bims-engexo 2026-10-18 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–10–18
fourteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered exosomes for breast cancer immunotherapy: Emerging strategies and translational potential.
Exosomes and Extracellular Vesicles in Oncology: Next-Generation Smart Nanocarriers for Precision Cancer Therapy.
An engineered exosome-based platform for targeted delivery to endogenous neural stem cells and fate modulation after spinal cord injury.
Single-Particle Deconvolution of Electroporation Artifacts Guides the Rational Engineering of CD47-EV-Liposome Hybrids for siRNA Delivery.
Dynamic tensile conditioning of mesenchymal stem cell-laden auxetic scaffolds for enhanced YAP-dependent miR-30 enrichment in extracellular vesicles for pulmonary fibrosis therapy.
Exploring tumor-derived exosomes as promising antigenic platforms: novel vaccine and immunotherapy strategies for "cold" colorectal cancer.
MSC-derived exosomes co-delivering anti-miR-221 and gemcitabine for inhibiting the proliferation of pancreatic cancer.
Engineering of bacterial outer membrane vesicles for biotechnological applications.
Exploring the potential of resveratrol-enriched cord mesenchymal stem cell derived exosomes in an in vitro Parkinson's model.
Advances and mechanisms in the application and treatment of functionalized stem cells and their derivatives in allergic rhinitis.
Harnessing the Bacterial Membrane-Derived Oral Vaccine to Potentiate Antitumor Immunity and Metabolic Control of T Cells.
Callicarpa nudiflora-Derived Extracellular Vesicle-Based Hydrogel Loaded with Apremilast for Enhanced Therapy of Psoriasis.
Lactoferrin-modified MSC-derived extracellular vesicles facilitate BBB penetration and enhance gastrodin-induced neuroprotection in Parkinson's disease: involvement of mitophagy.
Intratumoral Fusogenic Outer Membrane Vesicles Enhance Antitumor Immunity Through Tumor MHC-I Upregulation and Tumor Bacterization.

Biochem Biophys Rep. 2026 Dec;48 102822

Engineered exosomes for breast cancer immunotherapy: Emerging strategies and translational potential.

Niloufar Orooji, Mahsa Ghasemian-Irani, Nasrin Salari, Tamana Eskandari, Mehrshad Shams, Fatemeh Tavassoli Razavi, Dariush Haghmorad.

  Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide, despite significant advances in early detection and conventional therapies. Immunotherapy has emerged as a promising strategy to harness the body's immune system to combat tumors. However, limitations such as immune escape mechanisms and inefficient drug delivery continue to challenge its effectiveness. In recent years, engineered exosomes, cell-derived nanoscale vesicles, have gained attention as innovative carriers for cancer immunotherapy due to their natural biocompatibility, low immunogenicity, and inherent targeting capabilities. This review highlights recent advancements in the design and functionalization of exosomes for breast cancer immunotherapy, including the loading of immune-stimulating molecules, genetic cargos, and surface modifications to enhance tumor specificity. We also discuss their advantages over conventional nanocarriers, immunological mechanisms, preclinical evidence, and challenges related to clinical translation. While significant progress has been made, further research is needed to overcome current barriers and fully exploit the potential of engineered exosomes as a next-generation platform in breast cancer immunotherapy.

Keywords:  Breast cancer; Engineered exosomes; Extracellular vesicles; Immunotherapy; Nanocarriers; Targeted drug delivery

DOI:  https://doi.org/10.1016/j.bbrep.2026.102822
Cells. 2026 Oct 04. pii: 1812. [Epub ahead of print]15(19):

Exosomes and Extracellular Vesicles in Oncology: Next-Generation Smart Nanocarriers for Precision Cancer Therapy.

Mohd Masih Uzzaman Khan, Masood Alam Khan, Mohd Azam, Muhammad Afzal, Tariq G Alsahli.

  Exosomes are an evolved sub-type of extracellular vesicles (EVs) that have gained popularity in recent years as a novel biological nanocarrier system for targeted precision therapy in cancer owing to their excellent biocompatibility, low immunogenicity, and high stability. While other artificial systems can only deliver specific types of drug, exosomes have been found to effectively carry different types of therapeutic cargo, such as chemotherapeutic agents, proteins, peptides, mRNA, siRNA, miRNA, and even CRISPR/Cas gene editing elements. Recent progress in exosome engineering technologies, such as surface modification, donor cell modification, bionic hybrid vesicles, and stimuli-responsive exosomes, has improved their targeting efficacy, cargo-loading capacity, and controlled drug release properties. Apart from their therapeutic use, exosomes play an active role in promoting tumor development by regulating the tumor microenvironment, angiogenesis, metastasis, immune escape, maintenance of cancer stem cells, and drug resistance. This review provides a brief insight into the biological properties of exosomes, recent developments in isolation and characterization methods, engineering approaches, therapeutic cargo loading, and their uses in targeted chemotherapy, gene and RNA therapy, immunotherapy, phototherapy, sonodynamic therapy, chemo-dynamic therapy, and combinational therapy. Moreover, the existing issues in exosome research, such as exosome heterogeneity, large-scale production, quality control, and regulatory issues, are addressed. Finally, new approaches involving artificial intelligence, multi-omics technology, and personalized engineering of exosomes are presented as potential solutions to enhance the clinical use of exosomes.

Keywords:  exosomes; extracellular vesicles; gene therapy; immunotherapy; precision cancer therapy; targeted drug delivery; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15191812
Mater Today Bio. 2026 Dec;41 103718

An engineered exosome-based platform for targeted delivery to endogenous neural stem cells and fate modulation after spinal cord injury.

Qing Liu, Ang Lv, Yabin Lin, Jiawei Chen, Chunlei Zhang, Shuai Zhou, Liming Li, Luping Zhang, Weikang Wang, Fei Huang.

  Spinal cord injury (SCI) disrupts neural circuits, leading to persistent sensory and motor deficits. However, effective strategies to promote repair through endogenous neural stem cells (eNSCs) are still limited. In this work, we engineered exosomes with a newly identified peptide (TGP1) to achieve targeted delivery to eNSCs. These exosomes were further loaded with Apelin to stimulate eNSC activation and neuronal differentiation. Following tail-vein administration, TGP1-modified exosomes showed greater accumulation in the injured spinal cord and a 4.6-fold increase in co-localization with Nestin+/SOX2+ eNSC-enriched regions compared with unmodified exosomes. Consequently, the Apln-TGP1 group exhibited a 2.9-fold increase in eNSC proliferation (BrdU+/Nestin+), a 3.3-fold increase in newborn neurons (BrdU+/DCX+), and a 4.9-fold increase in BrdU+/NF200+ neuronal-lineage cells compared with the SCI group. Ultimately, the dual-functional treatment was associated with significant improvements in locomotor performance after SCI. Transcriptomic analysis and protein validation indicated that these treatment responses were accompanied by coordinated Apelin-APJ- and PPARγ-related signaling changes. Together, these findings establish a targeted exosomal strategy for modulation of eNSCs and highlight its potential for promoting endogenous repair following SCI.

Keywords:  Apelin; Differentiation; Endogenous neural stem cell; Exosome; Phage display-derived peptides; Spinal cord injury

DOI:  https://doi.org/10.1016/j.mtbio.2026.103718
ACS Appl Mater Interfaces. 2026 Oct 15.

Single-Particle Deconvolution of Electroporation Artifacts Guides the Rational Engineering of CD47-EV-Liposome Hybrids for siRNA Delivery.

Xiaozhen Zhan, Yurou Li, Chen Chen, Niangui Cai, Qingyuan Zhang, Yunyun Hu, Xiaomei Yan.

  The clinical translation of small interfering RNA (siRNA) therapeutics is hampered by the lack of efficient delivery systems. Extracellular vesicles (EVs) hold great promise as natural carriers, yet conventional loading methods, most notably electroporation, suffer from low encapsulation efficiency, structural damage, and poorly characterized aggregation artifacts. Using single-particle nano-flow cytometry, we deconvoluted these electroporation-induced artifacts and revealed that true loading efficiency is only ∼24%. To overcome these limitations, we engineered CD47-functionalized EV-liposome hybrid vesicles via membrane fusion of CD47-overexpressing EVs with siRNA-loaded liposomes. The hybrid design integrates the high payload capacity of synthetic liposomes with the intrinsic biocompatibility and immune-evasive functionality of CD47-engineered EVs. In a Transwell coculture model simulating the competitive uptake environment of the tumor microenvironment, the hybrid vesicles evaded macrophage clearance and delivered anti-PD-L1 siRNA to tumor cells, resulting in ∼60% PD-L1 gene silencing, three times that of electroporation (∼20%). By providing a rationally designed hybrid nanocarrier with validated immune-evasive and RNAi performance, this work offers a significant advancement for EV-based RNA interference (RNAi) therapeutics.

Keywords:  electroporation; extracellular vesicles; hybrid vesicles; siRNA delivery; single-particle detection

DOI:  https://doi.org/10.1021/acsami.6c16943
Biomaterials. 2026 Oct 13. pii: S0142-9612(26)00729-5. [Epub ahead of print]338(Pt B): 124705

Dynamic tensile conditioning of mesenchymal stem cell-laden auxetic scaffolds for enhanced YAP-dependent miR-30 enrichment in extracellular vesicles for pulmonary fibrosis therapy.

Jian-Xun Chen, Chia-Che Ho, Yen-Hong Lin, Cheng-Yu Chen, Min-Hua Yu, Shang-Hsiu Hu, Hsin-Yuan Fang, Der-Yang Cho, Ming-You Shie.

  Mesenchymal stem cell-derived extracellular vesicles are promising for treating pulmonary fibrosis. However, the generation of extracellular vesicles (EVs) bearing potent, specific therapeutic cargo remains a significant clinical challenge. This study aims to demonstrate how a material-instructive strategy can be utilized to engineer cargo-specific EVs by precisely mimicking the physiological breathing motion of the lung microenvironment. A dynamic culture system was developed by combining a photo-crosslinkable lung decellularized extracellular matrix with an auxetic scaffold. Mesenchymal stem cells (MSCs) were cultured on these scaffolds under dynamic stretching. The dynamically conditioned EVs (dEVs) were then collected, and their therapeutic mechanisms and efficacy were evaluated both in vitro and in vivo using bleomycin-treated human pulmonary fibroblasts and a bleomycin-induced rat pulmonary fibrosis model, respectively. Dynamic stretching on auxetic scaffolds enhanced MSC mechanotransduction, as indicated by the upregulation and nuclear accumulation of YAP. This mechanical activation drove a YAP-dependent biogenesis pathway, leading to the selective enrichment of miR-30 in dEVs. In vivo administration of dEVs effectively restored lung architecture and attenuated collagen deposition. Mechanistically, dEV-derived miR-30 exerted dual therapeutic effects by directly inhibiting myofibroblast activation and promoting the macrophage phenotype switch from pro-inflammatory M1 to anti-inflammatory M2. Furthermore, the EVs successfully restored mitochondrial homeostasis in damaged cells, thereby supporting tissue repair. EVs engineered with miR-30 mimics fully recapitulated the potent therapeutic effects of dEVs, significantly outperforming miR-100. This study successfully established an auxetic dECM scaffold-based mechanogenetic platform to engineer cargo-specific EVs. The findings indicate that mechanical priming optimizes EV therapeutic efficacy, highlighting the YAP/miR-30 axis and mitochondrial restoration as key targets for alleviating pulmonary fibrosis.

Keywords:  Auxetic; Extracellular vesicles; Idiopathic pulmonary fibrosis; Immunomodulation; miR-30

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124705
Front Immunol. 2026 ;17 1962696

Exploring tumor-derived exosomes as promising antigenic platforms: novel vaccine and immunotherapy strategies for "cold" colorectal cancer.

Xiaoting Liu, Xiaoyan Wang.

  Colorectal cancer (CRC) remains a formidable clinical challenge, largely due to the prevalence of microsatellite-stable tumors characterized by an immunologically "cold" tumor microenvironment (TME) that is resistant to immune checkpoint inhibitors (ICIs). Tumor-derived exosomes (TEXs) play a paradoxical dual role in this landscape. Native TEXs actively orchestrate immune evasion by delivering immunosuppressive molecules, such as programmed cell death 1 ligand 1 (PD-L1) and transforming growth factor-beta (TGF-β), which impair cytotoxic T-cell function and promote the expansion of regulatory T cells and M2 macrophages. Conversely, TEXs possess inherent biocompatibility and naturally harbor a broad repertoire of tumor-associated antigens (TAAs) and major histocompatibility complex (MHC) molecules, positioning them as potential cell-free platforms for cancer vaccination. Current evidence demonstrates that native TEXs establish their immunosuppressive niche primarily through the systemic PD-1/PD-L1 axis and microRNA-driven macrophage polarization. However, preclinical studies indicate that exosome engineering strategies-such as masking surface PD-L1 or loading vesicles with immune adjuvants, siRNAs, or CRISPR components-can effectively neutralize these suppressive traits and amplify antigen presentation. While clinical data in CRC remain limited, engineered TEXs exhibit strong preclinical promise for synergizing with ICIs to reprogram cold CRC into immune-responsive "hot" tumors. Advancing these early-stage therapies from the bench to the clinic will require overcoming significant translational hurdles, particularly regarding standardized isolation protocols and scalable manufacturing.

Keywords:  cancer vaccines; colorectal cancer; exosome engineering; immunotherapy; tumor microenvironment; tumor-derived exosomes

DOI:  https://doi.org/10.3389/fimmu.2026.1962696
J Transl Med. 2026 Aug 26. pii: 1298. [Epub ahead of print]24(1):

MSC-derived exosomes co-delivering anti-miR-221 and gemcitabine for inhibiting the proliferation of pancreatic cancer.

Bingqing Du, Haifeng Wang, Xiexie Qin, Xiaodong Song, Hailong Chen, Zhebing Song, Huihong Liang, Wujian Deng, Zili Shao, Xuewei Yang.

BACKGROUD: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and lethal malignancies, with a dismal 5-year survival rate of approximately 4%. The majority of patients with pancreatic cancer have a poor response to traditional chemotherapy due to its disadvantages, such as drug resistance and biological toxicity. Therefore, a novel therapeutic methods should be developed to improve the efficacy of chemotherapy drugs in pancreatic cancer. In this study, we developed a co-delivery system utilizing exosomes as carriers to simultaneously encapsulate a miR-221-targeting antisense oligonucleotide (anti-miR-221) and gemcitabine(Gem) for treatment of PDAC.
METHODS: A lentiviral plasmid carrying the green fluorescent protein (GFP) reporter gene and anti-miR-221 was constructed and used to transfect the human umbilical cord blood mesenchymal stem cell line (MSCs). Exosomes secreted by the MSCs were purified using the ExoQuick reagent kit. Gemcitabine was loaded into the exosomes via sonication. After DAPI staining, Panc-1 cells were incubated with the exosomes, and uptake of exosomes loaded with anti-miR-221 and Gem by Panc-1 cells was confirmed using fluorescence microscopy. Experimental groups were as follows: blank exosomes (blank-exo group); exosomes loaded with anti-miR-221 (exo-221 group); exosomes loaded with Gem (exo-Gem group); Gemcitabine monotherapy (Gem group); and exosomes co-loaded with anti-miR-221 and Gem (exo-Gem-221 group).The effects of drug delivery system on Panc-1 cell proliferation were assessed using the CCK-8 assay, and miR-221 expression levels in Panc-1 cells were measured via RT-PCR. For the study in vivo, treatments were administered via intratumoral injection into a nude mouse model with subcutaneous Panc-1 xenografts. The tumor volume and weight were measured to calculate the tumor inhibition rate. miR-221 expression in tumor tissues was detected by RT-PCR. Protein expression levels of VEGF and Caspase-3 in tumor tissues were evaluated by immunohistochemistry. Liver and kidney tissues from the mice were collected, subjected to H&E staining, and examined under a light microscope for pathological changes.
RESULTS: In both in vitro and in vivo experiments, miR-221 levels were significantly lower in the exo-221 and exo-Gem-221 groups compared to the blank-exo group (P < 0.01), demonstrating that exosome-delivered anti-miR-221 effectively silenced miR-221 expression in pancreatic cancer cells. The CCK-8 assay showed that cell viability was significantly reduced in the exo-221, exo-Gem, and Gem monotherapy groups compared to the blank-exo group (P < 0.05). Furthermore, the exo-Gem-221 group exhibited a more pronounced decrease in cell viability compared to the exo-Gem, exo-221, and Gem monotherapy groups (P < 0.01). Animal experiments revealed that tumor volume and weight were significantly decreased in the exo-221, exo-Gem, and Gem monotherapy groups compared to the blank-exo group (P < 0.05). The exo-Gem-221 group showed a more significant reduction in tumor volume and weight and a higher tumor inhibition rate compared to the exo-221, exo-Gem, and Gem monotherapy groups (P < 0.01). Immunohistochemistry indicated that protein levels of Caspase-3 were significantly increased, while VEGF levels were significantly decreased, in the exo-221, exo-Gem, and Gem monotherapy groups compared to the blank-exo group (P < 0.05). These changes were even more pronounced in the exo-Gem-221 group compared to the exo-221, exo-Gem, and Gem monotherapy groups (P < 0.01). H&E staining of liver and kidney tissues from nude mice showed hepatic sinusoid atrophy and disordered hepatic plate arrangement in the liver, as well as glomerular shrinkage and peri-glomerular cell necrosis in the kidneys, only in the Gem monotherapy group. No significant pathological changes were observed in the liver or kidney tissues of the other groups.
CONCLUSIONS: Exosomes derived from MSCs and co-loaded with anti-miR-221 and Gemcitabine significantly inhibit the proliferation of pancreatic cancer. This combined antitumor effect is superior to that of exo-221, exo-Gem, or Gemcitabine monotherapy. Furthermore, this approach demonstrates low liver and kidney toxicity, suggesting it may be a safe and effective method for treating pancreatic cancer.

DOI: https://doi.org/10.1186/s12967-026-08764-0
Biotechnol Adv. 2026 Oct 13. pii: S0734-9750(26)00279-X. [Epub ahead of print]94 109073

Engineering of bacterial outer membrane vesicles for biotechnological applications.

Yongjae Lee, Yoojeong Choi, Kangsan Kim, Dukwon Lee, Jongoh Shin, Sung Sun Yim, Sun Chang Kim, Ki Jun Jeong, Suhyung Cho, Byung-Kwan Cho.

  Outer membrane vesicles (OMVs) are spherical, nano-sized proteoliposomes naturally secreted by Gram-negative bacteria. By incorporating parental membrane components and encapsulating diverse cellular cargos, OMVs function as potent mediators of biological communication. Despite inherent challenges, including low production yields, heterogeneous composition, and stochastic cargo loading, OMVs hold immense promise across broad biotechnological landscapes. In this review, we examine current advancements in OMV chassis engineering and functional diversification, providing a comprehensive synthetic biology perspective on their role as modular and programmable systems. We discuss five established strategies for inducing hyper-vesiculation alongside two complementary frameworks for constructing synthetic vesicles. These engineered OMVs facilitate transformative applications spanning biomedical and biotechnological domains, notably as high-fidelity platforms for studying membrane proteins within their native lipid environments. As synthetic biology increasingly converges with materials science, future innovations such as stimuli-responsive vesicles, self-assembling architectures, and hybrid bio-synthetic materials are poised to emerge. Such advancements position synthetic OMVs at a critical intersection to address complex challenges in medicine, environmental remediation, and advanced materials science, offering unprecedented opportunities for both fundamental discovery and industrial applications.

Keywords:  Applied biotechnology; Bioengineering; Extracellular vesicles; Outer membrane vesicles; Synthetic biology

DOI:  https://doi.org/10.1016/j.biotechadv.2026.109073
Metab Brain Dis. 2026 Oct 15. pii: 238. [Epub ahead of print]41(1):

Exploring the potential of resveratrol-enriched cord mesenchymal stem cell derived exosomes in an in vitro Parkinson's model.

Suhair Rami Mohammed Shamshir, Gulen Melike Demirbolat, Sevim Isik.

  Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra and the pathological aggregation of α-synuclein (α-syn) into Lewy bodies and it is known as the second most prevalent neurodegenerative disorder. The pathogenesis of PD involves mitochondrial dysfunction, oxidative stress, impaired protein degradation, and neuroinflammation. Current therapeutic strategies are largely symptomatic and remain limited in their ability to halt disease progression. Resveratrol (Res) has been shown to mitigate oxidative stress, preserve mitochondrial integrity, and reduce α-syn aggregation in PD models due to its antioxidant and neuroprotective properties. Despite its promising therapeutic potential, its poor bioavailability and rapid metabolism hinder the achievement of the desired therapeutic effects, which calls for advanced drug delivery systems. Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) exosomes (Exos) are nanoscale extracellular vesicles with intrinsic neuroprotective, anti-inflammatory, and regenerative properties. They represent a promising carrier system owing to biocompatibility and the ability to cross the blood-brain barrier. Since the isolation technique is a critical parameter affecting both Exos yield and therapeutic efficacy, the study initially focused on optimizing the isolation process through a comparative investigation of ultracentrifugation and commercial isolation kits. Exos obtained with the highest yield and optimal characteristics, were subsequently subjected to Res loading through the probe sonication method. After the physicochemical characterization of Res-loaded exosomes (Exo-Res), their therapeutic potential was evaluated in an in vitro PD model established by rotenone-induced neurotoxicity in SH-SY5Y cells. Cell viability, oxidative stress, mitochondrial function, and whole protein aggregation were comprehensively assessed. Exo-Res isolated with Kit-1 showed a smaller particle size (94.0 nm) with high homogeneity (PDI < 0.3), high yield (3.9 × 1011 particles/mL), and good entrapment efficiency (58.3%). It released Res in a sustained manner over 4 h. Our findings confirmed that Exo-Res significantly reduced whole protein aggregation mitigated oxidative stress, enhanced neuronal survival, and preserved mitochondrial function more effectively than either free Res or unloaded Exos. These results show that Exo-Res is a promising biocompatible nanocarrier-based therapeutic strategy for PD and possibly other neurodegenerative disorders, overcoming the key challenge of Res bioavailability while benefiting from the biocompatibility and therapeutic performance of exosomes.

Keywords:  Exosomes; Human umbilical cord-derived mesenchymal stem cells; Parkinson’s disease; Protein aggregation; Resveratrol

DOI:  https://doi.org/10.1007/s11011-026-02003-7
Front Pediatr. 2026 ;14 1931883

Advances and mechanisms in the application and treatment of functionalized stem cells and their derivatives in allergic rhinitis.

Lijun Yu, Xiaojuan Xu, Haihua Chen, Bingbing Li, Lian Feng.

  Allergic rhinitis (AR) is characterized by Th2/Th17/Treg immune imbalance and nasal mucosal barrier damage, and current treatments struggle to restore immune homeostasis. Mesenchymal stem cells (MSCs) and their exosomes can exert anti-inflammatory and barrier-repairing effects through paracrine pathways, but natural MSCs have poor targeting and short local retention, limiting their efficacy. Recent functionalization and novel delivery systems have significantly enhanced their efficacy, and combination therapy strategies have shown synergistic potential. However, current evidence is largely derived from animal models, clinical studies lack large-scale, long-term data, and standardization of MSCs from different sources and engineered products is insufficient. Future research should leverage multi-omics and intelligent design to advance personalized treatment plans, providing a new direction for non-hormonal "immune reset" therapy for AR. This review systematically summarizes the mechanisms, strategies, and translational bottlenecks of functionalized stem cell derivatives in AR, providing a theoretical framework for subsequent precision cell therapy research.

Keywords:  allergic rhinitis; exosomes; functionalization; immune regulation; mesenchymal stem cells

DOI:  https://doi.org/10.3389/fped.2026.1931883
Adv Mater. 2026 Oct 13. e75342

Harnessing the Bacterial Membrane-Derived Oral Vaccine to Potentiate Antitumor Immunity and Metabolic Control of T Cells.

Wenfei Chen, Fan Yang, Beibei Wu, Gelin Xiang, Xiaoya Lu, Jingyao Ma, Yining Xu, Li Mo, Xun Sun, Jinhan He.

  The fluctuating gastrointestinal milieu and its restrictive epithelial barrier represent critical challenges for the design of oral cancer vaccines. Nevertheless, leveraging the gut microbiome as an interventional strategy has recently gained traction, especially in patients on immune checkpoint inhibitor (ICI) therapy. Here, microbial-derived double-layered membrane vesicles are developed as adjuvants and cell-free carriers, fused with cell-penetrating peptide-modified antigens, and encapsulated in an alginate/chitosan-microsystem to engineer oral vaccines. This design strategically harnesses the crosstalk between the gut microbiome and gut-associated lymphoid tissues, driving dendritic cell maturation, plasma cell activation, and production of immune-stimulatory cytokines within the mesenteric lymph nodes and lamina propria. In mouse prophylactic and therapeutic tumor models, the select Bifidobacterium bifidum-derived oral vaccine combined with anti-PD1 treatment enhances cytotoxic antitumor responses, along with Th1-, Th17-immunity, leading to potent tumor suppression, prolonged survival, and long-term protection against tumor rechallenge. Mechanistically, the vaccine promotes interferon-γ-producing T cells and antitumor efficacy with ICI therapy via the improved microbiota diversity and signaling metabolites, with an indole-3-acetic-acid (3IAA) enriched diet profoundly shaping T-cell recruitment and differentiation. Our findings uncover a tryptophan metabolite-driven immune axis that amplifies the specific antitumor immune response, redefining oral vaccines as a powerful tool for cancer immunotherapy.

Keywords:  bacterial membrane vesicles; cancer immunotherapy; gut microbiome; metabolite‐driven immunity; oral vaccination

DOI:  https://doi.org/10.1002/adma.75342
ACS Appl Bio Mater. 2026 Oct 14.

Callicarpa nudiflora-Derived Extracellular Vesicle-Based Hydrogel Loaded with Apremilast for Enhanced Therapy of Psoriasis.

Yingmiao Ou, Baoliang Pei, Chong Wang, Liang Chen, Jizhou Zhu, Peng Xu, Haijun Zhong, Hongbo Zhang, Feng Guo.

  Apremilast (APST) is an effective medication for psoriasis, but its clinical application is limited by its exclusive availability as an oral tablet formulation and the associated systemic adverse effects. Hydrogel-based transdermal delivery offers a promising alternative for localized APST administration. To address this, Callicarpa nudiflora-derived extracellular vesicle-based hydrogel loaded with APST (APST-EV-Gel) was developed. APST was first loaded into Callicarpa nudiflora-derived extracellular vesicles (APST-EVs) with a drug loading of 17.14% ± 0.13% and an encapsulation efficiency of 41.49% ± 0.48%. The resulting APST-EVs were then embedded in a carbomer hydrogel to form APST-EV-Gel. Pharmacodynamic evaluation demonstrated that APST-EV-Gel significantly ameliorated skin lesions and reduced splenic inflammation in mice. The treatment also decreased infiltration of T-lymphocytes and neutrophils, downregulated the proliferation marker Ki67, and markedly lowered levels of the inflammatory cytokines TNF-α, IL-17, and IL-23. Furthermore, APST-EV-Gel promoted apoptosis in hyperproliferative keratinocytes, thereby contributing to disease alleviation. In conclusion, the combination of APST and EVs exerts superior therapeutic efficacy against psoriasis compared to monotherapy with either agent alone. APST-EV-Gel represents a promising topical therapeutic strategy for psoriasis.

Keywords:   Callicarpa nudiflora ; apremilast; extracellular vesicle; hydrogel; psoriasis

DOI:  https://doi.org/10.1021/acsabm.6c01702
Int J Pharm X. 2026 Dec;12 100674

Lactoferrin-modified MSC-derived extracellular vesicles facilitate BBB penetration and enhance gastrodin-induced neuroprotection in Parkinson's disease: involvement of mitophagy.

Zi-Yu Luo, Ru-Jie Han, Tian-Jiao Guo, Hong Huang, Bai-He Su, Jia-Li Xu, Wang Zhang, Jin-Zhen Li, Zi-Wei Sang, Zi-Tong Mei, Kun Wang, Zhi-Qin Zhang, Sheng-Jun An, Hong-Xu Chen.

   Background: The blood-brain barrier (BBB) severely impedes neuroprotective agent delivery to the brain in Parkinson's disease (PD). Although gastrodin (Gas) possesses neuroprotective properties, its efficacy is limited by poor BBB permeability. This study aimed to develop a brain-targeted extracellular vesicle (EV) delivery system for Gas and elucidate its neuroprotective mechanisms.
Methods: A brain-targeted EV delivery system was developed using mesenchymal stem cell-derived EVs modified with lactoferrin (Lf). Gas was loaded into Lf-EVs via sonication to construct Lf-EVs-Gas nanocomplexes. The nanocomplexes were characterized by transmission electron microscopy, western blotting, and nano-flow cytometry. Trans-Barrier transport was evaluated using an in vitro Transwell BBB model (hCMEC/D3 cells), while therapeutic efficacy and biodistribution were assessed in an MPTP-induced PD mouse model.
Results: Lf-EVs-Gas exhibited a typical cup-shaped morphology, with a mean size of 79.08 nm and a drug loading efficiency of 47.08 ± 4.63%. Lf functionalization significantly enhanced BBB transport, achieving a brain Gas concentration of 10.34 ± 2.7 ng/g in PD mice versus undetectable levels for free Gas. The targeted system demonstrated superior brain accumulation versus non-targeted vesicles. In 6-OHDA-treated SH-SY5Y cells and MPTP-induced PD mice, the system upregulated tyrosine hydroxylase, reduced α-synuclein aggregation, inhibited neuronal apoptosis, and improved motor function. Mechanistically, these protective effects of Lf-EVs-Gas were associated with activation of PINK1-related mitophagy, as evidenced by elevated LC3-II/LC3-I ratio and increased TOMM20/LC3 colocalization.
Conclusion: Lf-EVs-Gas enhanced the brain delivery of Gas and produced neuroprotective effects in cellular and mouse toxin-based models of PD. These effects were associated with the activation of PINK1-related mitophagy, supporting Lf-modified EVs as a promising brain-targeted delivery platform for Gas. Further studies establishing mechanistic causality, long-term safety, and efficacy in progressive PD models are warranted.

Keywords:  Blood–brain barrier; Extracellular vesicles; Gastrodin; Mitochondrial autophagy; Parkinson's disease

DOI:  https://doi.org/10.1016/j.ijpx.2026.100674
Adv Sci (Weinh). 2026 Oct 15. e78279

Intratumoral Fusogenic Outer Membrane Vesicles Enhance Antitumor Immunity Through Tumor MHC-I Upregulation and Tumor Bacterization.

Xing Liu, Jiaxin Zhou, Guihong Lu, Chenjing Zhao, Weixiu Wang, Jichuan Chen, Fengqi Zhang, Fan Zhang, Hai-Yan Xie, Weidong Nie.

  Cold tumors evade APC and T-cell surveillance through low immunogenicity, defective antigen presentation, and immunosuppressive tumor microenvironments. We uncovered a non-canonical function of bacterial outer membrane vesicles (OMVs), whereby OMVs activated the TLR4-NF-κB-NLRC5 axis to induce tumor MHC I upregulation, thereby restoring tumor visibility to T cells. To further eliminate tumor invisibility to APCs, we reported a bacteria-inspired strategy that drives APCs to perceive tumor cells as bacteria. By fusing OMVs with fusogenic liposomes, we constructed fusogenic OMVs (FOs) that anchor bacterial membrane components onto tumor surfaces, thereby functionally "bacterizing" tumor cells. This modification markedly increased APC recruitment and effectively reprogrammed APC perception from silent tumor clearance to active microbial-like immune surveillance. Consequently, APCs exhibited enhanced phagocytic uptake of bacterized tumors, enabling efficient cross-presentation of the tumor-antigen repertoires to T cells. Concurrently, OMVs upregulated MHC I expression on tumor cells, which strengthened effector T cell recognition and cytotoxicity toward tumors. Furthermore, by loading 3-bromopyruvate into the vesicles, we endowed the system with metabolic reprogramming capability, characterized by glycolysis suppression and lactate depletion. Together, the synergistic immune-metabolic modulation resulted in durable suppression of tumor progression following intratumoral administration, offering a bacterization-inspired nanoplatform to overcome key immunological barriers in immune-cold tumors.

Keywords:  antigen presentation; bacterial outer membrane vesicles; immunotherapy; major histocompatibility complex; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.78279