bims-engexo 2026-03-29 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–03–29
nineteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Therapeutic efficacy of engineered exosomes in Alzheimer's disease: A systematic review and meta-analysis of preclinical animal models.
A Nanoparticle-Integrated Complete Manufacturing Pipeline of Chemically Engineered Exosomes.
Strategies, Challenges and Application Prospects for Exosome Engineering Modifications in Tumor Targeted Therapeutics.
Engineering of Extracellular Vesicles for Targeted Delivery of Prodigiosin.
Extracellular vesicle-mediated HIF-1α delivery promotes durable vascular remodeling via endothelial Dll1-dependent CD163+ macrophage differentiation.
A Bioinspired Approach to Next-Generation Vaccines in Solid Tumors with Engineered Cell Membranes.
Extracellular vesicles in chronic wound therapy: engineering strategies and advanced delivery systems for enhanced regeneration.
Engineering Yeast Extracellular Vesicle Biogenesis Through Rewiring Membrane Trafficking Pathways.
Metformin-Loaded Schwann Cell Exosomes Reprogram Macrophages and Enhance Neurogenesis in Spinal Cord Injury Through PI3K/AKT Activation.
Plant-Derived Nanocarriers for Drug Delivery: A Unified Framework Integrating Extracellular Vesicles, Engineered Phytocarriers, Hybrid Platforms, and Bioinspired Systems.
Immune-modified exosome vaccine loaded with liver cancer epitope peptides induces potent and specific antitumor immunity.
Harnessing semen-derived exosomes for noninvasive fundus drug delivery: A paradigm for exosome-based ocular fundus therapeutics.
Engineered Microglial Exosome-Liposome Hybrid Nanovesicles for Synergistic Therapy of Hypoxic-Ischemic Encephalopathy by Dual-Targeting Ferroptosis and Neuroinflammation.
Ampicillin-Loaded Fenugreek-Derived Exosomes Treat COPD via Anti-Inflammatory, Antibacterial and Anti-Fibrotic Effects.
Overcoming lysosomal barrier via V-ATPase: an exosome-based co-delivery platform for combined chemo/RNAi therapy against breast cancer.
Melatonin-loaded MSCs-derived exosomes as therapeutic carriers to alleviate levodopa-induced dyskinesia in Parkinson's disease.
Stability Challenges and Engineering Strategies of Plant-Derived Extracellular Vesicle-Like Particles: A Translational Perspective.
Aptamer-functionalized exosomes combined with doxorubicin suppress GBM progression and enhance chemoradiosensitivity by promoting pyroptosis.
Exosomes derived from TGF-β1-modified mesenchymal stem cells protect septic mice by inducing macrophage M2 polarization.

Neuroscience. 2026 Mar 20. pii: S0306-4522(26)00187-9. [Epub ahead of print]

Therapeutic efficacy of engineered exosomes in Alzheimer's disease: A systematic review and meta-analysis of preclinical animal models.

An Li, Weijun Peng, Beibei Wu, Chuyu Li, Jingjing Yang.

  Engineered exosomes are modified extracellular vesicles designed to enhance targeting and cargo delivery, and they have been proposed as a therapeutic strategy for Alzheimer's disease. We systematically reviewed preclinical animal studies evaluating engineered exosomes, synthesized evidence from comparisons with disease models and with natural exosomes, and reported the study in accordance with the PRISMA 2020 checklist. Outcomes included spatial learning and memory assessed by the Morris water maze, amyloid beta pathology, tau phosphorylation, and neuroinflammatory markers. Random effects meta-analyses suggested that engineered exosomes improved Morris water maze performance and reduced amyloid beta burden and pro-inflammatory cytokines compared with natural exosomes, whereas evidence regarding tau phosphorylation was limited and largely qualitative, and the overall certainty of evidence was low to very low. These findings support further investigation of engineered exosomes, but conclusions should be interpreted cautiously until confirmed by rigorously designed and blinded preclinical studies and clinical trials with standardized protocols.

Keywords:  Alzheimer’s disease; Cognitive function; Engineered exosomes; Neuroinflammatory; Preclinical animal models

DOI:  https://doi.org/10.1016/j.neuroscience.2026.03.019
Adv Sci (Weinh). 2026 Mar 24. e16075

A Nanoparticle-Integrated Complete Manufacturing Pipeline of Chemically Engineered Exosomes.

Xiaowei Wen, Zixing Xu, Zerun Hao, Yanming Chen, Kai Xie, Haofan Yin, Xueying Wang, Jie Min, Sihan Sun, Baiding Chen, Chengxiu Ling, Mingming Xu, Yizhao Chen, Gang Ruan.

  Clinical translation of engineered exosomes, an emerging class of cell therapies, is hampered by challenges in each step of the manufacture flow, namely biogenesis, cargo loading, isolation, and storage. Here, we present a technology termed Tat-PNCAS-MIMS-MSC-Exo for manufacturing chemically engineered exosomes, with the above four steps being integrated by the use of the nanoparticle PNCAS-Tat (Tat peptide-conjugated protein-nanoparticle co-assembly supraparticle). This technology enables drastic improvements in all four steps of the manufacture flow of chemically engineered exosomes derived from mesenchymal stem cells (MSCs), a commonly-used cell type for cell therapies. The stimulation effect of exosome biogenesis by Tat peptide can be amplified by nanoparticle conjugation, a previously unknown nano-effect. The novel design of magnet setup MIMS (mobile internal magnetic separation) enables a unique capacity for scale-up of magnetic isolation, i.e., near-identical time for different scales to achieve near-complete isolation. This offers an effective solution to the long-standing problem of scale-up in applying magnetic isolation for biomanufacturing, which usually requires larger scales than bioanalytical applications. The manufacture process is robust, scalable, and economical. We conduct mechanistic studies of the nano-bio interactions, and demonstrate applications of the products in multiple disease models.

Keywords:  cell therapy; extracellular vesicle; nanomedicine; production; separation

DOI:  https://doi.org/10.1002/advs.202516075
Int J Nanomedicine. 2026 ;21 572435

Strategies, Challenges and Application Prospects for Exosome Engineering Modifications in Tumor Targeted Therapeutics.

Xiaoyan Ge, Shuo Shan, Haozhong Lu, Weihua Wang, Chao Gao, Shunli Fu.

  Nanodrugs have significantly revolutionized tumor therapy. Nevertheless, conventional nanodrug delivery systems suffer from a critical limitation: only ~0.7% of administered nanoparticles effectively accumulate in solid tumors, severely restricting clinical therapeutic efficacy. In recent years, exosomes-natural extracellular vesicles-have emerged as highly promising candidates for tumor-targeted drug delivery. Endowed with inherent low immunogenicity, excellent biocompatibility, and intrinsic capacity to traverse biological barriers, exosomes offer distinct advantages over conventional nanocarriers. Their characteristic lipid bilayer membrane not only protects encapsulated cargo but also enables surface engineering for functional optimization. Through strategic engineering modifications, exosomes can be endowed with enhanced tumor-targeting specificity, tunable payload release profiles, and multimodal functionalities, thus enabling the development of "smart" therapeutic platforms. This review systematically outlines current methodologies for exosome isolation and characterization, with a particular focus on engineering strategies aimed at augmenting tumor targeting. We comprehensively analyze approaches based on physical manipulation, chemical conjugation, and biological engineering. Furthermore, we summarize recent advances in exosome-based targeted cancer therapies and discuss key challenges related to scalability, standardization, regulatory approval, and clinical translation. Finally, we highlight emerging opportunities and future perspectives for next-generation exosome-engineered therapeutic development, aiming to provide a robust technical and conceptual foundation for advancing tumor therapy.

Keywords:  engineering modifications; exosome; nanotechnology; tumor targeted therapeutics

DOI:  https://doi.org/10.2147/IJN.S572435
BioTech (Basel). 2026 Mar 01. pii: 21. [Epub ahead of print]15(1):

Engineering of Extracellular Vesicles for Targeted Delivery of Prodigiosin.

Ivan Guryanov, Sirina Sabirova, Svetlana Batasheva, Svetlana Konnova, Arthur Khannanov, Marianna Kutyreva, Ekaterina Naumenko.

  The therapeutic potential of prodigiosin as a hydrophobic anticancer agent can be enhanced by various approaches, one of which is the loading of PG into extracellular vesicles. Drug distribution and stability in aqueous media play a crucial role in targeting and accumulation, thereby enabling the attainment of therapeutically effective drug concentrations. Extracellular vesicles are nano-sized, cell-derived vesicles with a lipid bilayer membrane. Extracellular vesicles can be utilized as drug carriers for both water-soluble and non-water-soluble therapeutic agents. We hypothesized that microvesicles could effectively address the current challenges of prodigiosin delivery. Several different techniques have been developed for fabricating extracellular vesicles. These include microvesicles induction by cytochalasin B treatment as well as cell cultivation in serum depleted media. In our study, prodigiosin, like cytochalasin B, demonstrated efficacy in microvesicles formation based on protein quantification and Nanoparticle Tracking Analysis. In addition, Nanoparticle Tracking Analysis showed that vesicles from mesenchymal stem cells are more stable under ultrasound exposure. Microvesicles encapsulating prodigiosin, compared to unmodified naïve ones, demonstrated slightly increased zeta potentials and hydrodynamic diameters, which probably contributed to better stability. We demonstrated that ultrasonic treatment for the loading of prodigiosin does not significantly increase the proportion of prodigiosin-positive microvesicles in comparison with microvesicles induced with prodigiosin; moreover, this method cannot be considered as optimal due to its disadvantages, such as particle aggregation. Prodigiosin-induced and prodigiosin-loaded microvesicles from mesenchymal stem cells were significantly smaller and less polydisperse in size. Overall, prodigiosin encapsulated in extracellular vesicles might be more suitable for medical and clinical applications compared to pure forms of PG due to their cell membrane compatibility.

Keywords:  drug delivery systems; extracellular vesicles; prodigiosin; prodigiosin encapsulating; prodigiosin-induced membrane vesicles

DOI:  https://doi.org/10.3390/biotech15010021
J Control Release. 2026 Mar 24. pii: S0168-3659(26)00264-6. [Epub ahead of print] 114862

Extracellular vesicle-mediated HIF-1α delivery promotes durable vascular remodeling via endothelial Dll1-dependent CD163+ macrophage differentiation.

Seongeon Cho, Yeji Lee, Yeong Ha Hwang, Jiyoung Goo, Jihoon Han, Jiwan Woo, Gi-Hoon Nam, Cherlhyun Jeong, Iljin Kim, In-San Kim.

  Critical limb ischemia (CLI) is a severe vascular disease with limited pharmacologic treatments and a high risk of amputation. Conventional therapeutic angiogenesis, mainly based on single growth factors, has failed to achieve stable and functional vessel formation. Recent insights indicate that interactions between endothelial cells and immune cells, particularly perivascular macrophages, are critical for durable vascular remodeling. Here, we engineered a pH-responsive intein-based platform to load extracellular vesicles (EVs) with a stabilized, constitutively active form of hypoxia-inducible factor-1α (HIF-1α). In this study, we demonstrate that EV-mediated HIF-1α delivery markedly improves perfusion and reduces necrosis in a murine hindlimb ischemia model. HIF-1α-EVs activated a regenerative vascular program that coupled new vessel growth with structural maturation, resulting in enlarged collateral arteries and an expansion of type H and CD34+ endothelial populations. Notably, HIF-1α-EV treatment also increased CD163+ perivascular macrophages, which are known to support arteriogenesis by vessel stabilization. Mechanistically, EV-mediated delivery of HIF-1α upregulated endothelial Delta-like ligand 1 (Dll1), which directed macrophage differentiation toward a CD163+ reparative phenotype, thereby reinforcing vascular maturation and restoring blood flow. Collectively, this transcription factor delivery strategy offers a promising therapeutic avenue for durable revascularization in CLI and potentially other ischemic diseases.

Keywords:  Angiogenesis; Arteriogenesis; Dll1; Extracellular vesicle; HIF-1α; Ischemia; Perivascular macrophage

DOI:  https://doi.org/10.1016/j.jconrel.2026.114862
Research (Wash D C). 2026 ;9 1193

A Bioinspired Approach to Next-Generation Vaccines in Solid Tumors with Engineered Cell Membranes.

Weiyue Zhang, Maike Chen, Xin Huang.

In solid tumors, the immunosuppressive tumor microenvironment and antigenic heterogeneity pose important challenges for effective immunotherapy, often leading to limited T-cell infiltration and inadequate immune activation. To overcome these barriers in solid tumors, the development of next-generation vaccines capable of eliciting robust and durable anti-tumor immunity has constituted a major focus in the clinic. A promising strategy involves a bioinspired approach that functionalizes synthetic nanocarriers with native cell membranes. These engineered platforms are designed to preserve the surface properties of native cell membranes (immune cells, nonimmune cells, and hybrid cell membranes) to enhance antigen presentation, prolong systemic circulation, and improve biocompatibility. This study systematically examines the design principles and mechanisms of bioinspired vaccines with native cell membranes, highlighting their capability to integrate multiple antigenic and adjuvant signals for superior antigen presentation and T-cell activation. We further explore the synergistic therapeutic effects of the next-generation vaccines when combined with common anti-tumor therapies. Moreover, the primary challenges for their clinical translation in solid tumors are critically discussed. These bioinspired nanoplatforms represent a transformative direction for developing more effective and personalized immunotherapies for solid tumors.

DOI: https://doi.org/10.34133/research.1193
Mater Today Bio. 2025 Dec;35 102298

Extracellular vesicles in chronic wound therapy: engineering strategies and advanced delivery systems for enhanced regeneration.

Le Ding, Tingrui Zhang, Yixiao Pan, Jun Liu, Tianyou Ma, Hanxue Zhou, Quangang Zhu, Zongguang Tai, Zhongjian Chen.

  Chronic wounds, including diabetic foot ulcers, are notoriously difficult to heal due to their complex pathological microenvironments, which are marked by persistent inflammation and impaired angiogenesis. These challenges place a significant burden on both patients and healthcare systems. Extracellular vesicles (EVs), as natural carriers, can modulate the wound microenvironment and facilitate tissue regeneration by delivering bioactive molecules such as proteins and nucleic acids. EVs offer advantages including low immunogenicity and excellent biocompatibility. However, unmodified EVs face limitations such as low therapeutic payloads, limited targeting capability, and vulnerability to degradation. Building on this foundation, this review provides a detailed overview of the specific roles and mechanisms of EVs in wound healing. It focuses particularly on condition-specific strategies, engineering approaches, and the use of biomaterials to further enhance the therapeutic efficacy of EVs in treating chronic wounds. Finally, we highlight the current challenges faced in the clinical translation of EV-based therapies and propose emerging strategies to address these obstacles, offering new directions for chronic wound management.

Keywords:  Advanced delivery systems; Biomaterials; Chronic wound healing; Engineered EVs; Extracellular vesicles

DOI:  https://doi.org/10.1016/j.mtbio.2025.102298
Microb Biotechnol. 2026 Apr;19(4): e70338

Engineering Yeast Extracellular Vesicle Biogenesis Through Rewiring Membrane Trafficking Pathways.

Yueyan Li, XiaoRan Ma, Lichao Zhang, Ning Cao, Zhibo Li, Ruixin Khoo, Mei Wang, Changyan Li, Deping Hua, Xintian Zheng, Jinhai Huang, Lilin Zhang.

  Extracellular vesicles (EVs) are emerging as versatile therapeutic platforms, yet the mechanisms governing their biogenesis in yeast remain incompletely understood. Saccharomyces cerevisiae, a well-characterised and safe microbial chassis, naturally secretes abundant EVs and provides an attractive system for mechanistic dissection and engineering. Here, we establish S. cerevisiae as a tractable model for elucidating EV cargo loading. By combining multicopy expression of chicken interferon-λ (ChiIFN-λ) with cell wall perturbation, we achieved a tenfold increase in EV yield and efficient incorporation of ChiIFN-λ into EVs. Quantitative proteomics identified 1555 EV-associated proteins, including 501 predicted transmembrane proteins derived from multiple organelles. ChiIFN-λ overexpression and cell wall stress selectively reduced the abundance of key vesicle trafficking regulators, including SNARE, ESCRT and Rab proteins, indicating reprogramming of intracellular membrane trafficking pathways. Functional analyses further demonstrated that the SNARE proteins Sso2 and Nyv1 are enriched in the EV membrane and modulate EV size distribution and subpopulation composition. Together, these results reveal conserved protein-sorting machinery underlying yeast-derived extracellular vesicles (YDEVs) biogenesis and establish S. cerevisiae as a powerful platform for engineered EV production.

Keywords:   Saccharomyces cerevisiae ; SNARE components; chicken interferon‐λ; engineering yeast; extracellular vesicles

DOI:  https://doi.org/10.1111/1751-7915.70338
FASEB J. 2026 Apr 15. 40(7): e71628

Metformin-Loaded Schwann Cell Exosomes Reprogram Macrophages and Enhance Neurogenesis in Spinal Cord Injury Through PI3K/AKT Activation.

Shibo Ma, Duo Shan, Qingfeng Shen.

  Spinal cord injury (SCI) creates a hostile microenvironment characterized by persistent inflammation and glial scarring, which severely limits endogenous neural regeneration. To address these multifactorial barriers, we developed a targeted nanotherapeutic system comprising glutathione-functionalized Schwann cell-derived exosomes loaded with metformin (Exos-GSH@Met). In vitro and in vivo evaluations showed that GSH functionalization enabled the exosomes to effectively cross the blood-spinal cord barrier and selectively accumulate in macrophages at the injury site. Transcriptomic sequencing identified the PI3K/AKT pathway as a critical target activated by Exos-GSH@Met. Mechanistically, the treatment reprogrammed macrophages from a pro-inflammatory M1 phenotype to a reparative M2 phenotype via PI3K/AKT activation. This immunomodulatory shift subsequently orchestrated the differentiation of neural stem cells (NSCs) into functional neurons while suppressing astrocytic differentiation. Crucially, in vivo blockade of the PI3K pathway using the inhibitor LY294002 negated these regenerative effects, confirming the pathway's centrality. Furthermore, Exos-GSH@Met not only reduced the density of the glial scar but also significantly inhibited the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) by reactive astrocytes. Functionally, the treatment significantly improved motor recovery, restored electrophysiological conduction, and ameliorated bladder dysfunction in SCI mice. Collectively, these findings establish Exos-GSH@Met as a dual-action platform that coordinates immune microenvironment remodeling and neurogenesis through the PI3K/AKT axis, offering a promising strategy for SCI repair.

Keywords:  PI3K/AKT pathway; Schwann cell‐derived exosomes; macrophage polarization; metformin; neural stem cells; spinal cord injury

DOI:  https://doi.org/10.1096/fj.202502540R
Plants (Basel). 2026 Mar 15. pii: 908. [Epub ahead of print]15(6):

Plant-Derived Nanocarriers for Drug Delivery: A Unified Framework Integrating Extracellular Vesicles, Engineered Phytocarriers, Hybrid Platforms, and Bioinspired Systems.

Adina-Elena Segneanu, George Dan Mogoşanu, Cornelia Bejenaru, Roxana Kostici, Ludovic Everard Bejenaru.

  Plant-derived extracellular vesicles (PDEVs), engineered phytosomes, bioinspired polymeric plant-based nanoparticles (PBNPs), hybrid phyto-inorganic nanocomposites, green-synthesized metal nanoparticles, self-assembled nanoarchitectures, and multifunctional composites represent a rapidly advancing class of sustainable, nature-inspired nanocarriers. These platforms combine exceptional biocompatibility, negligible immunogenicity, and renewable sourcing with tunable drug loading, targeted delivery, and controlled release properties. This review synthesizes translational advances from 2020 to 2026, covering scalable isolation/bioprocessing (bioreactors, elicitation), multi-parametric physicochemical/multi-omics characterization, rational engineering/hybridization, and rigorous in vitro/in vivo assessments of uptake, biodistribution, pharmacokinetic (PK), and efficacy. Phytosomes and PBNPs markedly enhance oral bioavailability and targeted delivery of lipophilic phytochemicals, while PDEVs offer unique immunomodulatory, anti-inflammatory, and gene-regulatory activities. Hybrid and green-synthesized systems provide structural stability, redox modulation, and synergistic effects, and self-assembled/multifunctional composites address solubilization barriers with stimuli-responsive design. Early-phase human studies on grapefruit-, ginger-, turmeric-, and ginseng-derived PDEVs report excellent short-term safety, favorable PK, and preliminary bioactivity signals, with no observed immunogenicity or dose-limiting toxicities; however, these trials remain exploratory, constrained by small sample sizes and safety-focused endpoints. Despite challenges, including methodological heterogeneity, variable yields, long-term safety uncertainties (notably for inorganic hybrids), and regulatory ambiguities, emerging strategies such as clustered regularly interspaced short palindromic repeats (CRISPR)-engineered plant line; artificial-intelligence-driven process optimization; standardized guidelines, and integrated clinical, intellectual property, and commercialization frameworks are progressively addressing these barriers. Collectively, these advances position plant-derived nanocarriers as immunologically privileged, eco-friendly alternatives to synthetic and mammalian platforms, laying the foundation for a sustainable era of precision phytomedicine.

Keywords:  bioinspired systems; drug delivery; extracellular vesicles; hybrid platforms; nanocarriers; phytocarriers; plant

DOI:  https://doi.org/10.3390/plants15060908
J Nanobiotechnology. 2026 Mar 24.

Immune-modified exosome vaccine loaded with liver cancer epitope peptides induces potent and specific antitumor immunity.

Shumin Luo, Li Xiao, Fang Xu, Pengpeng Lu, Yiyue Wang, Chuanyun Li, Enhong Xing, Weihua Li.

   BACKGROUND: Dendritic cell-derived exosomes (DEXs) are emerging as effective platforms for cancer vaccines due to their capacity to present tumor antigens and regulate immune responses. Here, we developed a multifunctional DEX vaccine (DEXAGNP) that integrates liver cancer epitope presentation, innate immune activation, and checkpoint modulation. Human DEXAGNP was generated by loading HLA-A*02:01-restricted hAFP158-166 and hGPC3144-152 peptides, and murine DEXAGNP by loading mAFP212-219 and mGPC3127-136 peptides. The N-terminal functional domain of high-mobility group nucleosome-binding protein 1 (N1ND) was membrane-anchored via CHOL-PEG2000, and programmed death ligand 1 (PD-L1) of DEXs surface was blocked with anti-PD-L1 antibodies to mitigate immunosuppression.
RESULTS: DEXAGNP vaccine enhanced antigen-specific CD8⁺ T-cell responses, as supported by peptide-MHC tetramer staining, and promoted cytokine-associated effector activity. In vitro, DEXAGNP-primed T cells mediated cytotoxicity against both human and murine liver cancer cell lines. In vivo, DEXAGNP suppressed tumor growth in an immunocompetent subcutaneous H22 model and a humanized HepG2 xenograft model, and demonstrated antitumor activity in an orthotopic HCC model. In addition, DEXAGNP induced measurable killing in ex vivo assays using clinical HCC specimens and, in the prophylactic setting, was associated with enhanced memory-like T-cell responses.
CONCLUSION: DEXAGNP is a modular exosome vaccine that combines epitope-specific antigen presentation with immune activation and PD-L1 blockade, enabling robust antitumor T-cell responses across complementary liver cancer models. This engineered DEX platform provides a practical blueprint for developing next-generation exosome-based cancer vaccines.

Keywords:  Cancer vaccine; Dendritic cell-derived exosomes; Epitope peptides; Immunotherapy; Liver cancer; PD-L1 blockade

DOI:  https://doi.org/10.1186/s12951-026-04166-y
Sci Adv. 2026 Mar 27. 12(13): eadw7275

Harnessing semen-derived exosomes for noninvasive fundus drug delivery: A paradigm for exosome-based ocular fundus therapeutics.

Jiansong Zhao, Tian Yin, Yaxin Deng, Hongbing Liu, Mingli Wei, Chenxiao Chu, Xinxin Liang, Xiaoshuang Bi, Haibing He, Jingxin Gou, Xing Tang, Yu Zhang.

Exosomes, despite their promise as drug carriers for crossing biological barriers, remain underexplored for noninvasive posterior ocular delivery. Here, we demonstrate that semen-derived exosomes (SEVs) penetrate ocular barriers effectively, owing to their epidermal growth factor expression, which mediates reversible tight-junction disruption. SEVs reach the posterior segment via dual corneal and conjunctival routes. Using this, we engineered FA-SEVs@CMG eye drops, where SEVs are modified with folic acid (FA) and loaded with a nanozyme system (CMG) composed of carbon dots, manganese dioxide, and glucose oxidase. This eye drop leverages SEVs' excellent penetration ability and FA's targeting effect to enhance drug delivery to retinoblastoma (RB) cells. Internalized CMG induces intense oxidative stress, disrupts the autophagy-apoptosis balance, and triggers RB cell self-destruction. In vivo, FA-SEVs@CMG effectively inhibits RB growth while preserving retinal function. This work establishes the first SEV-based platform for noninvasive posterior segment delivery, offering a transformative strategy for treating posterior ocular diseases.

DOI: https://doi.org/10.1126/sciadv.adw7275
Adv Healthc Mater. 2026 Mar 23. e71060

Engineered Microglial Exosome-Liposome Hybrid Nanovesicles for Synergistic Therapy of Hypoxic-Ischemic Encephalopathy by Dual-Targeting Ferroptosis and Neuroinflammation.

Chanyue Wang, Kangqian Tian, Changfeng Jia, Liguo Song, Caifan Wang, Weipeng Gao, Zhaojuan Wang, Jiacan Xu, Yuchen Li, Yalin Li, Qian Liu.

  Hypoxic-ischemic encephalopathy (HIE) is a major cause of neurological injury in neonates, with pathological cascades such as neuroinflammation and ferroptosis driving disease progression. Current therapeutic strategies for HIE are largely limited to supportive care and therapeutic hypothermia, which fail to effectively target these mechanisms. To address this challenge, we developed a microglia-derived exosome-liposome hybrid membrane systems (HMS) (R+si@LPs-TK/TAT+Exo, abbreviated as Rs@LP-T/T-E) for the co-delivery of resveratrol (RES) and acyl-CoA synthetase long-chain family member 4 (ACSL4) siRNA. The nanosystem exhibited favorable stability, reactive oxygen species (ROS)-responsive drug release, and efficient blood-brain barrier (BBB) penetration, enabling targeted accumulation within ischemic brain regions. In experimental models, Rs@LP-T/T-E significantly attenuated neuroinflammation and ferroptosis, promoted microglial polarization toward the anti-inflammatory M2 microglial phenotype, and restored mitochondrial function, thereby reducing cerebral infarct volume and improving cerebral perfusion. In conclusion, this study presents an efficient, targeted, and biocompatible nanodelivery strategy that holds strong translational potential for HIE therapy.

Keywords:  acyl‐CoA synthetase long‐chain family member 4 (ACSL4) siRNA; hypoxic‐ischemic encephalopathy (HIE); microglia; nanovesicles; resveratrol (RES)

DOI:  https://doi.org/10.1002/adhm.71060
Int J Nanomedicine. 2026 ;21 578352

Ampicillin-Loaded Fenugreek-Derived Exosomes Treat COPD via Anti-Inflammatory, Antibacterial and Anti-Fibrotic Effects.

Haidiya Aierken, Bing Jia, Bahaerguli Aikeranmu, Pazula Aili, Weiming Yang, Changhao Zhong.

   Purpose: Chronic Obstructive Pulmonary Disease (COPD) is a major global health issue characterized by progressive airflow limitation, chronic inflammation, and recurrent infections. Current treatments largely alleviate symptoms but fail to simultaneously address infection-driven and inflammation-driven disease progression. Exosome-based strategies offer a promising alternative, and plant-derived exosomes possess distinct advantages, including low immunogenicity, natural abundance, and simple isolation compared with mammalian exosomes.
Methods: We developed a novel dual-functional nanotherapeutic agent by loading ampicillin into exosomes derived from Trigonella foenum-graecum. The resulting ampicillin-loaded exosomes (Exos-AM) harness the natural bioactivity and biocompatibility of plant exosomes to improve drug stability and cellular delivery. The therapeutic efficacy of Exos-AM was evaluated in a murine COPD model induced by lipopolysaccharide (LPS) instillation, cigarette smoke exposure, and P. aeruginosa infection.
Results: In vitro, Exos-AM exhibited potent antibacterial activity against S. aureus, E. coli, and P. aeruginosa, while promoting macrophage polarization toward the anti-inflammatory M2 phenotype, thereby alleviating inflammation and attenuating fibrotic responses. Transcriptomic analysis further revealed that Exos-AM modulated macrophage activation through suppression of the NF-κB and MAPK signaling pathways, providing mechanistic insight into its anti-inflammatory effects. In vivo, Exos-AM treatment significantly improved lung histopathology and enhanced bacterial clearance.
Conclusion: Our findings underscore the promise of plant-derived exosomes as versatile drug delivery platforms and position Exos-AM as a compelling therapeutic strategy for COPD by concurrently targeting infectious and inflammatory drivers.

Keywords:  COPD; anti-fibrosis; antibacterial; macrophage polarization; plant-derived exosomes

DOI:  https://doi.org/10.2147/IJN.S578352
J Nanobiotechnology. 2026 Mar 28.

Overcoming lysosomal barrier via V-ATPase: an exosome-based co-delivery platform for combined chemo/RNAi therapy against breast cancer.

Keyao Liu, Tingting Xiong, Xueyuan Wang, Ting Wang, Yudi Wang, Meng Lei, Lihua Shao, Liefeng Zhang, Yongqiang Zhu.

  Overcoming the lysosomal entrapment of nanotherapeutics remains a pivotal challenge for efficient drug delivery. Herein, we developed a nano-delivery system, designated as CEL-TPP@siSurvivin/TDNP NPs, consisting of a self-assembled nanocore formed by triphenylphosphine (TPP)-modified celastrol (CEL) and siSurvivin, encapsulated within turmeric-derived nanoparticles (TDNPs), for effective tumor treatment through a combined chemotherapy and gene therapy approach. The TPP modification confers mitochondrial targeting capability to CEL, which acts combinedly with siSurvivin-mediated gene silencing to significantly enhance tumor cell apoptosis. Notably, once the NPs enter cells and become sequestered within lysosomes, they induce the upregulation of the V-ATPase subunits ATP6V1A/ATP6V1G1. It hyperactivates lysosomal proton pumps, driving excessive acidification of the lysosomal lumen, which in turn facilitates NPs escape and ultimately enhances the silencing efficiency of the delivered siSurvivin. Furthermore, in vivo studies validated that the nano-delivery system exhibits potent antitumor efficacy in a 4T1 murine breast cancer model while maintaining a favorable biosafety profile. This study presents a novel strategy to overcome the lysosomal escape challenge in nanomedicine, while also establishing an efficient and low-toxicity delivery platform for combined chemotherapy and gene therapy with promising clinical translation prospects.

Keywords:  Combination therapy; Lysosomal escape; Plant exosomes; V-ATPase; siSurvivin

DOI:  https://doi.org/10.1186/s12951-026-04311-7
Nanomedicine. 2026 Mar 24. pii: S1549-9634(26)00023-7. [Epub ahead of print] 102922

Melatonin-loaded MSCs-derived exosomes as therapeutic carriers to alleviate levodopa-induced dyskinesia in Parkinson's disease.

Lin Liu.

  Parkinson's disease (PD) causes dopaminergic neuron damage in substantia nigra, with levodopa-induced dyskinesia (LID) as a side effect of long-term treatment with levodopa. Exosomes (Exo) from mesenchymal stem cells (MSC) are getting attention as nanosized carriers which facilitate the transfer of drugs through the blood-brain barrier. This study examined Melatonin-loaded Exo (MltExo) for neuroprotective effects in LID models of PD. MltExo was characterized for size, stability, and drug release. In vitro studies demonstrated improved cell viability, proliferation, reduced apoptosis, and ROS production when exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and levodopa. In vivo, experiments with mice showed that MltExo treatment protected against behavioral changes and locomotor deficits, enhancing cognitive function in LID group. Due to their antioxidant properties, MltExo preserved SNc, TH+, and nissl-stained cells. It reduced the inflammatory cytokines IL-1β and TNF-α at mRNA level. These findings suggest that MltExo is a promising therapeutic carrier for reducing LID in PD.

Keywords:  Exosome-based drug delivery; Levodopa induced dyskinesia; MSC-derived exosomes; Melatonin; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nano.2026.102922
Int J Nanomedicine. 2026 ;21 543674

Stability Challenges and Engineering Strategies of Plant-Derived Extracellular Vesicle-Like Particles: A Translational Perspective.

Hengyi Li, Yuxiang Yan, Meifang Lin, Shijie Wang, Yating Su, Jinhan Guo, Youguang Lu, Xiaohang Chen, Dali Zheng.

  Plant-derived extracellular vesicle-like particles (PD-EVLPs), composed of a phospholipid bilayer enriched with lipids, proteins, metabolites, and RNA, have emerged as promising therapeutic agents with intrinsic bioactivity (eg, anti-inflammatory and wound healing activities) as well as biocompatible nanocarriers. However, before their clinical translation, a key challenge lies in ensuring their stability in biological environments and achieving effective accumulation at disease sites. On one hand, the lack of standardized isolation protocols and preservation strategies where non-standardized methods compromise yield-purity balance, freeze-thaw cycles induce lipid rearrangements that lead to vesicle fusion, and lyophilization-induced ice crystals disrupt membrane integrity, poses a significant barrier to maintaining the dispersity, structural integrity, and purity of PD-EVLPs affecting their ex vivo stability. On the other hand, extreme conditions in gastric and intestinal fluids during administration can easily cause PD-EVLPs to degrade and their content to leak, while in vivo circulation necessitates avoiding rapid immune clearance in order to accumulate at target sites, further challenging their stability and bioavailability. In this review, we comprehensively evaluate the entire PD-EVLPs pipeline from preparation to application, dissecting potential stability concerns at each stage, including isolation, storage conditions, structural composition, and administration routes. We also explore the contribution of engineering strategies to enhancing PD-EVLPs stability while considering potential risks associated with these modifications. By establishing a comprehensive framework, we aim to provide concrete guidance for standardizing PD-EVLPs preparation protocols and designing preclinical studies, thereby streamlining their translation from bench to bedside.

Keywords:  administration; engineered modification; isolation; plant-derived extracellular vesicle-like particles; stability

DOI:  https://doi.org/10.2147/IJN.S543674
Mater Today Bio. 2026 Apr;37 103006

Aptamer-functionalized exosomes combined with doxorubicin suppress GBM progression and enhance chemoradiosensitivity by promoting pyroptosis.

Jing Wang, Li Peng, Xinxin Zhong, Siqi Zheng, Xiuhua Liang, Menghan Du, Xiangning Xia, Ting Guo, Lidan Zheng, Yingying Fang, Yinghong Tian, Yusheng Shi, Xingmei Zhang.

  Glioblastoma (GBM) is the highly lethal intracranial tumor characterized by low survival rates and high recurrence, partly attributable to the challenges posed by the blood-brain barrier (BBB). To enhance therapeutic efficacy, the Exo-U2-Dox complex was engineered by functionalizing mesenchymal stem cell (MSC)-derived exosomes with the GBM-targeting aptamer U2 and integrating them with doxorubicin (DOX). This complex is designed to augment the sensitivity of GBM to chemo-radiotherapy. Here, it is found that Exo-U2 effectively accumulates in GBM-bearing mice, thereby inhibiting tumor progression. When administered in conjunction with DOX and radiation, Exo-U2-Dox increases DNA damage in GBM cells, and diminishes invasiveness. Mechanistically, Exo-U2 targets and inhibits the autophosphorylation of Epidermal growth factor receptor variant Ⅲ (EGFRvⅢ) in GBM cells, thereby activating the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis pathway, which leads to increased expression of Gasdermin D (GSDMD) and Cysteine-aspartic acid protease-1 (caspase-1), ultimately suppressing GBM cell proliferation, migration, and invasion. Furthermore, the combination of Exo-U2 with X-ray treatment inhibits the expression of p53-binding protein 1 (53BP1), reduces phosphorylation of the Ataxia-Telangiectasia Mutated/Checkpoint kinase 2 (ATM/Chk2) pathway, resulting in the accumulation of DNA damage. Collectively, these findings underscore the potential of aptamer-functionalized exosomes in conjunction with DOX as a promising strategy for GBM treatment. This approach not only broadens the therapeutic applications of DOX but also provides a novel direction for targeted GBM therapies.

Keywords:  Aptamer; Chemo-radiosensitivity; Doxorubincin; Exosomes; Glioblastoma; Pyroptosis

DOI:  https://doi.org/10.1016/j.mtbio.2026.103006
Mol Biol Rep. 2026 Mar 25. pii: 538. [Epub ahead of print]53(1):

Exosomes derived from TGF-β1-modified mesenchymal stem cells protect septic mice by inducing macrophage M2 polarization.

Feng Liu, Liyao Liu, Xiao Zhao, Fachun Zhou.

   BACKGROUND: Exosomes derived from mesenchymal stem cells (MSCs) have been reported to improve the prognosis in septic mice. Additionally, we have confirmed that TGF-β1 plays a critical role in MSC-mediated protection against sepsis. In this study, we aimed to investigate whether exosomes derived from TGF-β1-overexpressing MSCs (TGF-β1-Exo) offer protective effects in sepsis.
METHODS: MSCs were collected from mouse MSCs stably transfected with TGF-β1 using a lentiviral vector. Exosomes were isolated and purified from MSCs (Exo), GFP-MSCs (GFP-Exo), and TGF-β1-MSCs (TGF-β1-Exo). A sepsis model was induced in mice via cecal ligation and perforation (CLP). After 6 h, exosomes from different sources were intravenously administered into septic mice. Mice were euthanised 24 h later, and histopathological changes were assessed using hematoxylin and eosin (H&E) staining. Inflammatory cytokine levels were measured using ELISA and RT-PCR. Flow cytometry was employed to evaluate macrophage phenotypes in lung tissues and in vitro macrophages. Additionally, we co-cultured fluorescently labeled exosomes with macrophages in vitro.
RESULTS: TGF-β1-Exo significantly ameliorated histopathological damage and improved survival rates in septic mice. ELISA and RT-PCR analyses revealed that several pro-inflammatory cytokines were notably suppressed in the TGF-β1-Exo group. Furthermore, TGF-β1-Exo promoted the polarization of M1 macrophages to M2 macrophages both in vivo. In vitro, TGF-β1-Exo were internalized by LPS-pretreated macrophages, promoting the shift from the M1 to M2 phenotype, reducing the expression of pro-inflammatory cytokines, and enhancing the production of anti-inflammatory factors.
CONCLUSIONS: Our findings suggest that TGF-β1-Exo exert therapeutic effects in septic mice by modulating macrophage polarization and inhibiting macrophage-mediated inflammation.

Keywords:  Exosome; Inflammation; Macrophage polarization; Sepsis

DOI:  https://doi.org/10.1007/s11033-026-11715-z