bims-engexo 2025-12-07 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–12–07
fifteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.
Oral delivery of chitosan/hyaluronic-acid-coated milk-derived exosomes for ulcerative-colitis amelioration.
Mesenchymal stem cell-derived exosome delivery of let-7a-5p enhances macrophage efferocytosis via Arid3a/Mertk axis in acute-on-chronic liver failure.
Exosome therapeutics: A paradigm shift in skin repair through multidimensional immunomodulation and biomaterial-driven delivery.
Advances in hybrid exosome-liposome nanoparticles for enhanced cancer therapy.
Extracellular vesicles cargo orchestration in colorectal cancer: immune evasion, stromal remodeling, and therapeutic frontiers.
Engineering Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Chronic Kidney Diseases.
Immunological conversion of triple-negative breast cancer by engineered extracellular vesicle-mediated pyroptosis.
Engineered extracellular vesicles as multifunctional therapeutics for restoring periodontal homeostasis.
Neutrophil-mimetic M2 macrophage extracellular vesicle for targeted spinal cord injury therapy.
Corneal Nerve Regeneration via MSC-Derived EVs: Tissue Source and Culture Dimensionality Dictate miRNA Cargo and Therapeutic Efficacy.
Engineered extracellular vesicles for nose-to-brain co-delivery of chlorotoxin and curcumin for treatment of glioblastoma.
Exosomes derived from Panax notoginseng promote osteogenic differentiation of rBMSCs via the PI3K/AKT signaling pathway.
Copper-Free Click Chemistry Enables High-Fidelity Engineering of Mitochondria-Targeted Brain-Derived Exosomes.
A self-assembled nano micelle-exosome with high selectivity and penetrability achieves precise intracartilage lipid delivery.

Theranostics. 2026 ;16(1): 545-579

Engineering exosomes for targeted neurodegenerative therapy: innovations in biogenesis, drug loading, and clinical translation.

Qinqin Huang, Shile Wang, Zeming Liu, Lang Rao, Ke Cheng, Xiaobo Mao.

  Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD) and multiple sclerosis (MS), are characterized by progressive neuronal dysfunction and limited therapeutic options, largely due to the restrictive nature of the blood-brain barrier (BBB). Exosomes, naturally occurring extracellular vesicles (EVs), have gained attention as innovative drug delivery vehicles owing to their intrinsic ability to cross the BBB, minimal immunogenicity, high biocompatibility, and capability to carry diverse therapeutic cargos such as proteins, nucleic acids, and small molecules. Furthermore, exosomes can be bioengineered to enhance drug-loading efficiency and targeting specificity, positioning them as a versatile and effective platform for treating NDDs. In this review, we summarize recent advances in exosome biogenesis, secretion, and engineering, with an emphasis on innovative strategies for exosome isolation, drug loading, and surface modification. We further explore their roles in modulating neuroinflammation, promoting neural regeneration, and enabling precise therapeutic delivery. Critical challenges associated with large-scale production, quality control, and regulatory compliance under Good Manufacturing Practices (GMP) are also discussed. Collectively, these developments underscore the transformative potential of engineered exosomes in advancing precision therapies for neurodegenerative disorders and offer strategic insights into their clinical translation.

Keywords:  blood-brain barrier (BBB); clinical trials; drug delivery; exosomes; neurodegenerative diseases (NDDs); targeted therapy

DOI:  https://doi.org/10.7150/thno.117143
Int J Pharm X. 2025 Dec;10 100447

Oral delivery of chitosan/hyaluronic-acid-coated milk-derived exosomes for ulcerative-colitis amelioration.

Chao Deng, Xinyi Cheng, Qingying Sun, Yeliaman Yeerbolati, Rui Zheng, Youyi Liu, Ying Yao, Yanbing Shen, Kewei Wang, Jianfeng Huang.

  Restoring intestinal-barrier homeostasis is crucial in treating ulcerative colitis (UC). Milk-derived exosomes, known for their potent biological properties, hold promise in promoting intestinal-barrier repair. However, their stability and targeting ability during gastrointestinal transit remain challenging. To address this, we engineered exosomes via layer-by-layer (LBL) encapsulation, enhancing their stability, controlled release, and targeted delivery. In a C57BL/6 J mouse model of UC induced by dextran sulfate sodium, oral administration of LBL-encapsulated milk-derived exosomes (LBL-Exos) significantly improved the intestinal barrier, including the physical, mucus, and immune barriers, thereby effectively alleviating the symptoms of UC, even at half the exosome dosage. These effects were also associated with reduced apoptosis and inhibition of the PI3K/AKT signaling pathway. This study demonstrates the therapeutic potential of engineered milk-derived exosomes in UC treatment, offering a promising approach for treating colitis and paving the way for the broader use of natural exosomes in related diseases.

Keywords:  Anti-inflammatory activity; Exosomes; Intestinal barrier; Layer-by-layer; UC therapy

DOI:  https://doi.org/10.1016/j.ijpx.2025.100447
Stem Cells Transl Med. 2025 Nov 24. pii: szaf058. [Epub ahead of print]14(12):

Mesenchymal stem cell-derived exosome delivery of let-7a-5p enhances macrophage efferocytosis via Arid3a/Mertk axis in acute-on-chronic liver failure.

Junyi Wang, Zhihui Li, Zhouhan Wang, Wei Liang, Shibo Meng, Junfeng Chen, Jialei Wang, Jing Zhang, Bingliang Lin.

   BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with a high mortality rate and limited therapeutic options. Macrophage efferocytosis plays an essential role in maintaining tissue homeostasis, and its dysfunction may be associated with the pathogenesis of ACLF. We previously found that mesenchymal stem cell (MSC) treatment in ACLF mice promoted macrophage M2 polarization and elevated the efferocytosis-related protein Mertk, but the underlying mechanisms remained unclear.
METHODS: The role of efferocytosis was investigated in liver tissues from ACLF patients and an ACLF mouse model treated with MSC-derived exosomes (MSC-Exos). In vitro experiments utilizing lipopolysaccharide-induced M1 macrophages were conducted to dissect the underlying mechanism, targeting the miRNA let-7a-5p. Engineered exosomes (MSC-Exoslet-7a-5p) were developed via electroporation to validate the therapeutic potential.
RESULTS: Impaired macrophage efferocytosis in liver tissues correlated with poor prognosis in ACLF patients. Treatment with MSC-Exos significantly improved histological morphology, liver function and enhanced efferocytosis in ACLF mice. Mechanistically, MSC-Exos delivered let-7a-5p to M1 macrophages, which downregulated Arid3a and upregulated Mertk expression. Furthermore, engineered MSC-Exoslet-7a-5p promoted efferocytosis more effectively than unmodified exosomes.
CONCLUSION: MSC-Exos enhance macrophage efferocytosis in ACLF via the let-7a-5p/Arid3a/Mertk axis. Engineered MSC-Exoslet-7a-5p, by boosting this pathway, provide a potential strategy for improving ACLF therapy.

Keywords:  Mertk; acute-on-chronic liver failure; efferocytosis; exosome; let-7a-5p; macrophage; mesenchymal stem cell

DOI:  https://doi.org/10.1093/stcltm/szaf058
Biomed Pharmacother. 2025 Nov 29. pii: S0753-3322(25)01024-8. [Epub ahead of print]193 118830

Exosome therapeutics: A paradigm shift in skin repair through multidimensional immunomodulation and biomaterial-driven delivery.

Tinghan Deng, Yiyi Zhang, Yabo Yao, Pingfang Ye, Dan Zhang, Fengrui Cheng, Jingping Wu, Hongbin Cheng, Jun Lu.

  Exosomes, nanoscale extracellular vesicles (30-150 nm) carrying bioactive molecules such as proteins, miRNAs, and lipids, are pivotal mediators of skin repair, modulating immune responses, angiogenesis, oxidative stress, and fibroblast function. This review synthesizes the mechanisms and clinical applications of exosomes in treating conditions such as diabetic ulcers, hypertrophic scars, photoaging, psoriasis, and alopecia. Exosomes from mesenchymal stem cells (MSCs), keratinocytes, and engineered sources regulate inflammatory pathways (e.g., NF-κB, IL-17/IL-23), promote angiogenesis through miRNA-mediated VEGF activation (e.g., miR-21-3p, miR-126), activate the NRF2 pathway to mitigate reactive oxygen species (ROS) accumulation, and modulate TGF-β/Smad signaling to reduce pathological scarring. Advanced delivery systems, including gelatin methacryloyl (GelMA) hydrogels, microneedles, and biomaterial scaffolds, enhance exosome stability and tissue penetration. Preclinical and early-phase clinical studies demonstrate accelerated wound healing, reduced scar formation, and enhanced skin regeneration. However, challenges such as standardized production, functional heterogeneity, long-term safety, and regulatory hurdles persist. Emerging technologies, such as single-exosome sequencing and artificial intelligence, offer solutions to optimize exosome therapy. As a promising cell-free therapeutic approach, exosomes require interdisciplinary collaboration to ensure efficacy and safety for clinical translation.

Keywords:  Cell-free therapy; Drug Delivery Systems; Extracellular Vesicles; Skin Regeneration; Translational Medicine

DOI:  https://doi.org/10.1016/j.biopha.2025.118830
Colloids Surf B Biointerfaces. 2025 Nov 25. pii: S0927-7765(25)00824-0. [Epub ahead of print]259 115317

Advances in hybrid exosome-liposome nanoparticles for enhanced cancer therapy.

Jinqiu Dou, Jiangye Wang, Guangyuan Zhang, Xiaoge Fu, Yuhang Zhang, Fengying Sun.

  Exosomes, endogenous nanoscale vesicles secreted by various cell types, have emerged as promising natural carriers for therapeutic delivery due to their excellent biocompatibility, low immunogenicity, prolonged systemic circulation, and intrinsic ability to cross the blood-brain barrier (BBB). They can encapsulate diverse bioactive molecules-including nucleic acids, proteins, and small-molecule drugs-showing great potential in cancer therapy. However, their clinical translation remains hindered by low production yield and limited drug-loading capacity. To overcome these limitations, engineered approaches such as exosome-liposome fusion have been developed. This strategy integrates the biological targeting and membrane stability of exosomes with the tunable physicochemical properties of liposomes, resulting in hybrid exosome-liposome nanoparticles (HELNs) that exhibit improved stability, loading efficiency, and therapeutic performance. This review systematically summarizes the biological characteristics of exosomes from different cellular origins, current methodologies for HELNs fabrication, and their recent advances in drug delivery, gene therapy, and immunotherapy. Finally, the review highlights key advantages of this hybrid strategy for cancer theranostics and discusses ongoing challenges and future perspectives for large-scale production and clinical translation.

Keywords:  Cancer therapy; Drug delivery; Exosome; Hybrid nanoparticles; Liposome

DOI:  https://doi.org/10.1016/j.colsurfb.2025.115317
Mol Cancer. 2025 Dec 06.

Extracellular vesicles cargo orchestration in colorectal cancer: immune evasion, stromal remodeling, and therapeutic frontiers.

Yukang Lu, Xiulan Liu, Tingting Zhang, Meijin Liu, Xiaoyan Liu, Jinyou Qiu, Linghan Zhang, Zhenzhen Wen.

  Extracellular vesicles (EVs), as pivotal "messengers" in intercellular communication within the tumor microenvironment (TME), play multifaceted regulatory roles in the initiation, progression, and therapeutic response of colorectal cancer (CRC). This review focuses on the roles of EVs in CRC progression, including the creation of an immunosuppressive microenvironment and the modulation of other cells within the TME. Additionally, the article briefly discusses the potential biomarker value of EVs for early diagnosis and metastasis prediction. Furthermore, several therapeutic strategies employing EVs for CRC treatment are introduced, such as adjuvant immunotherapy, the use of stem cell-derived EVs, and engineered EVs. In this context, we emphasize the limitations and challenges of EV-based research and explore the future prospects of this field, aiming towards the realization of its practical application in the precise diagnosis and treatment of CRC.

Keywords:  Colorectal cancer; Engineered extracellular vesicles; Extracellular vesicles; Immunosuppression; Therapeutic strategies; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02532-2
Tissue Eng Regen Med. 2025 Dec 03.

Engineering Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Chronic Kidney Diseases.

Hsiu-Jung Liao, Kai-Hsiang Shu, Wei-Che Yu, Yen-Ling Chiu.

   BACKGROUND: Chronic kidney disease (CKD) is a progressive disorder that leads to significant structural and functional changes in the kidneys, posing a major global health concern and contributing to high mortality rates.
METHODS: The urgent need for innovative treatments is evident. Mesenchymal stem cells (MSCs) are well-regarded in regenerative medicine for their ability to repair tissue and modulate immune responses. Emerging research indicates that the therapeutic benefits of MSCs are largely mediated by the secretion of extracellular vesicles (EVs), particularly exosomes (MSC-Exos), which replicate the effects of MSCs by delivering genetic materials and proteins to target cells.
RESULTS: MSC-Exos are novel natural carriers for targeted gene or drug delivery, offering biocompatibility, intrinsic targeting capabilities, and bioactive cargo to modulate recipient cells. They represent a groundbreaking platform for precision medicine, enhancing therapeutic efficacy with minimal immunogenicity and off-target effects. Moreover, embedding exosomes within hydrogels has emerged as a promising strategy to maintain their biological activity and enable a controlled release.
CONCLUSION: This review explores the roles of MSC-Exos in CKD pathophysiology, highlights the renoprotective effects of MSC-Exos for various sources, and provides a comprehensive overview of how hydrogel biomaterials present a promising approach for integrating exosomes to enhance therapeutic outcomes. The use of hydrogels to encapsulate exosomes improves their sustained release and stability in diseased kidney tissues, providing an innovative strategy to enhance precision therapies.

Keywords:  Chronic kidney disease (CKD); Engineered extracellular vesicle (Engineered-EV); Mesenchymal stem cell-derived extracellular vesicle (MSC-EV)

DOI:  https://doi.org/10.1007/s13770-025-00772-3
J Control Release. 2025 Dec 02. pii: S0168-3659(25)01107-1. [Epub ahead of print] 114493

Immunological conversion of triple-negative breast cancer by engineered extracellular vesicle-mediated pyroptosis.

Huan Zhang, Man Sun, Jiayi Chen, Simiao Wang, Jiayi Liu, Hongqun Yang, Luotong Liu, Siyuan Hu, Fang Yang, Lesheng Teng, Zhou Chen, Xiaobing Wang, Shiyan Dong, Yifan Ma, Jared L Edwards, Xiaotian Wang, Yen-Tzu Chang, Betty Y S Kim, Wen Jiang, Yaxin Cui, Zhaogang Yang.

  Although pyroptosis has emerged as a promising strategy for immunotherapy in triple-negative breast cancer (TNBC), its clinical translation remains hindered by systemic off-target toxicity and pronounced immune exclusion. To address these limitations, we developed a high-throughput double nanosecond pulsed microfluidic electroporation system to generate engineered extracellular vesicle (GDEV). These extracellular vesicles co-encapsulate gasdermin E N-terminal (GSDME-N) mRNA to induce pyroptosis and discoidal domain receptor 1 (DDR1) shRNA to suppress immune exclusion, respectively. Proteomics analysis of clinical TNBC specimens identified CD156 as a TNBC-specific surface biomarker. To achieve tumor-specific delivery and minimize off-target effects, GDEV was further functionalized with anti-CD156 antibody and the GALA pH-sensitive peptide, yielding pTGDEV. In the acidic tumor microenvironment, pTGDEV facilitates the precise release of its therapeutic cargo, simultaneously activating pyroptotic signaling and mitigating immune exclusion. In both orthotopic murine TNBC models and patient-derived xenograft models, pTGDEV significantly inhibited tumor progression and prolonged median survival. Treatment with pTGDEV also reduced the population of myeloid-derived suppressor cells while enhancing the infiltration of dendritic cells, CD4+ T cells, and CD8+ T cells, effectively reprogramming the tumor microenvironment from immunosuppressive to immunostimulatory. These results demonstrate that pTGDEV offers a potent and targeted approach for TNBC immunotherapy, with strong potential for clinical translation.

Keywords:  Cancer immunotherapy; Drug delivery system; Extracellular vesicle; Microfluidic technology; Pyroptosis

DOI:  https://doi.org/10.1016/j.jconrel.2025.114493
Acta Biomater. 2025 Nov 27. pii: S1742-7061(25)00896-7. [Epub ahead of print]

Engineered extracellular vesicles as multifunctional therapeutics for restoring periodontal homeostasis.

Junjie Shi, Zongshuai Liu, Jirong Xie, Ze Zhao, Xin Huang, Zhengguo Cao.

  Periodontal homeostasis refers to the dynamic equilibrium between host defense, microbial control, and tissue remodeling in periodontal tissues. Periodontitis is a chronic inflammatory disease characterized by the destruction of periodontal tissues, in which periodontal homeostasis is disturbed. Although many strategies have been developed, treatment of periodontitis and restoration of periodontal homeostasis remain challenging. Extracellular vesicles (EVs) have emerged as a potential cell-free platform for therapeutic applications due to their intrinsic capacity for intercellular communication and biocompatibility. With the advances in engineering, EVs can be functionally tailored to exhibit improved stability, targeting, and bioactivity, attracting increasing attention as regulators for periodontal homeostasis. Accumulating evidence indicates that engineered EVs exert diverse regulatory effects in the periodontal microenvironment, including anti-bacterial activity, anti-inflammatory properties, immunomodulation, antioxidant protection, regulation of programmed cell fate, and promotion of regeneration. Such multifunctional properties enable engineered EVs to address periodontal dysregulation and contribute to the stabilization of tissue homeostasis. This review highlights recent advances in the application of engineered EVs in periodontal research, summarizes their emerging therapeutic roles across these biological domains, and emphasizes their potential as versatile modulators for the maintenance and restoration of periodontal homeostasis. STATEMENT OF SIGNIFICANCE: This review uniquely integrates recent progress in engineering extracellular vesicles (EVs) with biomaterial-based strategies to restore periodontal homeostasis, a perspective not comprehensively addressed in existing literature. By systematically analyzing approaches such as cargo and surface modification, scaffold incorporation, and artificial vesicle design, it highlights how engineered EVs overcome the limitations of native vesicles and achieve multifunctional regulation of microbial, immune, and regenerative processes. This work provides insights into the convergence of materials science, nanotechnology, and oral biology, and outlines future directions for translating engineered EVs into next-generation therapeutic platforms with broad relevance for biomaterial innovation and regenerative medicine.

Keywords:  Drug delivery; Engineered extracellular vesicles; Periodontal homeostasis; Periodontitis; Regenerative medicine

DOI:  https://doi.org/10.1016/j.actbio.2025.11.060
Biomater Adv. 2025 Nov 25. pii: S2772-9508(25)00454-6. [Epub ahead of print]181 214627

Neutrophil-mimetic M2 macrophage extracellular vesicle for targeted spinal cord injury therapy.

Yinghui Shang, Wei Wang, Tehan Zhang, Enlin Qi, Linlin Jiang, Haiting Liu, Qinghai Wang, Shiqing Feng.

  Spinal cord injury (SCI) results in severe neurological dysfunction primarily due to secondary inflammation and neuronal apoptosis. Developing effective therapies with both targeting capability and neuroprotective effects remains a significant challenge. In this study, we engineered a novel biomimetic nanoplatform by fusing neutrophil membranes with M2 macrophage-derived extracellular vesicles (M2EVs), generating hybrid vesicles termed N-M2EVs. These vesicles were uniformly sized, exhibited good biocompatibility, and retained membrane markers from both parent sources. In vitro experiments using oxygen-glucose deprivation/reoxygenation (OGD/R)-injured HT22 neurons demonstrated that N-M2EVs preferentially targeted damaged cells, enhanced cell viability, reduced reactive oxygen species, and inhibited apoptosis more effectively than M2EVs alone. In a mouse SCI model, intravenously administered N-M2EVs showed higher accumulation at injury sites, improved motor function recovery as assessed by BMS score, CatWalk gait analysis, and motor evoked potentials, and promoted neuronal survival and axonal regeneration while reducing glial scarring. Mechanistically, RNA sequencing and Western blot analysis revealed that N-M2EVs exerted their therapeutic effects by suppressing the TNF-α/NF-κB/apoptosis signaling pathway. Histological examination confirmed the absence of toxicity in major organs, indicating a favorable safety profile. Overall, presents the first application of neutrophil membrane-fused M2EVs for targeted SCI therapy, combining site-specific homing with immunomodulatory and neuroprotective functions. This biomimetic strategy holds strong translational potential for SCI and other neuroinflammatory disorders.

Keywords:  Extracellular vesicle; M(2) macrophage; Neutrophil membrane fusion; Spinal cord injury; TNF-α/NF-κB pathway; Targeted delivery

DOI:  https://doi.org/10.1016/j.bioadv.2025.214627
Small. 2025 Dec 03. e07451

Corneal Nerve Regeneration via MSC-Derived EVs: Tissue Source and Culture Dimensionality Dictate miRNA Cargo and Therapeutic Efficacy.

Hamed Massoumi, Eitan A Katz, Melinda Alviar, Qiang Zhou, Mauricio Gonzalez Oyarzun, Deepshikha Tiwari, Makayla Dove, Hanieh Niktinat, Tara Nguyen, Seyed Mahbod Baharnoori, Khandaker Anwar, Mark Maienschein Cline, Yuanxiang Li, Xiaowei Wang, Victor H Guaiquil, Mark I Rosenblatt, Ali R Djalilian, Elmira Jalilian.

  Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication and tissue repair, offering a promising cell-free platform for regenerative therapies. In the cornea, sensory nerves are critical for maintaining epithelial integrity and ocular homeostasis. Nerve injury resulting from trauma, surgery, or disease leads to persistent epithelial defects and impaired vision, with limited treatment options. Here, the neuro-regenerative potential of mesenchymal stem cell-derived EVs (MSC-EVs) isolated from human cornea (Co-MSC) and bone marrow (BM-MSC) cultured under 2D and 3D conditions is investigated. EVs are characterized by nanoparticle tracking analysis, ExoView profiling, and Western blot, and their effects on nerve regeneration are evaluated using primary trigeminal ganglion neurons in vitro and a murine corneal injury model in vivo. EVs from both tissue sources promoted neurite outgrowth; however, 3D-derived EVs demonstrate superior efficacy compared to 2D-derived EVs in vitro and in vivo. Co-MSC-EVs show a consistent trend toward enhanced regenerative effects over BM-MSC-EVs. Small RNA sequencing reveals that EV cargo is influenced by both tissue origin and culture dimensionality, with Co-MSC-EVs enriched in miRNAs regulating the extracellular matrix and immune pathways, while BM-MSC-EVs are enriched in neurotrophic signaling miRNAs. These findings support the rational design of MSC-EV-based therapies for neuro-ophthalmic repair.

Keywords:  3D culture; corneal nerves; exosomes; extracellular vesicles; mesenchymal stem cell

DOI:  https://doi.org/10.1002/smll.202507451
Nanomedicine (Lond). 2025 Dec 03. 1-9

Engineered extracellular vesicles for nose-to-brain co-delivery of chlorotoxin and curcumin for treatment of glioblastoma.

Mincheol Son, Jae Young Park, Subin Kang, Kangmin Park, Minhyung Lee.

   AIM: Extracellular vesicles (EVs) were developed as a co-delivery carrier of curcumin and chlorotoxin (CTX) into the brain.
MATERIALS & METHODS: CTX was linked to the surface of EVs by genetic engineering. Curcumin was loaded onto CTX-linked EVs (CTX-EV) by hydrophobic interaction. Dynamic light scattering, flow cytometry, and cytotoxicity assay were performed in vitro characterization. The therapeutic effect was evaluated in the glioblastoma animal models.
RESULTS: The size and zeta-potential of curcumin-loaded CTX-EV (CTX-EV/Cur) were around 295 nm and -35 mV. The curcumin delivery efficiency of CTX-EV/Cur was higher than that of curcumin alone or Unmod-EV/Cur, suggesting that CTX facilitated the cellular uptake of CTX-EV/Cur. Cytotoxicity assay showed that the viability of C6 glioblastoma cells was decreased by CTX-EV compared with Unmod-EV. The results suggest that CTX has an anti-tumor effect. Finally, anti-tumor therapeutic effects of CTX-EV/Cur were evaluated in glioblastoma animal models after intranasal administration. We found that CTX-EV/Cur enhanced expression of the programmed cell death protein 4 (PDCD4) gene and induced apoptosis in the tumor compared with the other groups. In addition, the tumor size was effectively decreased by CTX-EV/Cur.
CONCLUSION: The results suggest that CTX is not only an anti-tumor drug, but also a targeting ligand for enhanced cellular uptake. Therefore, enhanced therapeutic effects of CTX-EV/Cur may be due to synergistic effects of CTX and curcumin. Combined delivery of curcumin and CTX using CTX-EVs may be useful for treatment of glioblastoma.

Keywords:  Chlorotoxin; curcumin; extracellular vesicles; glioblastoma; intranasal delivery

DOI:  https://doi.org/10.1080/17435889.2025.2598338
Front Pharmacol. 2025 ;16 1682548

Exosomes derived from Panax notoginseng promote osteogenic differentiation of rBMSCs via the PI3K/AKT signaling pathway.

Nan Wu, Lintao Zhang, Hua Guo.

   Objective: This study aims to investigate the effect of exosomes derived from Panax notoginseng on the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) and to elucidate the underlying intracellular signaling mechanisms.
Methods: Exosomes from Panax notoginseng were isolated using differential centrifugation combined with sucrose density gradient centrifugation. The morphology of the exosomes was characterized by transmission electron microscopy (TEM), while size distribution and concentration were determined via nanoparticle tracking analysis (NTA). rBMSCs were isolated and identified by flow cytometry, and the uptake of fluorescently labeled Panax notoginseng exosomes by rBMSCs was confirmed using confocal microscopy. The optimal concentration of exosomes was determined using the CCK-8 assay. Osteogenic differentiation was evaluated by measuring alkaline phosphatase (ALP) activity, performing ALP staining, and conducting Alizarin Red S staining. The expression levels of osteogenic markers (collagen type I(COL1), ALP, osteopontin (OPN), and Runt-related transcription factor 2 (RUNX2)) were quantified at the mRNA (RT-qPCR) and protein (Westem blotting)levels. High-throughput RNA sequencing and bioinformatics analyses (Gene Ontology (GO),Kyoto Encyclopedia of Genes and Genomes (KEGG)) were employed to identify differentially expressed genes and enriched pathways. Key pathways were validated using specific inhibitors.
Results: Exosomes derived from Panax notoginseng promote the osteogenic differentiation of rBMSCs through the activation of the PI3K/AKT signaling pathway. This study provides experimental evidence and theoretical support for the application of herbal exosomes in bone tissue engineering and the treatment of osteoporosis.
Conclusion: Panax notoginseng exosomes promote osteogenic differentiation of rBMSCs by activating the PI3K/AKT pathway, providing experimental evidence and theoretical support for the application of herbal exosomes in bone tissue engineering and osteoporosis treatment.

Keywords:  BMSCs; PI3K/Akt pathway; Panax notoginseng exosomes; bone metabolism; osteogenic differentiation; osteoporosis

DOI:  https://doi.org/10.3389/fphar.2025.1682548
bioRxiv. 2025 Nov 19. pii: 2025.11.19.689327. [Epub ahead of print]

Copper-Free Click Chemistry Enables High-Fidelity Engineering of Mitochondria-Targeted Brain-Derived Exosomes.

Xin Yan, Xinqian Chen, Shanshan Hou, Xiaoxu Li, Jingyue Ju, Zhiying Shan, Lanrong Bi.

Mitochondrial dysfunction is a hallmark of neurodegenerative and neuroinflammatory disorders, including hypertension and cardiovascular disease, yet strategies for safe and precise mitochondrial-targeted delivery remain limited. Here, we establish strain-promoted azide-alkyne cycloaddition (SPAAC) as a biocompatible, high-fidelity chemical platform for engineering mitochondria-targeted brain-derived exosomes (BR-EVs). Copper-free click conjugation of a mitochondrial-targeting ligand (e.g. Cy5-DBCO) under mild aqueous conditions preserved vesicle morphology (30-150 nm core; 120-200 nm hydrodynamic), proteomic composition, and uptake dynamics. Time-course imaging and fluorescence recovery after photobleaching (FRAP) revealed unaltered endocytic kinetics, >75 % mitochondrial colocalization, and intact organelle architecture. In vivo neuroinflammation and biodistribution analyses demonstrated immunological neutrality, strong central nervous system retention, and minimal peripheral dispersion following intracerebroventricular administration. Proteomic profiling of unlabeled Sprague-Dawley (SD) and hypertensive Dahl salt-sensitive (DSS) BR-EVs uncovered hypertension-driven enrichment of oxidative and complement pathways correlating with mitochondrial fragmentation and reactive oxygen species generation in neuronal cultures. These findings establish SPAAC-mediated ligand conjugation as a biocompatible and chemically precise approach for generating mitochondria-targeted exosomes that preserve exosomal identity, biodistribution, and signaling fidelity-advancing a foundational platform for organelle-specific delivery and mechanistic imaging in the central nervous system.

DOI: https://doi.org/10.1101/2025.11.19.689327
Sci Adv. 2025 Dec 05. 11(49): eadv8999

A self-assembled nano micelle-exosome with high selectivity and penetrability achieves precise intracartilage lipid delivery.

Ming-Yang Li, Li-Min Wu, Hui-Qi Xie, Bin Shen.

To address the challenge of extremely low drug bioavailability in osteoarthritis (OA) cartilage, we developed a self-assembled micelle-exosome system (Mic-Exo) tailored to the specific characteristics of OA cartilage. The hydrophobic lipid layer of Mic-Exo enables efficient loading of therapeutic lipids (DHA), while the incorporation of 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) reverses surface charge to enhance penetration. The hydrophilic polyethylene glycol (PEG) shell protects Mic-Exo from rapid clearance and undesired endocytosis. The amphiphilic monomers in the micelle incorporate a matrix metalloproteinase (MMP)-responsive peptide (GPLGVRG), which undergoes hydrolysis in response to elevated MMP activity at lesion sites, enabling rapid uptake by nearby chondrocytes. In vitro experiments confirmed the high selectivity of Mic-Exo for OA chondrocytes and its rapid penetration capabilities. In animal models, the DHA/Mic-Exo group significantly retarded OA progression, as evidenced by reduced Osteoarthritis Research Society International (OARSI) scores and mitigated cartilage thickness loss.

DOI: https://doi.org/10.1126/sciadv.adv8999