bims-engexo 2026-09-20 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2026–09–20
twelve papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered Exosomes for Oral Administration: Breaking Gastrointestinal Barriers for Disease Therapy.
Engineered microvesicle-mediated multimodal therapy resolves ulcerative colitis via synergistic immunoregulation, barrier restoration, and microbiota remodeling.
Reprogramming PD-L1 endosomal recycling and lysosomal degradation via engineered exosome-based nanocomposites overcomes immune resistance in lung cancer brain metastasis.
Bacillus subtilis extracellular vesicles surface-displaying superoxide dismutase attenuate alcoholic liver injury by activating the Nrf2/HO-1 axis.
Engineered bacterial outer membrane vesicle vaccine prevents T cell exhaustion for antibacterial immunotherapy.
Balancing stability and cellular interaction in surface-engineered small extracellular vesicles for pulmonary delivery.
Synthesis of RARα-PROTAC and its delivery via Polygonatum sibiricum exosome-like nanoparticles for the treatment of colorectal cancer.
Delivery of Anti-VEGFA Antibody by Plant-Derived Exosome-like Nanovesicles Alleviates Corneal Angiogenesis and Fibrosis via Topical Ocular Administration.
Hybrid extracellular vesicles for targeted delivery of therapeutic cargoes to combat osteoporotic bone loss.
Intranasal delivery of cerium oxide nanozyme and superoxide dismutase in exosomes for Parkinson's disease therapy.
Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
Preparation of Mesenchymal Stromal Cells-Derived Extracellular Vesicles as Carriers for Paclitaxel Delivery.

J Drug Target. 2026 Sep 15. 1-37

Engineered Exosomes for Oral Administration: Breaking Gastrointestinal Barriers for Disease Therapy.

Ying Ma, Tong An, Pan Wu, Daqin Li, Runxuan Wang, Huijuan Song, Qiang Liu, Ningning He.

  Extracellular vesicles (EVs) and exosomes are nanoscale vesicles from diverse biological sources, including animals, plants, and bacteria. Due to their pharmacological activity, high biosafety, and biocompatibility, they attract attention in intercellular signaling and therapeutic delivery. Oral administration is more convenient than invasive routes. Engineering strategies (surface modification, hybridization, gastric acid-resistant encapsulation) significantly enhance gastrointestinal stability and targeting. This review summarizes research progress of engineered EVs or exosomes for oral administration in disease treatment. We discuss exosomes from different sources, compare their biogenesis, isolation, purification, characterization methods, examine engineering strategies for gastrointestinal stability, and summarize application potential. We place special emphasis on the clinical trials of oral exosome administration that have not yet obtained clinical approval, and further discuss the current challenges and prospects for clinical translation. Establishing unified production, quality control, and regulatory standards for exosomes in preclinical stage, analyzing structural characteristics and mechanisms of crossing the gastrointestinal barrier, and combining with the quantitative analysis of exosomes in the gastrointestinal tract combining quantitative analysis of exosomes in the gut will help formulate more effective clinical translation strategies.

Keywords:  Disease Application; Drug Delivery; Exosomes; Oral Engineering Strategy; Oral Vaccine

DOI:  https://doi.org/10.1080/1061186X.2026.2733612
Mater Today Bio. 2026 Oct;40 103623

Engineered microvesicle-mediated multimodal therapy resolves ulcerative colitis via synergistic immunoregulation, barrier restoration, and microbiota remodeling.

Cuihua Qi, Chaoyue Liang, Sha Wang, Hui Zhang, Han Wei, Xiaojun He, Weigang Chen.

  Ulcerative colitis (UC) represents a major global health challenge characterized by immune dysregulation and disruption of the epithelial barrier, with current therapies demonstrating limited efficacy. Microvesicles (MVs) engineered through alternative macrophage activation possess immunomodulatory and restorative cargo. However, their therapeutic potential for UC and the underlying mechanisms remain largely unexplored. Herein, we demonstrate that these engineered MVs significantly mitigate colitis symptoms, including weight loss, rectal bleeding, and colon shortening, while also reducing histopathological damage and restoring barrier function in UC. They suppress pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and upregulate IL-10 by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Furthermore, they reshape gut microbiota, enhance microbial diversity, and rectify dysbiosis. Collectively, our findings establish a multimodal therapy mediated by engineered MVs, which includes the inhibition of inflammatory signaling, repair of the disrupted epithelial barrier and remodeling of dysbiotic microbiota, as a promising strategy for UC, thereby expanding the therapeutic potential of extracellular vesicles for precision management of UC.

Keywords:  Gut microbiome; Immunotherapy; M2 macrophage-derived microvesicles; TLR4-NF-κB signaling; Ulcerative colitis

DOI:  https://doi.org/10.1016/j.mtbio.2026.103623
Mater Today Bio. 2026 Oct;40 103628

Reprogramming PD-L1 endosomal recycling and lysosomal degradation via engineered exosome-based nanocomposites overcomes immune resistance in lung cancer brain metastasis.

Xiujuan Hong, Xiaoqi Wang, Wankun Wang, Weiye Ren, Wenjia Ding, Dashan Yin, Chenli Wang, Chuan Sun, Jun Chen, Ji-Gang Piao, Zhibing Wu.

  While anti-PD-L1 antibody (αPD-L1) therapy holds promise, its efficacy against lung cancer brain metastasis (LCBM) is severely limited by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment and adaptive immune resistance. To overcome these barriers, we engineered a pH-responsive nanocomposite (VP-αPD-L1@REB) by functionalizing brain-metastatic tumor cell-derived exosomes (EB) with RGD peptides (REB) for targeted co-delivery of verteporfin (VP) and αPD-L1. Benefiting from homotypic affinity and integrin-mediated transcytosis, VP-αPD-L1@REB efficiently crosses the BBB, accumulates within intracranial tumors, and undergoes pH-responsive cargo release. Mechanistically, VP induces a lethal reactive oxygen species (ROS) storm for direct tumor ablation. Simultaneously, VP downregulates the chaperone protein CMTM6 and activates cellular autophagy, forcibly driving internalized PD-L1 toward degradation via dual "endosome-lysosome" and "autophagy-lysosome" pathways. Driven by the synergy of VP's robust intracellular clearance and αPD-L1's surface blockade, this targeted nanoplatform successfully remodels the intracranial immunosuppressive microenvironment and triggers potent systemic anti-tumor immunity. This study provides a highly promising translational paradigm for overcoming adaptive immune resistance in central nervous system (CNS) malignancies.

Keywords:  Adaptive immune resistance; Blood-brain barrier; Engineered exosomes; Lung cancer brain metastasis; Lysosomal degradation; Verteporfin

DOI:  https://doi.org/10.1016/j.mtbio.2026.103628
Bioresour Bioprocess. 2026 Sep 12. pii: 132. [Epub ahead of print]13(1):

Bacillus subtilis extracellular vesicles surface-displaying superoxide dismutase attenuate alcoholic liver injury by activating the Nrf2/HO-1 axis.

Baoxian Li, Jiali Chen, Chaozhi Wei, You Wei, Chunqiang Pan, Tao Liu, Qingchi Wang, Shiyu Li, Yao Zhao, Mengyu Zhang, Chenfan Sun, Chengran Guan, Domenico Nuzzo, Jintao Cheng, Yuanxiang Jin, Guiling Yang.

  Alcoholic liver disease (ALD) represents a globally prevalent progressive hepatic disorder with continuously rising incidence. Its pathological mechanisms mainly stem from the direct toxic effects of alcohol metabolites, accompanied by aggravated oxidative stress, lipid overaccumulation and inflammatory infiltration.. While current therapies that act on these pathogenic mechanisms alleviate symptoms, they are often limited by gastrointestinal adverse effects and long-term hepatic metabolic burden. Bacterial extracellular vesicles (BEVs), emerging as natural carriers of bioactive molecules and mediators of intercellular communication, offer a novel hepatoprotective strategy against alcoholic liver injury. Superoxide dismutase (SOD), as a crucial antioxidant, has been extensively verified for its capacity to eliminate free radicals. Here, we leverage the advantages of BEVs and the multiple effects of SOD, utilizing surface display technology to locate SOD in Bacillus subtilis 168-derived EVs (termed SEVs). In vitro simulated digestive fluids experiment confirms the stability and digestive resistance of SEVs, while in vivo biodistribution assays demonstrate the liver-targeting capability. In ethanol-exposed hepatocytes, SEVs significantly attenuate reactive oxygen species (ROS) overproduction and lipid deposition. In a murine ALD model, SEVs administration reduces hepatic steatosis, serum transaminase levels, and inflammatory infiltration. Mechanistically, SEVs activate the Nrf2/HO-1 antioxidant pathway, a key regulator of cellular redox balance and inflammation, thereby counteracting oxidative damage and inflammatory reaction caused by alcohol stimulation. Notably, SEVs exhibit superior biocompatibility without inducing secondary hepatic burden. Our findings emphasize the dual advantages of SEVs as liver-targeted delivery vehicles and multifunctional liver-protective agents, highlighting their translational potential for ALD management.

Keywords:  Alcoholic liver disease; Bacterial extracellular vesicles; Nrf2/HO-1; Superoxide dismutase; Surface display

DOI:  https://doi.org/10.1186/s40643-026-01112-6
Cell Rep. 2026 Sep 15. pii: S2211-1247(26)01032-6. [Epub ahead of print]45(9): 117954

Engineered bacterial outer membrane vesicle vaccine prevents T cell exhaustion for antibacterial immunotherapy.

Zhibang Li, Ying Wang, Zhiyan Zhou, Danyang Wang, Ning Wang, Xiaoyi Liu, Yi Chen, Junkun Feng, Zhuolin Li, Ruiqing Yu, Kai Li, Wenjun Wang, Weiwei Zhao, Yao Sun, Jianhua Li, Shaohua Ge.

  Gram-negative pathogens evade immune clearance and promote chronic infections by residing intracellularly. While outer membrane vesicles (OMVs) hold promise as antibacterial vaccine platforms, their clinical potential is limited by lysosomal entrapment of antigens and endotoxin-induced toxicity. Herein, we present an innovative nano-encapsulation strategy to engineer OMVs and overcome these two obstacles. We engineered Porphyromonas gingivalis (P. gingivalis) OMVs by incorporating metal ion adjuvants, coordinated with phenolic ligands, to form a rigid, acid-responsive nanoshell. This shell enhances dendritic cell uptake and promotes lysosomal escape, redirecting antigens to cytosolic cross-presentation and reprogramming CD8+ T cell responses through STING signaling. Nano-encapsulation also attenuates endotoxin-induced systemic cytokine storms, reducing lethality. In murine periodontitis, the engineered OMV vaccine lowers P. gingivalis burden, prevents T cell exhaustion, and mitigates inflammatory tissue damage. These findings provide a safe and effective strategy to counteract immune evasion by intracellular pathogens, with promising potential for immunotherapy against chronic bacterial infections.

Keywords:  CP: immunology; CP: microbiology; P. gingivalis; PD-1; STING; T cell exhaustion; chronic bacterial infections; intracellular infection; metal-phenolic networks; outer membrane vesicle; periodontitis; vaccine

DOI:  https://doi.org/10.1016/j.celrep.2026.117954
Mater Today Bio. 2026 Oct;40 103637

Balancing stability and cellular interaction in surface-engineered small extracellular vesicles for pulmonary delivery.

Maria José Sanchez, Pablo Leivar, Soraia Pinto, Helena Almeida, Margalida Esmeralda Artigues, Bruno Sarmento, Martí Lecina, Cristina Fornaguera.

  Small extracellular vesicles (sEVs) are emerging as promising nanocarriers for non-invasive pulmonary drug delivery, yet their effectiveness is limited by sequential barriers imposed by airway mucus and the pulmonary epithelium-endothelium interface. Here, we investigated how post-secretory surface engineering with exogenous phospholipids modulates sEVs transport across lung-relevant barriers. eGFP-CD81 engineered sEVs were post-secretory modified at their surface composition using different lipid-to-vesicle ratios of either the zwitterionic lipid 1,2- Dilauroyl-sn-glycero-3-phosphocholine (DLPC) or the PEGylated lipid 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) -PEG(5000) - Azide (DPA). Both modifications enabled controlled tuning of surface charge and colloidal stability without altering vesicle size at optimized lipid-to-vesicle ratios, although excessive DPA induced aggregation. The physicochemical properties and transport behaviour of engineered sEVs were evaluated in a reconstituted mucin gel and a 3D pulmonary epithelial-endothelial co-culture model. In mucin-containing medium, lipid-engineered sEVs showed enhanced diffusion compared with unmodified vesicles, with DLPC at a 30,000:1 ratio providing the highest cumulative permeability, sustained apparent permeability coefficients, and more diffusive motion profiles, as confirmed by multiple particle tracking. In the 3D co-culture, the same modification achieved the greatest cumulative permeability and basolateral accumulation, indicating efficient transcellular passage, while DPA-functionalized vesicles displayed moderate permeability and predominant retention at the apical epithelial layer. Through fluorescently-labelling EVs, we confirmed that all formulations were internalized by apical cells, but only DLPC-engineered sEVs reached detectable levels in basolateral cells. Neither DLPC nor DPA affected cell viability or barrier morphology. Overall, our results identify DLPC at 30,000:1 as a lead formulation that balances mucus penetration and efficient crossing of the pulmonary barrier, while DPA is better suited for applications requiring strong epithelial engagement. Our findings highlight rational phospholipid engineering as a powerful approach to tailor sEVs-based nanomedicines for pulmonary delivery.

Keywords:  3D lung model; Mucus penetration; Pulmonary drug delivery; Small extracellular vesicles; Surface engineering

DOI:  https://doi.org/10.1016/j.mtbio.2026.103637
Mater Today Bio. 2026 Oct;40 103651

Synthesis of RARα-PROTAC and its delivery via Polygonatum sibiricum exosome-like nanoparticles for the treatment of colorectal cancer.

Gengzhen Zhu, Yanping Zhao, Mingzhu Chen, Shi Lu, Lilan Xu, Guanyu Chen, Lupeng Zeng, Jinghua Chen.

  Retinoic acid receptor α (RARα) is a promising yet challenging target in treating colorectal cancer (CRC). Traditional RARα-binding modulators often fail to fully inhibit downstream oncogenic pathways and cannot eliminate the pre-existing RARα protein, frequently resulting in drug resistance and treatment failure. To overcome these limitations, we designed a series of proteolysis-targeting chimeras (PROTACs) based on the ligand CA77.1, which are bifunctional molecules that recruit the ubiquitin-proteasome system for RARα degradation.Among these candidates, compound Z1 proved the most potent degrader, demonstrating a DC50 of 6.02 ± 1.05 μM and effective suppression of CRC cell proliferation and migration. Considering the generally poor solubility and membrane permeability of PROTACs, we encapsulated Z1 within Polygonatum sibiricum exosome-like nanoparticles (PsELNs). Compared with free Z1, the Z1/PsELNs delivery system enhanced RARα degradation in vitro by 2.2-fold and improved in vivo antitumor efficacy by 1.8-fold, while also promoting tumor targeting and overall bioavailability. These findings provide a feasible strategy for degrading RARα in CRC and highlight the potential of plant-derived exosome-like nanoparticles as efficient carriers for PROTAC delivery, indicating a new direction for targeted cancer therapy.

Keywords:  Colorectal cancer; Drug delivery; PROTAC; Polygonatum sibiricum exosome–like nanoparticles; RARα

DOI:  https://doi.org/10.1016/j.mtbio.2026.103651
Molecules. 2026 Aug 28. pii: 3026. [Epub ahead of print]31(17):

Delivery of Anti-VEGFA Antibody by Plant-Derived Exosome-like Nanovesicles Alleviates Corneal Angiogenesis and Fibrosis via Topical Ocular Administration.

Xuan Chen, Qian Li, Hong-Ping Cui.

  Background: Pathological angiogenesis and stromal fibrosis after ocular chemical injury are primary drivers of corneal opacification and permanent vision loss. Topical administration of anti-VEGFA antibody is hampered by rapid tear clearance and poor penetration across the corneal epithelial barrier, resulting in insufficient intraocular drug accumulation and suboptimal therapeutic efficacy. Although intraocular injection elevates local drug concentration, this invasive procedure carries risks of complications and is not suitable for long-term repeated treatment. This study constructed red cabbage-derived exosome-like nanovesicles (Rabexo) to load an anti-VEGFA antibody, formulated into PVA/HA hydrogel, aiming to develop a topical sustained-release ocular delivery system for alleviating corneal angiogenic and fibrotic lesions. Methods: Rabexo was isolated and physicochemically characterized. Anti-VEGFA antibody was encapsulated into Rabexo via electroporation to prepare aV-Rabexo, which was further incorporated into commercial PVA/HA hydrogel. Cellular uptake, anti-angiogenic functions were verified in vitro, and therapeutic efficacy was evaluated in a mouse corneal alkali burn model via ophthalmic topical administration. Results: The prepared Rabexo showed uniform size and favorable colloidal stability with 40.3% antibody encapsulation efficiency. aV-Rabexo exhibited stronger in vitro anti-migration, anti-proliferation and anti-tube formation effects than free antibody. In vivo, aV-Rabexo-Gel substantially suppressed corneal neovascular area and length, restored stromal collagen arrangement, and downregulated CD31, VEGFA and α-SMA expression at day 14 post-injury, with statistically significant differences compared with the free antibody gel. Conclusions: This plant-derived nanocarrier hydrogel system realizes synergistic therapeutic effects via nanocarrier delivery, antibody neutralization and prolonged ocular retention. With advantages of easy production and low immunogenicity, it provides a promising non-surgical strategy for treating ocular surface pathological angiogenesis and fibrosis.

Keywords:  anti-VEGFA antibody; corneal alkali burn; corneal fibrosis; corneal neovascularization; drug delivery; ophthalmic hydrogel; plant-derived nanovesicles

DOI:  https://doi.org/10.3390/molecules31173026
Cell Biomater. 2026 Jun 05. pii: 100496. [Epub ahead of print]

Hybrid extracellular vesicles for targeted delivery of therapeutic cargoes to combat osteoporotic bone loss.

Hilal Ahmad Rather, Sajeeshkumar Madhurakkat Perikamana, Nicole Angel, Yu-Ru V Shih, Jiaul Hoque, Huchen Tao, Hunter Newman, Giwon Cho, Shyni Varghese.

  Osteoporosis arises from an imbalance between bone-resorbing osteoclasts and bone-forming osteoblasts, driving progressive bone loss. Here, we engineer bone-targeting hybrid vesicles by fusing extracellular vesicles with lipid nanoparticles to enable coordinated delivery of complementary therapeutics. These vesicles present and carry osteoprotegerin (OPG) protein and mRNA, and are fused with adenosine-loaded nanoparticles to form OPG-EV-LNP-Ado. Acting as a decoy for RANKL, OPG directs bone-specific targeting and uptake, enhancing delivery to osteoblasts. Systemic administration results in preferential bone accumulation and significantly attenuates osteoporotic pathology, demonstrating a modular platform for targeted, multi-cargo therapy to restore bone homeostasis.

Keywords:  Osteoporosis; adenosine; extracellular vesicles; lipid nanoparticles; osteoprotegerin; targeted delivery

DOI:  https://doi.org/10.1016/j.celbio.2026.100496
Mater Today Bio. 2026 Oct;40 103629

Intranasal delivery of cerium oxide nanozyme and superoxide dismutase in exosomes for Parkinson's disease therapy.

Xinxin Shao, Kefei Li, Yanbo Wang, Xinai He, Boyu Xiong, Shengcai Yang, Quanshun Li.

  The excessive reactive oxygen species (ROS) play an important role in the occurrence and progression of Parkinson's disease (PD). To investigate whether the antioxidant enzymes can scavenge the ROS level in vivo and treat PD efficiently, superoxide dismutase (SOD) was encapsulated into HEK293-derived exosomes to prepare SOD-loaded exosomes (SOD@EXO), and catalase (CAT)-like cerium oxide nanozyme (CeO2) was mixed with SOD@EXO to construct the formulation, namely SOD@EXO + CeO2. The formulation with cup-shaped morphology showed high SOD and CAT activities, which could scavenge the ROS level in a cascade manner. In vitro neuroprotective trials against SH-SY5Y cells revealed that SOD@EXO + CeO2 could efficiently prevent the neurotoxicity in 1-methyl-4-phenylpyridine-induced PD cell model. Moreover, the exosomes could be significantly accumulated in brain after the intranasal administration in comparison to the intravenous injection. Finally, the system was found to ameliorate the behavior disorder and relieve the inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice model after the intranasal administration of SOD@EXO + CeO2. In a word, SOD@EXO + CeO2 could act in a cascade manner to scavege ROS, relieve the inflammatory response and improve the behavior disorder. Our results provide a new paradigm to construct the prevention and treatment strategy of dyskinesia diseases in central nervous system in future.

Keywords:  Exosome; Intranasal administration; Nanozyme; Parkinson's disease; Superoxide dismutase

DOI:  https://doi.org/10.1016/j.mtbio.2026.103629
Mater Today Bio. 2026 Oct;40 103636

Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.

Xianquan An, Li Zhang, Xin Zhang, Meidan Fang, Cong Wang, Yu Han, Zheng Wang, Jinfeng Wang, Shuting Zuo.

  Neuropathic pain remains a major clinical challenge due to limited efficacy and tolerability of current treatments. Mitochondrial dysfunction in dorsal root ganglion (DRG) cells is recognized as a key pathogenic mechanism, but effective strategies to restore mitochondrial homeostasis are lacking. Here, we first identified profound deficits in mitochondrial quantity and quality in DRG neurons and satellite glial cells (SGCs) from a chemotherapy-induced peripheral neuropathy (CIPN) model. To address this, we developed an extracellular vesicle-based nanoplatform (EVs@Mi/UR) loaded with a mitophagy inducer, which integrates exogenous mitochondrial transplantation with mitophagy induction. EVs@Mi/UR not only increased mitochondrial mass in DRG neurons and SGCs through efficient mitochondrial transplantation, but also improved mitochondrial quality by eliminating damaged organelles, thereby enhancing mitochondrial respiration and metabolic function. In both CIPN and spared nerve injury (SNI) mouse models, EVs@Mi/UR significantly alleviated mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity with superior efficacy. Notably, even in SNI models that did not exhibit baseline mitochondrial deficits, EVs@Mi/UR still produced analgesic effects by improving mitochondrial quality. This work establishes mitochondrial remodeling as a promising strategy for neuropathic pain and provides a translatable EV-based nanoplatform for dual-modality mitochondrial intervention.

Keywords:  Dorsal root ganglion; Extracellular vesicles; Mitochondrial transplantation; Mitophagy; Neuropathic pain

DOI:  https://doi.org/10.1016/j.mtbio.2026.103636
Methods Mol Biol. 2027 ;3074 159-169

Preparation of Mesenchymal Stromal Cells-Derived Extracellular Vesicles as Carriers for Paclitaxel Delivery.

Angela Marcianti, Catia Traversari, Daniela Lisini.

  Mesenchymal stromal cells-derived extracellular vesicles (MSCs-EVs) represent innovative tools as a drug delivery system. Here, we described the standardized manufacturing process to prepare MSCs-EVs loaded with the chemotherapeutic drug Paclitaxel (PTX), starting from adipose tissue lipoaspirates of healthy donors.

Keywords:  Cell culture; Drug delivery; Extracellular vesicles; Good manufacturing practice; Investigational medicinal product; Mesenchymal stromal cells

DOI:  https://doi.org/10.1007/978-1-0716-5539-9_10