ;21 584872
    ROS-pH Dual-Responsive Polydopamine Nanoparticles for Targeted Fasudil Delivery Ameliorate Multiple Pathologies in Diabetic Retinopathy.
    Jiaqi Li, Zheng Zhong, Yuhe Tan, Xiaohong Ma, Ruohong Wang, Guoyao Gao, Xian Zhang, Ziqing Zhou, Yin Zhao, Jia Liu, Xufang Sun.
       Background: The multifaceted pathogenesis of diabetic retinopathy (DR) involves numerous pathways, among which oxidative stress and Rho-associated kinase (ROCK) signaling are critically implicated. The failure of current anti-VEGF monotherapies to address these key pathological processes limits their efficacy. While the ROCK inhibitor Fasudil is a promising candidate, its clinical translation for DR is hindered by poor ocular retention and lack of target specificity.
    Methods: We engineered a reactive oxygen species (ROS)- and pH-dual responsive polydopamine nanoplatform (Fasudil@PDA) to deliver Fasudil while concurrently scavenging oxidative stressors.
    Results: The Fasudil@PDA nanoparticles achieved a high drug loading capacity of ~28%. The release kinetics were specifically engineered to be responsive to the DR microenvironment. Under high ROS conditions in vitro, the platform demonstrated a sustained and efficient release profile, achieving a cumulative release of 87.3% over 56 days - demonstrating remarkable longevity. Separately, the pH-responsive drug release capability was also confirmed under acidic conditions. The platform effectively neutralized multiple ROS species in vitro and significantly restored endothelial barrier integrity by inhibiting the ROCK/MLC pathway. In a laser-induced choroidal neovascularization model, a single injection suppressed pathological angiogenesis by 45%. In diabetic mice, the same treatment markedly reduced vascular leakage, attenuated neuroinflammation, and restored retinal function, with b-wave amplitudes recovering to near-normal levels.
    Conclusion: This study establishes a multi-faceted nanotherapeutic strategy that synergizes sustained, long-acting ROCK inhibition with innate antioxidant activity. Designed to be activated by the pathological cues of DR, including acidic pH and ROS, our approach precisely targets multiple pathological pathways, offering a promising and translatable paradigm for overcoming the limitations of current monotherapies.
    Keywords:  ROCK inhibition; combination therapy; diabetic retinopathy; pH-responsive; polydopamine nanoparticles; reactive oxygen species
    DOI:  https://doi.org/10.2147/IJN.S584872
  61. J Nanobiotechnology. 2026 Jun 04.
    Targeted delivery of TGF-β inhibitor via LHRH-NanoTi reverses the NAT10/ac4C-mediated cisplatin-induced immunosuppressive tumor microenvironment in ovarian cancer.
    Fei Lv, Qihang Zhao, Ruoyao Zou, Xiaoye Ye, Yidan Shen, Lijun Meng, Jialu Guo, Yahui Wang, Yingling Zheng, Yanpeng Liu, Shuai Wang, Yongfeng Wu, Jinyi Tong.
       BACKGROUND: Platinum-based chemotherapy for ovarian cancer is frequently compromised by the development of drug resistance, which is often accompanied by an immunosuppressive tumor microenvironment. The molecular mechanisms linking cisplatin resistance to immune evasion remain poorly understood, hindering the development of effective combination therapies.
    RESULTS: This study revealed that cisplatin-induced resistance and immunosuppression were driven by reduced N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification, which produced two distinct unfavorable effects: (1) activation of the DNA damage repair pathway, thereby promoting cisplatin resistance; and (2) activation of the TGF-β pathway through enhanced translation efficiency of Gdf6 and Inhba. Mechanistically, NAT10 bound to ribosomal proteins RPS3 and RPS6, creating a steric barrier that inhibited the loading of ac4C-modified mRNAs onto ribosomes. Elevated TGF-β signaling increased the infiltration of myeloid-derived suppressor cells, M2 macrophages, exhausted CD8 + T cells, and regulatory T cells within the tumor microenvironment. To target this pathway, we developed a luteinizing hormone-releasing hormone (LHRH) receptor-targeted nanodelivery system (NanoTi) for a TGF-β inhibitor, which synergized with cisplatin to achieve superior antitumor efficacy by effectively reversing the immunosuppressive microenvironment.
    CONCLUSIONS: Our findings suggest that cisplatin-induced NAT10/ac4C downregulation may contribute to platinum resistance and immunosuppression in ovarian cancer, and targeted TGF-β inhibition reverses cisplatin-induced immunosuppression in preclinical ovarian cancer models.
    Keywords:  LHRH; NAT10; Ovarian cancer; TGF-β; Tumor microenvironment; ac4C
    DOI:  https://doi.org/10.1186/s12951-026-04631-8
  62. Adv Mater. 2026 Jun 01. e73560
    A Self-Cascading Immunomodulatory Hydrogel for Remodeling Infected Diabetic Wounds.
    Yulong Lan, Xiaoliang Qi, Jing Chen, Lifeng Tan, Jianliang Shen.
      Methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic foot ulcers (DFUs) remain refractory to healing owing to persistent inflammation, hyperglycemia, and impaired tissue regeneration. Current antimicrobial strategies primarily eliminate viable bacteria but overlook pathogen-associated molecular patterns (PAMPs) released upon bacterial death, which sustain NF-κB/NLRP3 activation and prevent immune resolution. However, suppressing microbial burden without neutralizing PAMP-driven inflammation fails to restore the regenerative wound microenvironment. Here, we report a self-cascading hypoglycemic immunomodulatory hydrogel integrating Fe3O4@Au nanozymes with phenylboronic acid-modified hyaluronic acid and dopamine-functionalized silk fibroin. The platform exploits endogenous glucose to drive cascade catalysis for efficient MRSA eradication (∼99.99% with near-infrared assistance), while dynamically exposing catechol and boronic acid motifs to sequester PAMPs and suppress inflammatory signaling. Consequently, macrophages are reprogrammed from pro-inflammatory M1 to pro-healing M2 phenotypes, enabling immune microenvironment remodeling. In MRSA-infected DFU models, this coordinated antibacterial-immunomodulatory strategy markedly accelerates wound closure, leaving only ∼13.97% residual area after 14 days. These results establish a design paradigm that couples biocatalysis with immune regulation for treating complex infected wounds.
    Keywords:  diabetic wound healing; immune microenvironment remodeling; methicillin‐resistant Staphylococcus aureus; pathogen‐associated molecular patterns; self‐cascading hydrogel
    DOI:  https://doi.org/10.1002/adma.73560
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