bims-engexo 2026-10-25 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–10–25
twenty papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered extracellular vesicles: pharmacological barriers, engineering strategies, and translational opportunities.
Engineering exosome-based delivery of IL-37 to enhance cytokine stability and antitumor activity in vitro and in vivo.
Mannose-cRGD Engineered Lactobacillus helveticus-Derived Exosomes Enhance Loaded Pterostilbene Bioavailability: From Dual Insights of Membrane Lipid Orderliness and Dual-Targeting Endocytosis Modulation.
An Easy Oligonucleotide Platform for Rapid, Post-Isolation EV Modification: Dual-Function Uptake Control and Enhanced Targeting.
A Modular Glycoengineered Exosome Platform for Targeted Delivery via Chemoenzymatic Engineering of Surface Sialic Acids.
Hybrid exosome-liposome nanovesicles as delivery platforms for therapeutic applications: merging the best of both worlds.
Engineering extracellular vesicles for inflammatory bowel disease and colitis-associated colorectal cancer: from therapeutic innovation to clinical translation.
HAMA microneedles patch loaded with muscle-targeting engineered apoptotic vesicles and attenuating sarcopenia by regulating mitochondrial homeostasis.
A Diabetic Wound Microenvironment-Responsive HAMA-PBA/PVA Hydrogel for Localized Delivery of Netrin-1-Enriched Adipose-Derived Stem Cell-Derived Exosomes Promotes Diabetic Wound Healing through Immunomodulation and Angiogenesis.
Macrophage-derived exosomes in bone tissue regeneration: spatiotemporal immunomodulation, engineering advances, and translational frontiers.
Programming Extracellular Vesicle-Biomaterial Interfaces for Diabetic Wounds: Barrier-Matched Design and Translational Criteria.
Hybrid membrane vesicle-enabled sonodynamic therapy using ciprofloxacin for treating biofilm-associated infections.
Engineered hUC-MSC exosomes loaded with pterostilbene induce Nrf2/SKN-1-dependent microglial M2 polarization and neuroprotection in Alzheimer's disease in vitro and in Caenorhabditis elegans.
Engineered mitochondria-derived vesicles suppress colorectal cancer through metabolic reprogramming and mtDNA-cGAS-STING signaling.
Targeted Inhibition of Intracellular Coxiella burnetii by Overcoming the Vacuolar Barrier with Autologous Exosomal Doxycycline.
Engineering Tripterygium wilfordii-derived exosome-like nanoparticles for targeted therapy in rheumatoid arthritis.
Hybrid nanovesicle artificial antigen-presenting cells integrate endogenous tumor antigen display with senescence-mimetic erythrocyte membrane-directed splenic T-cell priming.
Bioactive M2 exosome hybrid nanocomposites for immune therapy of psoriasis.
Extracellular vesicle-delivered siRNA targeting RCN1 suppresses acute myeloid leukemia through TFAM-dependent mtDNA-cGAS-STING signaling.
Engineered ZFP36-overexpressing AC16 cell-derived extracellular vesicles attenuate ferroptosis-related endothelial injury and functionalize NiTi vascular interfaces.

Extracell Vesicles Circ Nucl Acids. 2026 ;7(3): 1345-1368

Engineered extracellular vesicles: pharmacological barriers, engineering strategies, and translational opportunities.

Jiao Xu, Zhi Li, Da Liu, Libo Zhao, Yongqing Li.

  Extracellular vesicle (EV) therapeutics are progressing from broad proof-of-concept studies toward product-specific engineering and clinically defined applications. Native EVs offer biological membrane functions and the capacity to transport diverse molecular cargoes, but their therapeutic performance is limited by low cargo stoichiometry, rapid mononuclear phagocyte system clearance, clearance-dominated biodistribution, and inefficient functional cargo release. This Review examines how EV engineering strategies are used to address these barriers. We compare approaches for cargo loading, circulation control, tissue- and cell-selective targeting, and intracellular delivery, while considering the immunogenicity and manufacturing risks introduced by engineering. We also assess recent preclinical and clinical progress, including programs that were paused or discontinued, and discuss the practical constraints of cost, supply chain, and cold-chain distribution. Current evidence suggests that engineered EVs are unlikely to replace established lipid nanoparticles or viral vectors across all applications. Their near-term value is more likely to arise in localized delivery, immune-microenvironment modulation, complex cargo delivery, and defined cell-targeting settings in which biological membrane functions provide a measurable advantage.

Keywords:  Extracellular vesicles; bioengineering; drug delivery; engineered extracellular vesicles; therapeutic translation

DOI:  https://doi.org/10.20517/evcna.2026.85
Nanomedicine. 2026 Oct 19. pii: S1549-9634(26)00142-5. [Epub ahead of print]78 103041

Engineering exosome-based delivery of IL-37 to enhance cytokine stability and antitumor activity in vitro and in vivo.

Zaheer Abbas, Naoakusa Fujimura, Samia Afzal, Muhammad Akram, Saad Tahir, Nadeem Ahmed.

  Interleukin-37 (IL-37) is an anti-inflammatory cytokine with antitumor activity, yet its clinical utility is constrained by poor bioavailability and rapid degradation. This study engineered NCI-H226-derived exosomes as IL-37 nanocarriers and evaluated their anticancer efficacy in cellular and hepatic carcinoma models. Exosomes were isolated using Total Exosome Isolation (TEI) reagent and qEV10 size-exclusion chromatography. IL-37 loading by sonication achieved >80% encapsulation efficiency and sustained release, with cumulative release of 65.11 ± 0.25% and 59.95 ± 0.43% for qEV10- and TEI-isolated exosomes, respectively. IL-37-loaded exosomes exhibited greater cytotoxicity than free IL-37 across tested cancer cells. In the DEN-1 rat model, IL-37-loaded exosomes significantly reduced tumor burden, liver fibrosis, and serum ALT, AST, ALP level. Gene expression analysis showed normalization of inflammatory (IL-6, IL-1β) and fibrotic (α-Sma, Col1α1) markers. These findings support further investigation of exosome-based IL-37 delivery as a better immunotherapy platform.

Keywords:  Exosomes; IL-37 encapsulated exosomes; Immunotherapy; Nanocarriers; Recombinant IL-37

DOI:  https://doi.org/10.1016/j.nano.2026.103041
J Agric Food Chem. 2026 Oct 07. 74(39): 31080-31100

Mannose-cRGD Engineered Lactobacillus helveticus-Derived Exosomes Enhance Loaded Pterostilbene Bioavailability: From Dual Insights of Membrane Lipid Orderliness and Dual-Targeting Endocytosis Modulation.

Qiu-Ya Ji, Ran Meng, Si-Jie Wu, Ran Feng, Bao Zhang.

  Exosomes derived from probiotics are emerging as innovative oral nanocarriers but face challenges in targeted delivery and stability. Here, Lactobacillus helveticus-derived exosomes (LHexo) were dual-functionalized with mannose and cRGD (McRLHexo), yielding improved membrane lipid ordering, denser PEG brush layer, and distinct "cloud-like" surface nanostructure. McRLHexo exhibited enhanced stability under UV (transmittance reduction > 98%), thermal, and digestive conditions (drug retention >86%), and increased pterostilbene (PTS) loading. Functionally, McRLHexo@PTS achieved efficient epithelial translocation via cRGD-integrin pathways and macrophage targeting via Man/cRGD dual-recognition. In DSS-induced colitis mice, McRLHexo showed optimal targeting accumulation and uptake in the colon. Importantly, McRLHexo@PTS markedly alleviated colitis, restoring body weight, colon length, and epithelial integrity while reducing inflammatory cytokines and oxidative stress and enhancing antioxidant defenses. This study establishes a dual-targeted probiotic exosome platform for oral therapy and provides insights into ligand-membrane engineering for precision intestinal delivery.

Keywords:  dual-target functionalization; inflammatory microenvironment; membrane engineering; oral nanocarriers; probiotic exosomes; pterostilbene

DOI:  https://doi.org/10.1021/acs.jafc.5c16503
ACS Appl Bio Mater. 2026 Oct 19.

An Easy Oligonucleotide Platform for Rapid, Post-Isolation EV Modification: Dual-Function Uptake Control and Enhanced Targeting.

Christopher G Blum, Shan Ying, Huda Usman, Phil G Campbell, Tagbo Niepa, Elizabeth Ransey, Jonathan E Henninger, Subha R Das.

  Extracellular vesicles (EVs) hold immense therapeutic potential, yet their clinical translation is hindered by nonspecific cellular uptake and the complexity and cost of surface engineering. Here, we present the EZON (Easy OligoNucleotide) EV modification platform, a cost-effective, post-isolation modification system that addresses both limitations simultaneously. The EZON platform employs unmodified DNA aptamers that bind directly to tetraspanin proteins on EV surfaces, eliminating the need for cholesterol conjugation, covalent chemistry, or genetic engineering of producer cells. EVs are thus easily and rapidly functionalized in a single incubation step at substantially reduced oligonucleotide cost. The EZON platform enables dual functionality: (1) the oligonucleotide anchor (ONA) sequence inhibits nonspecific cellular uptake, while (2) the display strand enables targeted delivery through ligand-mediated internalization. We demonstrate that our optimized ONA construct efficiently functionalizes EVs from multiple mammalian cell types. Cancer cells selectively internalized EZON-modified EVs functionalized with AS1411, an aptamer that targets nucleolin, whereas off-target internalization was suppressed. The platform's versatility extends to protein display via histidine-tag aptamers and therapeutic cargo delivery, as demonstrated by targeted doxorubicin delivery to head and neck squamous cell carcinoma cells. This rapid, modular approach transforms unmodified EVs into precision delivery vehicles within hours, offering a scalable solution for targeted therapeutics.

Keywords:  DNA; aptamer; drug delivery; exosome; extracellular vesicle; membrane engineering

DOI:  https://doi.org/10.1021/acsabm.6c01051
ACS Biomater Sci Eng. 2026 Oct 19.

A Modular Glycoengineered Exosome Platform for Targeted Delivery via Chemoenzymatic Engineering of Surface Sialic Acids.

Ziwei Wu, Ronglian Xu, Luncai Chen, Ling Zhang, Shihan Wang, Xiaorong Fan, Ziang Wang, Xinru Zhang, Zhifang Zhou, Haofei Hong, Zhimeng Wu, Jie Shi.

  Bovine milk-derived exosomes (mExos) are scalable, biocompatible nanocarriers well-suited for the cross-barrier transport and protection of labile nucleic acid therapeutics. However, achieving precise active targeting for cargo delivery remains challenging, as conventional surface functionalization methods often lack site-specificity, unintentionally altering native physicochemical properties or obscuring essential membrane interactions. Herein, we report a modular glycoengineering strategy that leverages the dense sialic acid coating on mExos to introduce versatile anchoring sites for targeting ligand modification via sequential chemoenzymatic remodeling. Specifically, the native terminal sialic acids on the mExo surface were enzymatically removed and replaced with azide-modified sialic acid analogs, which was achieved efficiently through an integrated multienzyme reaction. In principle, the resulting platform, mExo-N3, enables the glycan-selective conjugation of any dibenzocyclooctyne (DBCO)-modified targeting ligands for targeted delivery, avoiding the limitations of random modifications. To validate this platform, we conjugated mExo-N3 with an anti-EGFR nanobody (7D12) and encapsulated a microRNA-21 inhibitor (miR-21i). The resulting mExo-7D12@miR-21i construct maintained colloidal stability and exhibited specific internalization by EGFR-positive cancer cells. Intracellular delivery of miR-21i restored the expression of tumor suppressors PTEN and PDCD4, inducing apoptosis and suppressing proliferation. Furthermore, in an A431 xenograft model, the targeted system achieved 58.3% tumor growth inhibition in vivo without evident systemic toxicity. By converting native glycans into functional anchoring sites, this approach provides a translatable framework for customizing exosomal delivery vectors into targeted therapeutics.

Keywords:  cancer therapy; click chemistry; glycoengineering; milk-derived exosomes; targeted drug delivery

DOI:  https://doi.org/10.1021/acsbiomaterials.6c01221
Theranostics. 2026 ;16(16): 9261-9276

Hybrid exosome-liposome nanovesicles as delivery platforms for therapeutic applications: merging the best of both worlds.

Jian Yu, Lujiao Yu, Fei Ren, Kai Cui, Gongping Sun, Hong Pan.

  Exosomes are increasingly employed to treat various diseases because of their remarkable ability to enhance the stability of encapsulated cargoes. This capability is attributed to their outstanding homologous targeting, desirable biocompatibility, and low immunogenicity, thereby contributing to improved therapeutic outcomes. Nevertheless, exosomes are constrained by some limitations, including poor loading capacity, inherent heterogeneity, and challenges in large-scale production. Consequently, hybrid exosome-liposome (EL) systems, which can circumvent these limitations, are playing an increasingly crucial role in therapeutic applications. Herein, we introduce the two primary strategies for drug loading into exosomes -- passive loading and active loading. We further elaborate on the fabrication methods of hybrid ELs and their applications in drug delivery, highlighting the innate advantages of these state-of-the-art nanovesicles over conventional exosomes and liposomes. Major challenges and future perspectives of hybrid ELs in treating various diseases are also discussed.

Keywords:  drug delivery; exosome; liposome; membrane fusion; nanovesicle

DOI:  https://doi.org/10.7150/thno.135691
Front Immunol. 2026 ;17 1933602

Engineering extracellular vesicles for inflammatory bowel disease and colitis-associated colorectal cancer: from therapeutic innovation to clinical translation.

Minrui Huang, Jintao Yuan, Peter Muro, Tao Jin, Fei Mao, Wenjun Zhu.

  Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory disorder that increases the risk of colitis-associated colorectal cancer (CAC). Despite major advances in biologics and small-molecule therapies, many patients experience primary or secondary treatment failure, adverse effects, and disease recurrence, underscoring the need for more effective, targeted therapeutic strategies. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as promising nanoscale therapeutic platforms owing to their intrinsic biocompatibility, low immunogenicity, cargo-protective lipid bilayer, and natural ability to mediate intercellular communication. Recent advances in EV engineering have further expanded their therapeutic potential through genetic modification of parental cells, cargo loading, surface functionalization, and hybrid biomaterial systems, enabling enhanced targeting, drug delivery, immune modulation, tissue regeneration, and anti-tumor activity. This review summarizes the biological characteristics of EVs and discusses recent progress in engineering strategies aimed at improving their therapeutic efficacy in IBD and CAC. We critically evaluate current preclinical evidence regarding immunomodulation, restoration of intestinal barrier integrity, regulation of gut microbiota, targeted drug delivery, cancer immunotherapy, and inhibition of metastasis. Finally, we discuss the major translational challenges, including manufacturing standardization, quality control, large-scale production, safety evaluation, regulatory considerations, and future perspectives necessary for successful clinical implementation of engineered EV-based therapies.

Keywords:  IBD; colitis-associated colorectal cancer; extracellular vesicle engineering; extracellular vesicles; targeted drug delivery

DOI:  https://doi.org/10.3389/fimmu.2026.1933602
J Nanobiotechnology. 2026 Jul 24. pii: 969. [Epub ahead of print]24(1):

HAMA microneedles patch loaded with muscle-targeting engineered apoptotic vesicles and attenuating sarcopenia by regulating mitochondrial homeostasis.

Jiayao Zhang, Zhao Lin, Haiqi Ding, Mingjuan Zhang, Yibin Su, Linhai Yang, Dingqiang Chen, Xuanhao Chen, Jun Luo, Fuli Wen, Guoyu Yu, Zineng Yan, Jie Xu.

   BACKGROUND: Sarcopenia is an age-related disorder characterized by the progressive loss of skeletal muscle mass and function, primarily driven by mitochondrial dysfunction, oxidative stress, and impaired satellite cell activity. Conventional therapeutic strategies have shown limited efficacy in restoring muscle performance. Apoptotic vesicles (ApoVs) derived from mesenchymal stem cells (MSCs) have recently emerged as promising therapeutic agents capable of delivering bioactive cargos to regulate cellular metabolism and attenuate tissue aging. However, the targeted delivery and functional stability of ApoVs remain major challenges.
RESULTS: We engineered human umbilical cord MSC-derived ApoVs with the muscle-specific aptamer A01B and encapsulated them in a methacrylated hyaluronic acid (HAMA) hydrogel microneedle patch to enhance tissue targeting and enable sustained release. In vitro, ApoVs were efficiently internalized by C2C12 myotubes and alleviated dexamethasone-induced atrophy by promoting proliferation, reducing oxidative stress, restoring mitochondrial structure and function, and modulating the PTEN-PI3K-AKT signaling pathway. miRNA profiling identified miR-21-5p as a key ApoV-delivered effector that activates this pathway. In vivo, treatment with the aptamer-functionalized ApoV microneedle system significantly improved muscle mass, myofiber cross-sectional area, mitochondrial oxidative capacity, and functional endurance in sarcopenic mice compared with controls.
CONCLUSIONS: Our findings demonstrate that the muscle-targeted delivery of engineered ApoVs via HAMA microneedles effectively reverses key hallmarks of sarcopenia by restoring mitochondrial homeostasis and activating PI3K/AKT signaling through miR-21-5p. This microneedle-based ApoV platform provides a promising cell-free therapeutic strategy for ameliorating muscle atrophy and functional decline.

Keywords:  Apoptotic vesicles; Hydrogel microneedles; Mesenchymal stem cells; Mitochondria; Sarcopenia

DOI:  https://doi.org/10.1186/s12951-026-04813-4
ACS Appl Mater Interfaces. 2026 Oct 20.

A Diabetic Wound Microenvironment-Responsive HAMA-PBA/PVA Hydrogel for Localized Delivery of Netrin-1-Enriched Adipose-Derived Stem Cell-Derived Exosomes Promotes Diabetic Wound Healing through Immunomodulation and Angiogenesis.

Yanming Chen, Yucang He, Xingye Pan, Chenyi Wen, Hanmo Wang, Housheng Chen, Yifei Chen, Yuning Lai, Chuanmeng Pan, Siyuan Zou, Zhongqiu Lu, Longwang Chen, Zihao Li, Hua Yu, Liqun Li.

  Diabetic wounds are characterized by persistent inflammation, endothelial dysfunction, impaired angiogenesis, and poor local retention of therapeutic agents, all of which hinder effective repair. Here, we combined Netrin-1-enriched exosomes (NTN-Exos) from genetically modified adipose-derived stem cells with a photo-crosslinkable phenylboronic acid-modified hyaluronic acid methacryloyl/polyvinyl alcohol (HAMA-PBA/PVA) hydrogel to create a diabetic wound-responsive exosome-hydrogel system. NTN-Exos@Gel enabled prolonged local exosome retention owing to its favorable injectability, biocompatibility, and pH- and reactive oxygen species-responsive degradation and release behavior. In vitro, NTN-Exos reduced high-glucose-induced endothelial apoptosis and restored endothelial migration, proliferation, and tube-forming capacity. Additionally, NTN-Exos reduced inflammatory reactions and promoted macrophage polarization toward a reparative phenotype. NTN-Exos@Gel dramatically accelerated wound closure, improved blood perfusion, boosted neovascularization, improved re-epithelialization and collagen deposition, and decreased local inflammatory cytokine production in a diabetic full-thickness wound model. Mechanistically, transcriptome and protein analysis showed that the pro-angiogenic action of NTN-Exos was associated with altered Hippo signaling, which is typified by higher YAP/TAZ expression, decreased phosphorylation of LATS1 and YAP, and increased expression of CD146. These results suggest that NTN-Exos@Gel is a viable cell-free approach for the healing of diabetic wounds.

Keywords:  adipose-derived stem cells; angiogenesis; exosomes; macrophage polarization; netrin-1; wound healing

DOI:  https://doi.org/10.1021/acsami.6c16731
J Transl Med. 2026 Jul 25. pii: 1329. [Epub ahead of print]24(1):

Macrophage-derived exosomes in bone tissue regeneration: spatiotemporal immunomodulation, engineering advances, and translational frontiers.

Shuang Lai, Xinxiong Xia, Yandong Mu.

   BACKGROUND: Bone regeneration unfolds through sequential inflammatory, reparative, and remodeling phases, with macrophages functioning as pivotal regulators across these stages. Accumulating evidence identifies macrophage-derived exosomes (M-Exos) as key mediators of intercellular communication that dynamically shape the bone healing microenvironment.
MAIN BODY: This review synthesizes current evidence on the spatiotemporal roles of M-Exos during bone healing and discusses how donor macrophage states may shape vesicle function across inflammatory, reparative, and remodeling phases. The discussion elucidates how dynamic macrophage functional states shape exosomal cargo and biological activity during distinct stages of repair. Concurrently, emerging engineering strategies to harness and enhance M-Exos' regenerative functions are evaluated, including exosome engineering, therapeutic cargo optimization, and biomaterial-assisted delivery approaches. In addition, this paper scrutinizes the translational landscape of M-Exos, emphasizing their potential as a cell-free therapeutic modality for bone tissue engineering while outlining key challenges critical for clinical implementation.
CONCLUSIONS: By integrating the spatiotemporal functions of macrophage-derived exosomes (M-Exos) and single-cell-resolved landscapes of macrophage functional states, this review delineates the mechanistic links among macrophage state transitions, M-Exo cargo profiles, and regenerative outcomes across distinct phases of bone healing. It further provides a theoretical basis for developing stage-adaptive and functionally tunable M-Exo-based strategies for bone regeneration.

Keywords:  Bone regeneration; Exosomes; Immunomodulation; Macrophages; Tissue engineering

DOI:  https://doi.org/10.1186/s12967-026-08613-0
Adv Healthc Mater. 2026 Oct 20. e71859

Programming Extracellular Vesicle-Biomaterial Interfaces for Diabetic Wounds: Barrier-Matched Design and Translational Criteria.

Baoting Wu, Jing Ruan, Ke Zhang, Xinlu Wang, Si You, Rongbing Chen, Hanbing Wang, Zongyun He, Qinsi Yang, Wei Wu, Da Sun, Jin Yang.

  Diabetic wounds are sustained by a coupled network of unresolved inflammation, vascular insufficiency, oxidative injury, infection and biofilms, and matrix dysfunction. Although extracellular vesicles (EVs) can convey regenerative signals and engineered cargo, therapeutic performance is ultimately determined by how a wound-contact material preserves, presents, and releases them. This review reframes EV-based treatment as the programming of an EV-biomaterial interface. It relates wound barriers to cargo function; compares donor-cell engineering, post-isolation loading, surface modification, EV mimetics, and hybrid systems; and examines how composition, crosslinking, architecture, adhesion, mechanics, degradation, and stimulus responsiveness govern local exposure. Preclinical and emerging clinical evidence is evaluated alongside product-defining measurements, including EV identity and purity, cargo content and encapsulation efficiency, removal of free cargo, recovery, release, potency, safety, sterility, and batch consistency. The analysis shows that added functional complexity is not inherently advantageous unless each component is mechanistically necessary and quantitatively controlled. A barrier-matched, fully characterized interface therefore offers a rigorous basis for developing reproducible and clinically testable EV-enabled wound therapeutics.

Keywords:  biomaterial interfaces; cargo engineering; diabetic wound healing; extracellular vesicles; translational quality control

DOI:  https://doi.org/10.1002/adhm.71859
J Mater Chem B. 2026 Oct 21.

Hybrid membrane vesicle-enabled sonodynamic therapy using ciprofloxacin for treating biofilm-associated infections.

Xueyi Xiao, Manzhen Yan, Li Yang, Qingling Li, Lingxuan He, Zhixin Yuan, Yaoyu Guo, Xinyi Zhong, Xin Ding.

Biofilm-associated infections on indwelling medical devices pose significant clinical challenges due to antibiotic resistance and poor drug penetration. Sonodynamic therapy (SDT) is a promising strategy utilizing ultrasound to activate sonosensitizers for generating reactive oxygen species (ROS). However, the lack of safe and effective sonosensitizers and bacterial-targeting delivery systems limits its application in treating biofilm infection. To address these limitations, we developed antibiotic ciprofloxacin-loaded hybrid membrane vesicles (CIP@HMVs), where ciprofloxacin acts as a safe sonosensitizer and HMVs serve as a detoxified bacterial-targeted delivery system. HMVs were engineered by fusing Pseudomonas aeruginosa-derived outer membrane vesicles (PAEVs) with macrophage membrane vesicles (MMVs), creating a dual-functional nanoplatform with homotypic bacteria-targeting and detoxification capabilities. CIP@HMVs exploited ciprofloxacin's sonosensitizer properties to generate singlet oxygen (1O2) under ultrasound, while HMVs enhanced bacterial uptake in P. aeruginosa. This enabled synergistic bactericidal effects against planktonic bacteria via membrane disruption and intracellular ROS burst, achieving a 5.7-log bacterial reduction in catheter biofilms in vitro. Crucially, HMVs neutralized PAEVs' LPS toxicity in vitro and demonstrated negligible systemic toxicity in vivo. In a murine catheter-infection model, CIP@HMVs under ultrasound achieved 99.8% bacterial eradication and reduced inflammation. This bacterial-targeting sonodynamic platform provides a transformative strategy for treating device-associated biofilm infections with high efficacy and biosafety.

DOI: https://doi.org/10.1039/d6tb01238h
Int Immunopharmacol. 2026 Oct 23. pii: S1567-5769(26)01423-2. [Epub ahead of print]191(Pt 1): 117575

Engineered hUC-MSC exosomes loaded with pterostilbene induce Nrf2/SKN-1-dependent microglial M2 polarization and neuroprotection in Alzheimer's disease in vitro and in Caenorhabditis elegans.

Yuehan Zhang, Ying Su, Linyan Huang, Haien Guan, Zhenhua Qiu, Chunlin Zou.

  Alzheimer's disease (AD) is aggravated by overactivated pro-inflammatory M1 microglia. Although pterostilbene (PTE) possesses anti-oxidative and anti-neuroinflammatory activity, its therapeutic application in AD is limited by poor aqueous solubility and weak blood-brain barrier (BBB) penetration. Here, we fabricated pterostilbene-loaded human umbilical cord mesenchymal stem cell exosomes (PTE-Exos) with enhanced BBB permeability via freeze-thaw loading. In vitro BBB and microglia-neuron co-culture models were used to evaluate targeting, immunomodulation, and neuroprotection, while Nrf2 loss-of-function assays and transgenic Caenorhabditis elegans AD strains enabled cross-species mechanistic verification. PTE-Exos efficiently cross the BBB in vitro and selectively accumulate in activated microglia, shifting CD86+ M1 cells toward the CD206+ anti-inflammatory M2 phenotype, reducing pro-inflammatory cytokines, restoring Aβ phagocytosis and alleviating Aβ-induced tau hyperphosphorylation and synaptic injury. Mechanistically, PTE-Exos simultaneously suppressed the NLRP3 inflammasome and NF-κB signaling and activated the Nrf2/HO-1 cascade to mitigate mitochondrial oxidative stress, and stabilized Nrf2 by attenuating its K48-linked polyubiquitination and prolonging its apparent half-life in a proteasome-dependent manner while preserving the KEAP1-Nrf2 complex. Nrf2 knockdown or pharmacological inhibition abolished these protective effects, and SKN-1 silencing eliminated PTE-Exos-mediated neuroprotection in C. elegans. Collectively, hUC-MSC exosomes resolve the pharmacokinetic limitation of PTE and remodel microglial phenotypes via the conserved Nrf2/SKN-1 axis, providing a biomaterial foundation for Nrf2-targeted nanotherapies against neuroinflammatory neurodegeneration.

Keywords:  Alzheimer's disease; Caenorhabditis elegans; Exosomes; Microglia; Neuroinflammatory diseases; Nrf2; Pterostilbene

DOI:  https://doi.org/10.1016/j.intimp.2026.117575
Cell Signal. 2026 Oct 22. pii: S0898-6568(26)00623-6. [Epub ahead of print] 112963

Engineered mitochondria-derived vesicles suppress colorectal cancer through metabolic reprogramming and mtDNA-cGAS-STING signaling.

Ziqi Zhang, Zi Yan, Suiqing Huang, Xiaozhi Yang, Qingshi Wang, Junhai Huang, Haihao Wang, Yuxian Du, Tianxiang Qi, Liubing Hu, Xiaoyu Ouyang, Xiaodong Wang, Zhenning Dai.

  Metabolic reprogramming and innate immune signaling are closely involved in colorectal cancer (CRC) progression, but the effects of extracellular mitochondria-derived vesicles (MDVs) on these processes remain unclear, partly because of their low natural yield. In this study, we overexpressed MDV formation-related genes in mesenchymal stem cells and identified OPA1 and PINK1 as regulators that increased the recovery of extracellular MDVs. The resulting OPA1- and PINK1-MDV preparations were characterized and then incubated with LOVO and SW480 CRC cells to assess their uptake, metabolic effects, inflammatory signaling, and antitumor activities. OPA1-MDVs contained a TOMM20-positive/PDHE1α-positive vesicle population and shifted CRC cell metabolism away from glycolysis toward oxidative phosphorylation, as shown by reduced glycolytic enzyme activity and lactate production, together with increased oxygen consumption, respiratory-chain activity, and mitochondrial membrane potential. These changes were accompanied by reduced reactive oxygen species levels and impaired CRC cell proliferation, migration, and invasion. In contrast, PINK1-MDVs impaired mitochondrial function, increased reactive oxygen species production, and were associated with activation of cGAS-STING-related inflammatory signaling, possibly through the delivery of mitochondrial DNA. Both MDV preparations suppressed tumor growth in an immunocompetent syngeneic MC38 tumor model. These findings suggest that MDVs derived from OPA1- or PINK1-overexpressing cells suppress CRC growth through distinct metabolic and innate immune mechanisms and provide a potential strategy for engineering extracellular mitochondrial vesicles for cancer research.

Keywords:  Colorectal cancer; Engineered extracellular vesicles; Metabolic reprogramming signaling; Mitochondria-derived vesicles; cGAS-STING signaling

DOI:  https://doi.org/10.1016/j.cellsig.2026.112963
ACS Infect Dis. 2026 Oct 09. 12(10): 3445-3461

Targeted Inhibition of Intracellular Coxiella burnetii by Overcoming the Vacuolar Barrier with Autologous Exosomal Doxycycline.

Yuchen Zhang, Xiaoxiao Chen, Jinru Lin, Jun Jiao, Yonghui Yu, Wenbo Wei, Shan Zhang, Yufei Jiang, Yinhui Lin, Ziyuan Zhang, Shaoya Liu, Hui Yue, Xuan OuYang, Yajun Song.

  Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular bacterium that replicates within the Coxiella-containing vacuole (CCV), a lysosome-like compartment. The acidic microenvironment within the CCV impairs the activity of weak-base antibiotics such as doxycycline, necessitating prolonged, high-dose therapy. To overcome this fundamental delivery barrier, we engineered a biomimetic nanoplatform by encapsulating doxycycline (DOX) within exosomes derived from THP-1 cell-derived macrophages (tExo). DOX@tExo nanoparticles displayed characteristic exosomal morphology and protein markers and demonstrated favorable biocompatibility both in vitro and in vivo. Importantly, DOX@tExo were efficiently internalized by macrophages, trafficked specifically to lysosomes, and accumulated within CCVs. This precise targeting resulted in an enhancement of antibacterial potency, reducing the minimal effective concentration for marked inhibition of intracellular bacterial growth to 0.015 μg/mL, more than an order of magnitude lower than that of free DOX. Beyond direct drug delivery, DOX@tExo treatment concurrently reduced autophagic cargo delivery, as indicated by decreased p62 accumulation, thereby potentially disrupting a host process coopted by the pathogen. In a murine model of pulmonary infection, DOX@tExo treatment significantly reduced bacterial burdens in multiple organs. Collectively, this work establishes a homologous exosome platform derived from THP-1 cells that combines targeted antibiotic delivery with host-directed immunomodulation, offering a therapeutic strategy against refractory intracellular bacterial infections.

Keywords:   Coxiella burnetii ; Autophagy; Coxiella-containing vacuole (CCV); Doxycycline; Exosomal drug delivery

DOI:  https://doi.org/10.1021/acsinfecdis.6c00459
Extracell Vesicles Circ Nucl Acids. 2026 ;7(3): 1534-1553

Engineering Tripterygium wilfordii-derived exosome-like nanoparticles for targeted therapy in rheumatoid arthritis.

Yunyi Yang, Zhi Gong, Gongming Shi, Yong Yang, Yun He, Hongjie Yang, Dajian Yang, Xiaohong Yang.

  Aim: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by excessive activation of pro-inflammatory macrophages and elevated levels of reactive oxygen species (ROS), resulting in synovial hyperplasia, cartilage destruction, and joint dysfunction. This study aimed to develop an engineered Tripterygium wilfordii-derived exosome-like nanoparticle system (TWELP@GlcN-HA) that integrates antioxidant, anti-inflammatory, immunomodulatory, and joint-targeting activities for synergistic RA therapy. Methods: Tripterygium wilfordii-derived exosome-like nanoparticles (TWELP) were isolated from fresh Tripterygium wilfordii and sequentially surface-modified with glucosamine (GlcN) for cartilage protection and hyaluronic acid (HA) for targeted uptake by inflammatory cells. Their physicochemical properties, including morphology, particle size, structural integrity, and surface potential, were systematically characterized. In vitro assays were performed to evaluate ROS scavenging, inhibition of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)], and macrophage polarization. Biodistribution and therapeutic efficacy were evaluated in a collagen-induced arthritis (CIA) mouse model by assessing synovial inflammation, cartilage damage, joint morphology, and joint function. Results: TWELP@GlcN-HA exhibited a uniform spherical morphology, stable surface potential, and preserved structural integrity. In vitro, it efficiently scavenged ROS, suppressed TNF-α and IL-6 secretion, and promoted macrophage polarization from M1 to M2, thereby restoring immune homeostasis. In vivo, HA-mediated targeting promoted nanoparticle accumulation in inflamed joints. TWELP@GlcN-HA significantly alleviated synovial inflammation and cartilage destruction, improved joint morphology and function, and exhibited excellent biosafety with no systemic toxicity. Conclusion: TWELP@GlcN-HA provides a multifunctional combinatorial strategy for RA treatment by synergistically regulating ROS, reprogramming pro-inflammatory macrophages, protecting cartilage, and achieving targeted joint delivery. Its enhanced therapeutic efficacy and favorable safety profile make it a promising candidate for future clinical translation in RA management.

Keywords:  Rheumatoid arthritis; Tripterygium wilfordii; exosome-like nanoparticles

DOI:  https://doi.org/10.20517/evcna.2026.66
Biomaterials. 2026 Oct 19. pii: S0142-9612(26)00741-6. [Epub ahead of print]338(Pt B): 124717

Hybrid nanovesicle artificial antigen-presenting cells integrate endogenous tumor antigen display with senescence-mimetic erythrocyte membrane-directed splenic T-cell priming.

Zhijuan Yang, Sha Li, Yunqi Guo, Tao Wang, Huize Han, Muye Ma, Yongliang Zhang, Wei Tang.

Artificial antigen-presenting cells (aAPCs) provide a non-genetic approach to T-cell activation, but their in vivo performance is often limited by predefined peptide-major histocompatibility complex class I (pMHC-I) repertoires and inefficient delivery to secondary lymphoid organs. Here, we engineer senescence-derived hybrid nanovesicles that integrate endogenous antigen display and organ-directed trafficking within a single membrane material. Nanovesicles derived from senescent cancer cells retain increased levels of endogenously generated pMHC-I complexes, whereas nanovesicles derived from senescence-mimetic red blood cells confer spleen-directed biodistribution. Fusion of these membranes generates SS-hNVs, which are further functionalized with anti-CD28 and interleukin-2 to form SS-aAPCs that provide coordinated T-cell receptor (TCR), costimulatory, and cytokine signals. Hybrid membrane composition governs splenic accumulation and CD8+ T-cell engagement following intravenous administration. SS-aAPCs expand antigen-specific CD8+ T cells and TCF-1+PD-1+ progenitor-like populations, enhance cytotoxic responses, and suppress tumor growth in B16-OVA and MC38 models. Combination with programmed death-ligand 1 (PD-L1) blockade further improves tumor control. By assigning endogenous antigen display and lymphoid trafficking to distinct source membranes, this platform establishes a structure-function strategy for constructing systemically administered aAPCs. These findings support that physiologically remodeled membranes can be assembled as modular biomaterials to coordinate molecular immune signaling with organ-level biodistribution, enabling in vivo T-cell priming without predefined epitope loading or genetic modification of immune cells.

DOI: https://doi.org/10.1016/j.biomaterials.2026.124717
Biomater Adv. 2026 Oct 16. pii: S2772-9508(26)00556-X. [Epub ahead of print]191 215256

Bioactive M2 exosome hybrid nanocomposites for immune therapy of psoriasis.

Yanan Wei, Siyu Chen, Nengjie Yang, Xinyu Tao, Hao Zhang, Yulou Zhao, Yujuan Zhu, Zhifeng Gu.

  Psoriasis is a chronic autoimmune skin disease characterized by persistent oxidative stress and sustained inflammation, affecting approximately 1-8% of the global population, with no curative therapy has been well-established to date. To address this, we developed a bioactive hybrid nanocomposite (Exo-Ce) by chemically conjugating M2 macrophage-derived exosomes with cerium oxide nanoparticles (CeNP), which was applied for synergistic and immunomodulatory therapy of psoriasis. This nanohybrid system effectively integrates the natural immunomodulatory properties of exosomes with the reliable antioxidant enzyme-mimetic activities of CeNP. In vitro, mild thiol-maleimide click chemistry minimizes exosome damage; Exo-Ce maintains parental M2-exosome core bioactivity and exhibits ROS-scavenging capacity, significantly reducing intracellular ROS levels and suppressing the secretion of pro-inflammatory cytokines (IL-6 and TNF-α). Following subcutaneous administration in an imiquimod (IMQ)-induced psoriasis mouse model, Exo-Ce markedly ameliorated psoriatic lesions, as evidenced by reduced lesional area, attenuated epidermal hyperkeratosis and acanthosis, and decreased immune cell infiltration. More specifically, Exo-Ce could promote the polarization of macrophages toward an anti-inflammatory M2 phenotype via its ROS-scavenging activity, as well as downregulate key psoriasis-associated cytokines (e.g., IL-1β and TNF-α), thereby facilitating the restoration of tissue homeostasis in vivo. Altogether, our findings position Exo-Ce as a biocompatible and synergistic nanohybrid platform for psoriasis immunotherapy, potentially offering a promising strategy for clinical translation.

Keywords:  Cerium oxide nanozyme; Immune therapy; M2 macrophage exosomes; Psoriasis; ROS-scavenging

DOI:  https://doi.org/10.1016/j.bioadv.2026.215256
Extracell Vesicles Circ Nucl Acids. 2026 ;7(3): 1228-1248

Extracellular vesicle-delivered siRNA targeting RCN1 suppresses acute myeloid leukemia through TFAM-dependent mtDNA-cGAS-STING signaling.

Huan Chen, Na An, Linlin Yang, Jin Lou, Yuming Pan, Minh T N Le, Xin Du, Qiaoxia Zhang.

  Aim: Acute myeloid leukemia (AML) remains a highly aggressive hematologic malignancy with limited therapeutic options. This study aimed to elucidate how reticulocalbin-1 (RCN1) regulates mitochondrial DNA (mtDNA)-mediated innate immune signaling in AML and to evaluate the therapeutic potential of extracellular vesicle (EV)-mediated small interfering RNA (siRNA) delivery targeting RCN1. Methods: Stable RCN1 knockdown was achieved in AML cells using lentiviral delivery of short hairpin RNA. Mitochondrial transcription factor A (TFAM) expression, mtDNA leakage, and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-type I interferon pathway were analyzed by immunoblotting and quantitative polymerase chain reaction. Protein interactions were assessed by co-immunoprecipitation, proximity ligation assay, and immunofluorescence. TFAM rescue experiments were performed to evaluate its contribution to the downstream effects of RCN1 knockdown. For translational evaluation, EVs were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, and marker protein detection, followed by loading with siRNA targeting RCN1. Therapeutic efficacy and safety were assessed in an AML xenograft mouse model. Results: RCN1 knockdown reduced TFAM expression, leading to cytoplasmic mtDNA accumulation and activation of the cGAS-STING-type I interferon signaling pathway. Restoration of TFAM expression attenuated mtDNA leakage and downstream signaling. EV-delivered siRCN1 effectively suppressed tumor growth in vivo without detectable toxicity. Conclusion: RCN1 silencing destabilizes mtDNA integrity and activates innate immune signaling in AML. EV-based delivery of siRCN1 may represent a promising and potentially safe therapeutic strategy for AML.

Keywords:  Extracellular vesicles; acute myeloid leukemia; cGAS-STING pathway; mitochondrial DNA; reticulocalbin-1; siRNA therapeutics

DOI:  https://doi.org/10.20517/evcna.2026.36
Colloids Surf B Biointerfaces. 2026 Oct 15. pii: S0927-7765(26)00849-0. [Epub ahead of print]270 116261

Engineered ZFP36-overexpressing AC16 cell-derived extracellular vesicles attenuate ferroptosis-related endothelial injury and functionalize NiTi vascular interfaces.

Demin Li, Yachen Hou, Yang Lu, Pengchong Du, Ge Zhang, Yan Lv, Ke Hu, Rilige Su, Bolin Jiao, Yangyang Wu, Yujia Wang, Jinying Zhang, Junnan Tang.

  Myocardial infarction (MI) is associated with persistent myocardial injury and vascular dysfunction despite advances in reperfusion therapy. Delayed endothelial recovery, inflammation, and vascular remodeling remain important challenges during post-MI repair and vascular intervention. Here, we investigated whether extracellular vesicles (EVs) derived from ZFP36-overexpressing AC16 cells could attenuate ferroptosis-related endothelial injury, improve cardiac function after MI, and be integrated into a bioactive NiTi surface for vascular repair. Bioinformatic screening identified ZFP36 as an MI-associated candidate linked to ferroptosis-related processes; increased expression was subsequently observed in the mouse MI model. ZFP36-overexpressing AC16 cells were generated, and the released EVs were designated ZFP36OE-EV. In RSL3-treated HUVECs, ZFP36OE-EV improved cell viability, reduced oxidative stress, preserved mitochondrial membrane potential, and partially restored ferroptosis-related molecular changes. In a mouse MI model, intramyocardial delivery of ZFP36OE-EV improved cardiac function and reduced myocardial fibrosis. To explore the use of the same engineered EV preparation for vascular interface functionalization, ZFP36OE-EV was immobilized onto a polydopamine/hyaluronic acid (PDA/HA)-modified NiTi surface to generate the NPH@Z-EV coating. The coating supported EV loading and gradual particle release in vitro. Under direct cell-material contact conditions, the NPH@Z-EV coating exhibited endothelial protective activity under ferroptosis-related stress. In a rat femoral artery injury model, the NPH@Z-EV coating supported vascular repair, with improved endothelial recovery, reduced local inflammatory activation, attenuated lipid peroxidation-associated vascular injury, and a VSMC marker pattern consistent with reduced phenotypic switching. These findings support further evaluation of engineered EVs as a strategy for functionalizing NiTi vascular interfaces to improve vascular healing after implantation.

Keywords:  Endothelial repair; Extracellular vesicles; Ferroptosis; Myocardial infarction; ZFP36

DOI:  https://doi.org/10.1016/j.colsurfb.2026.116261