bims-engexo 2026-08-30 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–08–30
twelve papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered exosomes for CRISPR/Cas delivery to overcome oncogene-driven drug resistance.
Engineered Exosomes as Next-generation Nanotherapeutics for Glioma: Crossing the Blood-brain Barrier Toward Precision Medicine.
Targeted Lactic Acid Regulation via Engineered Exosomes for Synergistic Metabolic and Photodynamic Tumor Therapy.
Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.
Engineered exosomes with RNA-motif short hairpin RNA loading and Rab4-boosted production enable controlled ferroptosis in endometrial carcinoma.
Hydrogel microneedles loaded with engineered extracellular vesicles accelerate diabetic wound healing by promoting angiogenesis and modulating macrophage polarization.
Engineered P. distasonis-Derived Membrane Vesicles Ameliorate Gut-Liver Axis Disorders by Remodeling Intestinal Immunity and Bile Acid Homeostasis.
Curcumin-Loaded Milk-Derived Exosomes Improve the Developmental Competence of Yak Oocytes by Regulating Mitophagy.
Engineered outer membrane vesicle-like nanoparticles from Lactobacillus plantarum for oral IL-22 mRNA delivery and treatment of DSS-induced colitis.
Hyaluronic Acid Hydrogel Incorporating Dexpanthenol-Engineered Extracellular Vesicles for Accelerated Wound Closure and Mitigated Secondary Infection Risk.
Engineering Plant-Derived Exosome-like Nanoparticles as Bioinspired Nanocarriers: From Physicochemical Properties to Tumor Delivery Performance.
Engineering Aerosol-Resilient EV-Liposome Hybrid Vesicles for Inhalable Nintedanib Delivery in Pulmonary Fibrosis.

Exp Cell Res. 2026 Aug 28. pii: S0014-4827(26)00276-4. [Epub ahead of print] 115159

Engineered exosomes for CRISPR/Cas delivery to overcome oncogene-driven drug resistance.

Daniel Ejim Uti.

  Engineered exosomes are emerging as biocompatible nanocarriers for delivering CRISPR/Cas components to resistant tumor cells, enabling targeted disruption of oncogenic drivers and resistance-associated pathways. Engineered exosomes offer several delivery-platform advantages, including biocompatibility, membrane-mediated cargo protection, programmable tumor targeting, and potential tissue penetration. Selection of the CRISPR modality, Cas9 ribonucleoprotein, mRNA, base editor, or prime editor, depends on payload size, stability, editing duration, endosomal escape, and nuclear delivery requirements. Therapeutically, these systems may disrupt oncogenic drivers, inhibit resistance pathways, restore tumor-suppressor activity, and re-sensitize tumors to targeted therapy, chemotherapy, or immunotherapy. Clinical translation will require scalable manufacturing, reproducible cargo loading, standardized characterization, validated potency assays, off-target control, and clearly defined regulatory pathways. The goal of this review is to outline a realistic pathway featuring proof-of-concept research, through discoveries to the creation of manufacturable, safe, and effective exosome/CRISPR therapeutics that can trigger durable therapeutic responses in resistant malignancies.

Keywords:  CRISPR/Cas; cancer nanomedicine; drug resistance; engineered exosomes; oncogene editing

DOI:  https://doi.org/10.1016/j.yexcr.2026.115159
Curr Neurovasc Res. 2026 Aug 10.

Engineered Exosomes as Next-generation Nanotherapeutics for Glioma: Crossing the Blood-brain Barrier Toward Precision Medicine.

Shatrudhan Prajapati, Shikha Yadav.

   BACKGROUND: Glioma is one of the most aggressive and treatment-resistant malignancies of the central nervous system, characterized by rapid progression and poor prognosis. Conventional treatment approaches, including surgery, radiotherapy, and chemotherapy, often fail to achieve long-term remission due to the restrictive nature of the blood-brain barrier and the inherent heterogeneity of tumor cells.
METHODS: This review summarizes and critically analyzes current preclinical and clinical evidence on exosome biology, including their biogenesis, molecular cargo, and therapeutic engineering strategies. It further highlights recent advances in exosome-based delivery of chemotherapeutic agents, microRNAs, and gene-editing systems for glioma management.
RESULTS: Tumor- and stem cell-derived exosomes have demonstrated the ability to cross biological barriers while carrying functional biomolecules and modulating the tumor microenvironment. Their inherent stability, low immunogenicity, and capacity for surface modification make them promising nanocarriers for therapeutic applications. Engineered exosomes loaded with anti- tumor microRNAs, small interfering RNAs, or chemotherapeutic nanoparticles have shown promising results in enhancing drug sensitivity and reducing tumor proliferation in experimental glioma models.
DISCUSSION: The findings support the therapeutic potential of exosome-based platforms while also highlighting major challenges, including inconsistencies in isolation protocols, limited cargo- loading capacity, targeting specificity, and in vivo stability. Although exosomes have demonstrated the ability to overcome biological barriers and therapeutic resistance, standardized manufacturing protocols and robust clinical validation remain essential for successful clinical translation.
CONCLUSION: Exosome-based systems represent a promising approach for the diagnosis and treatment of glioma. Their dual role as biomarkers and therapeutic drug carriers offers significant potential for personalized medicine through non-invasive disease monitoring and targeted therapeutic strategies. However, further optimization of large-scale production, purification methods, and clinical translation is necessary before exosome-based therapeutics can be integrated into standard glioma treatment protocols.

Keywords:  Exosomes; biomarkers; blood-brain barrier; chemoresistance; drug delivery; glioma; microRNA; nanomedicine

DOI:  https://doi.org/10.2174/0115672026464128260804075922
Adv Healthc Mater. 2026 Aug 28. e71659

Targeted Lactic Acid Regulation via Engineered Exosomes for Synergistic Metabolic and Photodynamic Tumor Therapy.

Sisi Zhou, Yu Cao, Xianbiao Wang, Songqin Liu.

  Tumor cells exhibit a hyper-glycolytic phenotype, resulting in massive lactic acid (LA) production that acidifies the tumor microenvironment (TME) and fosters immunosuppression. Current lactate-targeted therapies often lack synergistic dual-directional regulation. Herein, we engineer an exosomal nanoplatform, PpIX/siRNA@EXO-LOD, to simultaneously disrupt intra- and extracellular LA homeostasis, thereby enabling synergistic metabolic and photodynamic therapy (PDT). The system integrates three key components: protoporphyrin IX (PpIX) for PDT, siRNA targeting monocarboxylate transporter 4 (MCT4) for intracellular metabolic interference, and surface-displayed lactate oxidase (LOD) for extracellular catalytic starvation. Upon epithelial cell adhesion molecule (EpCAM)-mediated targeting, the nanovesicle triggers a cascade of synergistic effects. Crucially, siRNA-mediated silencing of MCT4 induces lethal intracellular acidosis, leading to significant intracellular H2O2 accumulation. This elevated H2O2 level acts as a booster for PpIX-generated reactive oxygen species (ROS) upon laser irradiation, creating an amplified oxidative stress burst that overwhelms tumor cell defenses. Concurrently, surface-anchored LOD consumes extracellular LA, alleviates lactate-induced immunosuppression. In vivo studies demonstrate that this dual-regulation strategy effectively inhibits tumor growth, downregulates metastasis-related factors (amphiregulin (AREG), ATP-binding cassette sub-family B member 1 (ABCB1)), and reprograms the TME from an immunosuppressive state to an immunologically active state. This work presents a precision nanomedicine strategy that leverages the interplay between metabolic modulation and photodynamic amplification for enhanced cancer treatment.

Keywords:  exosome engineering; lactate metabolism regulation; photodynamic therapy; synergistic therapeutic strategy; tumor‐targeted delivery

DOI:  https://doi.org/10.1002/adhm.71659
Bioact Mater. 2027 Jan;67 497-523

Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.

Hang Chen, Yuanquan Si, Qian Cheng, Qian Yu, Zhikang Cui, Shuyi Yu, Xiaoyi Zhao, Yan Jin, Yunshan Wang, Ming Li, Zhiming Lu.

  Exosomes (EXOs) derived from the plasma of young individuals are believed to have the potential to ameliorate aging-related memory deficits. However, their specific roles and mechanisms in Alzheimer's disease (AD) therapy have not yet been systematically investigated. In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived EXOs to construct RVG-engineered EXOs (RVG-EXOs), and their therapeutic potential and underlying mechanisms in AD models were systematically evaluated. In 3×Tg AD model mice, exogenous administration of young plasma-derived EXOs and their engineered product (RVG-EXOs) revealed that RVG-EXOs could more efficiently enter brain tissue and target neurons, significantly reduce Aβ plaque and phosphorylated Tau (P-Tau) pathological deposition, restore synaptic structure, promote neuronal survival, and improve cognitive behavior. Mechanistic studies demonstrated that RVG-EXOs inhibited RPTOR expression, thereby activating the autophagy pathway and promoting the clearance of pathological proteins. Both in vitro and in vivo experiments confirmed that overexpression of RPTOR significantly suppressed the therapeutic effects of RVG-EXOs. single-cell transcriptomic profiling further revealed that RVG-EXOs not only increased neuronal proportion and modulated excitatory/inhibitory neuronal balance but also reshaped the microglial landscape by reducing deleterious disease-associated while increasing homeostatic surveillant microglia. In summary, this study not only reveals for the first time the potential value of young plasma-derived EXOs in AD treatment but also, through RVG engineering strategies and the elucidation of the RPTOR-autophagy mechanism, provides new insights for targeted therapy of neurodegenerative diseases.

Keywords:  Alzheimer's disease; Autophagy; Exosome; RPTOR

DOI:  https://doi.org/10.1016/j.bioactmat.2026.08.008
Bioeng Transl Med. 2026 Aug 28. e70163

Engineered exosomes with RNA-motif short hairpin RNA loading and Rab4-boosted production enable controlled ferroptosis in endometrial carcinoma.

Jiarui Zhang, Yuwei Yao, Wan Shu, Shuangshuang Cheng, Guanglei Zhong, Jia Yu, Jinhua Chen, Kejun Dong, Yingying Peng, Jun Zhang, Hongbo Wang.

  Therapeutic challenges in endometrial carcinoma (EC) arise from the limited efficacy and toxicity of current treatments. Although exosome-based RNA interference shows promise, its clinical translation is hindered by inefficient cargo loading, low yields, and poor tumor targeting. We have engineered an exosome platform (cRGD-ExoM) that integrates the following innovations: Firstly, RNA motifs enable the enrichment of shRNA loading by over 80-fold for targeting of ferroptosis regulators (glutathione peroxidase 4/ferroptosis suppressor protein 1/ferritin heavy chain [GPX4/FSP1/FTH]). Secondly, Rab4 silencing amplifies exosome biogenesis via dysregulated endosomal recycling, enhancing tumor cell uptake by impairing endosome maturation-a dual-action mechanism that boosts both production and delivery. Thirdly, cRGD peptides confer αvβ3-integrin-specific targeting. cRGD-ExoM induces potent ferroptosis by increasing lipid peroxidation and downregulating GPX4/FSP1/FTH, significantly suppressing EC tumor growth in vivo without causing systemic toxicity. The platform's modular design allows for spatiotemporal control of loading, production, and targeting, demonstrating its scalability. This study provides new insights into the precision treatment of endometrial cancer by developing engineered, multifunctional, exosome-based therapeutic drugs that combine mechanism precision and translational feasibility in tumor treatment.

Keywords:  RNA motif; endometrial carcinoma; ferroptosis; targeted therapy; therapeutic exosomes

DOI:  https://doi.org/10.1002/btm2.70163
Mater Today Bio. 2026 Oct;40 103555

Hydrogel microneedles loaded with engineered extracellular vesicles accelerate diabetic wound healing by promoting angiogenesis and modulating macrophage polarization.

Shaoyihan Fang, Jingjie Min, Zhenzhen Chen, Shuangyan Li, Yulu Zhou, Jingwen An, Zhongyi Chen, Dewu Liu.

  Oxidative stress, impaired angiogenesis, and persistent inflammation contribute to delayed diabetic wound healing. In this study, ALDH2-loaded liposomes were associated with extracellular vesicles derived from human amniotic mesenchymal stem cells to generate an ALDH2@Lipo/EV hybrid formulation, which possess pro-angiogenic, antioxidant, and anti-inflammatory properties that modulate mitochondrial homeostasis in cells within diabetic wounds. To enhance the penetration efficiency of EVs in the wound, ALDH2@Lipo/EV were loaded into methacrylated gelatin (GelMA) hydrogel to fabricate the ALDH2@Lipo/EV-MN patch system. The microneedles technology enabled precise and efficient delivery of ALDH2@Lipo/EV, ensuring an optimal depth of delivery for maximum therapeutic efficacy. Mechanistically, ALDH2@Lipo/EV promoted angiogenesis in vitro and alleviated oxidative damage and inflammation in macrophages by inhibiting the activation of dynamin-related protein 1 (Drp1) and activating the PINK1/Parkin signaling pathway. Furthermore, the ALDH2@Lipo/EV-MN patch was shown to enhance diabetic wound healing in a mouse model. This study explored the functions and mechanisms of the ALDH2@Lipo/EV-MNs system, providing a new strategy for the treatment of refractory diabetic wounds.

Keywords:  Diabetic wound healing; Engineered extracellular vesicles; Mesenchymal stem cell-derived extracellular vesicles; Microneedles

DOI:  https://doi.org/10.1016/j.mtbio.2026.103555
Small. 2026 Aug 28. e75446

Engineered P. distasonis-Derived Membrane Vesicles Ameliorate Gut-Liver Axis Disorders by Remodeling Intestinal Immunity and Bile Acid Homeostasis.

Beibei Wu, Gelin Xiang, Zhilong Jia, Jun Zhao, Yutong Shu, Cuitong Wang, Xiao Li, Wenjing Wang, Fan Yang, Qinhui Liu, Li Mo, Yining Xu, Wenfei Chen, Jinhan He.

  The gut-liver axis is a central conduit through which intestinal immunity and metabolism regulate liver health. Although gut probiotics such as Parabacteroides distasonis (P. distasonis) and their postbiotics show promise for treating related disorders, safety and stability concerns and inconsistent efficacy limit their further application. Here, outer membrane vesicles (OMVs) derived from P. distasonis are engineered (termed POTA) for enhanced oral delivery. Specifically, biomineralization with tannic acid and encapsulation within calcium alginate microbeads boost their anti-inflammatory properties and enable targeted intestinal release. In mouse models of inflammatory bowel disease, POTA restores intestinal barrier integrity and suppresses inflammation by driving macrophage polarization from an M1 to M2 phenotype via fine-tuned STING signaling. Furthermore, POTA reprograms intestinal immune homeostasis, particularly by rebalancing regulatory T (Treg) and T helper 17 (Th17) cell populations. These changes are supported by a restored microbiota and elevated levels of immunomodulatory bile acids, including isoallolithocholic acid (isoalloLCA). Notably, this localized gut intervention elicits systemic benefits, alleviating hepatic steatosis, inflammation, and insulin resistance in metabolic liver disease. Collectively, engineered bacterial OMVs represent a safe and effective oral platform for ameliorating gut-liver axis disorders.

Keywords:  bile acids; gut microbiome; inflammatory bowel disease; intestinal immunity; metabolic dysfunction‐associated steatohepatitis; outer membrane vesicles

DOI:  https://doi.org/10.1002/smll.75446
Antioxidants (Basel). 2026 Jul 24. pii: 922. [Epub ahead of print]15(8):

Curcumin-Loaded Milk-Derived Exosomes Improve the Developmental Competence of Yak Oocytes by Regulating Mitophagy.

Tingting Lu, Xin Ma, Meng Wang, Yangyang Pan, Xiaoqing Yang, Shantong Qiu, Xueru Yang, Sijiu Yu.

  Yaks are a distinctive livestock species native to the Qinghai-Tibet Plateau. However, the low in vitro maturation rate of their oocytes significantly limits the efficiency of assisted reproductive technologies. Curcumin (CUR), known for its bioactive functions, including antioxidant and anti-inflammatory properties, suffers from low water solubility and bioavailability, which restricts its practical applications. This study aimed to develop a curcumin-loaded bovine milk-derived exosome nanodelivery system (CUR-mEXOs) and investigate its effects on the in vitro maturation of yak oocytes and the embryonic development of parthenogenetic embryos, leveraging its natural biocompatibility and targeted delivery properties. The results indicated that the isolated mEXOs exhibited typical exosome morphology and nanoscale particle size characteristics and were effectively internalized by the oocytes. During in vitro maturation, treatment with 10 μM CUR produced optimal outcomes. Compared to free CUR, CUR-mEXOs significantly enhanced the cumulus expansion index and the rate of first polar body expulsion, reduced intracellular ROS accumulation and mitochondrial superoxide levels, and improved mitochondrial function and spindle morphology, while simultaneously upregulating the expression of factors related to mitochondrial autophagy and oocyte maturation. Following intervention with the mitochondrial autophagy inhibitor CsA, the promotive effect of CUR-mEXOs was significantly diminished, leading to increased blastocyst apoptosis and a decrease in the total cell count. In summary, CUR-mEXOs can enhance the quality of in vitro maturation of yak oocytes and their embryonic developmental capacity following parthenogenesis by regulating mitochondrial autophagy. This study established an experimental foundation for optimizing the in vitro maturation system of yak oocytes and developing strategies for the delivery of natural bioactive substances. Additionally, this study provides a theoretical basis for enhancing the efficiency of assisted reproductive technologies in yaks.

Keywords:  curcumin; drug delivery; in vitro oocyte maturation; milk-derived exosomes; mitophagy; yak

DOI:  https://doi.org/10.3390/antiox15080922
Mol Cell Biochem. 2026 Aug 28.

Engineered outer membrane vesicle-like nanoparticles from Lactobacillus plantarum for oral IL-22 mRNA delivery and treatment of DSS-induced colitis.

Wenbo Yuan, Lixia Tan, Yingying Du, Tongtong Xu, Zuchao Du, Liping Wu, Daxiang Cui, Qirui Zhao.

  This study developed an engineered Lactobacillus plantarum-derived vesicle system for oral delivery of interleukin-22 mRNA (IL-22 mRNA) and evaluated its effects on epithelial barrier repair in DSS-induced colitis. The vesicle formulation, termed P-OMVs@IL-22 m, was prepared from L. plantarum protoplasts through lysozyme treatment, ultrasonic disruption, OptiPrep density-gradient purification, and incubation-based mRNA loading. The formulation achieved an IL-22 mRNA encapsulation efficiency of 72.43 ± 6.60% and a loading capacity of 35.97 ± 3.67 ng mRNA/µg P-OMV protein. mRNA loading increased the mean particle diameter from 119 ± 3 to 389 ± 7 nm and reduced the detectable particle concentration from 7.83 ± 0.81 × 10⁹ to 6.00 ± 0.78 × 10⁹ particles/mL. P-OMVs@IL-22 m protected IL-22 mRNA from RNase-mediated degradation, remained stable under simulated gastrointestinal conditions, and exhibited pH-associated release behavior. DiR-based IVIS imaging demonstrated persistent gastrointestinal signals after oral administration. In vitro, P-OMVs@IL-22 m was taken up by intestinal epithelial cells, increased IL-22 expression, activated STAT3 signaling, and enhanced Occludin, Claudin-1, and MUC2 expression. Functional assays showed increased transepithelial electrical resistance, reduced FITC-dextran permeability, and enhanced epithelial migration and proliferation. In DSS-induced colitis, oral P-OMVs@IL-22 m mitigated weight loss, lowered disease activity index scores, preserved colon length and tissue architecture, reduced inflammatory cytokine production, and restored epithelial barrier proteins. RNA sequencing and validation analyses linked treatment to changes in lipid metabolism, proteolysis, MAPK signaling, and mTOR-related pathways. These findings establish a preclinical proof-of-concept for engineered probiotic-derived vesicles as an oral IL-22 mRNA delivery platform for epithelial barrier repair in DSS-induced colitis.

Keywords:   Lactobacillus plantarum-derived vesicles; DSS-induced colitis; Epithelial barrier repair; IL-22/STAT3 signaling; Oral mRNA delivery

DOI:  https://doi.org/10.1007/s11010-026-05704-w
Pharmaceutics. 2026 Aug 13. pii: 1003. [Epub ahead of print]18(8):

Hyaluronic Acid Hydrogel Incorporating Dexpanthenol-Engineered Extracellular Vesicles for Accelerated Wound Closure and Mitigated Secondary Infection Risk.

Hyeyoung Shin, Juwon Youn, Chang Kyu Lee, Seungwoon Baik, Tae-Keun Ahn, Dong Keun Han.

  Background: Loss of epithelial integrity leaves the wound bed open to opportunistic bacterial colonization, and the risk of secondary infection persists for as long as the defect remains unclosed. Wound dressings must therefore provide an immediate external barrier while accelerating restoration of the skin's own barrier. This study aims to develop and evaluate a bioactive nanotechnological platform comprising dexpanthenol (Dxp)-engineered extracellular vesicles (EVs) embedded within cross-linked hyaluronic acid hydrogels (HA@Dxp-engineered EVs) for targeted wound treatment and protection against external contaminants. Methods: EVs were engineered via exogenous (extrusion; Exo EV) and endogenous (co-incubation; Endo EV) strategies to encapsulate Dxp. The physicochemical properties of the HA@Dxp-engineered EV systems were characterized, and their therapeutic efficacy was validated through in vitro assays, including fibroblast migration and endothelial tube formation, and in vivo using a full-thickness excisional wound model in mice. Results: Both engineering strategies successfully encapsulated Dxp while preserving the structural integrity of the EVs. The HA hydrogel enabled sustained EV release and provided a physical barrier. In vitro, HA@Endo EVs significantly promoted fibroblast proliferation, migration, and the formation of mature capillary-like networks in HUVECs compared to controls. In vivo, the HA@Endo EV group demonstrated accelerated wound closure, achieving 99.88% healing by day 10, and promoted tissue remodeling with upregulated expression of COL1A1, VEGF, and HIF-1α. Conclusions: The HA@Endo EV system provides a dual-action strategy against secondary infection risk. It supplies an immediate physical barrier over the wound bed and simultaneously accelerates re-epithelialization, thereby shortening the interval during which the tissue remains exposed.

Keywords:  dexpanthenol; extracellular vesicles; hydrogel; secondary infection prevention; wound healing

DOI:  https://doi.org/10.3390/pharmaceutics18081003
Biomedicines. 2026 Jul 28. pii: 1689. [Epub ahead of print]14(8):

Engineering Plant-Derived Exosome-like Nanoparticles as Bioinspired Nanocarriers: From Physicochemical Properties to Tumor Delivery Performance.

Mengru Cai, Yu Qiu, Mingkai Yao, Jiahui Kong, Xiang Li, Qian Zhang, Yiman Jia, Zicheng Zhu, Yukun Zhao, Dong Bai, Yuqin Yang.

  Plant-derived exosome-like nanoparticles (PELNs) are lipid bilayer nanostructures containing endogenous lipids, proteins, nucleic acids, and phytochemicals, which have attracted increasing interest as bioinspired carriers for cancer therapy. This review evaluates how plant source, isolation, purification procedures, vesicle composition, cargo-loading strategy, and administration route shape the quality and tumor-delivery performance of PELNs. The available evidence indicates that plant source and processing are major determinants of particle size, purity, surface charge, cargo profile, and biological activity. Ultracentrifugation remains widely used but is limited by contaminant co-isolation and poor scalability, whereas density-gradient purification and size-exclusion chromatography improve purity, and ultrafiltration and tangential flow filtration offer greater potential for large-scale manufacturing. Passive incubation generally preserves vesicle integrity and is most suitable for hydrophobic small molecules, whereas electroporation, sonication, and extrusion can increase cargo loading but may cause aggregation, membrane remodeling, or loss of endogenous components. Preclinical studies suggest that PELNs can exert intrinsic antitumor effects, modulate the tumor microenvironment, improve chemotherapeutic delivery, and help overcome drug resistance. However, evidence for in vivo tumor-targeting remains less robust than evidence for cellular uptake, and direct comparisons with established nanocarriers remain scarce. Clinical translation will require standardized nomenclature and characterization, reproducible manufacturing, quantitative loading and release assays, route-specific biodistribution studies, and repeated-dose safety evaluation. These findings provide a framework for the rational development of PELNs as reproducible tumor-oriented nanocarriers.

Keywords:  cancer therapy; drug delivery; nanomedicine; natural nanocarriers; plant-derived exosome-like nanoparticles; translational challenges; tumor-targeting

DOI:  https://doi.org/10.3390/biomedicines14081689
Adv Healthc Mater. 2026 Aug 27. e71647

Engineering Aerosol-Resilient EV-Liposome Hybrid Vesicles for Inhalable Nintedanib Delivery in Pulmonary Fibrosis.

Xin Yan, Qi Zhang, Jing Xu, Hengkai Qi, Jing Bian, Honglian Zhao, Aiping Zang, Lingmin Zhang, Xueli Huang, Xi Kang, Jun Zhu, Dandan Xiao, Xianyi Sha.

  Extracellular vesicles (EVs) are promising biomimetic nanocarriers for pulmonary delivery, but their inhalation translation is limited by membrane fragility under aerosol-induced shear and air-liquid interfacial stress. Here, we developed an EV-liposome hybrid vesicle formulation (NIN@SV) for inhalable delivery of nintedanib and identified a composition-dependent balance between EV-derived biological functionality and aerosol robustness. An optimized EV protein:NIN@LP lipid mass ratio of 3:7 enhanced mucus penetration and cellular association while minimizing post-nebulization size drift and preserving aerodynamic performance. Density-gradient fractionation and physical-mixture controls supported the formation of a hybrid vesicle-enriched population rather than simple coexistence of unfused EVs and liposomes. In parallel, FRET-assisted membrane-proximity analysis, calibrated using disruption controls, indicated improved resistance of NIN@SV to aerosol-induced membrane perturbation. Functionally, NIN@SV enhanced formulation-associated cellular association, prolonged pulmonary retention, and attenuated bleomycin-induced pulmonary fibrosis under the tested nominal inhaled dosing regimen. Mechanistically, NIN@SV suppressed fibroblast activation and attenuated pro-fibrotic macrophage-associated features. Together, these findings support an aerosol-resilient EV-liposome membrane-engineering strategy and provide a practical design rationale for inhalable hybrid vesicles in pulmonary drug delivery.

Keywords:  EV‐liposome hybrid vesicles; FRET‐assisted membrane‐proximity analysis; extracellular vesicles; inhalable nanotherapeutics; nintedanib; pulmonary fibrosis

DOI:  https://doi.org/10.1002/adhm.71647