bims-engexo 2025-04-13 papers

Liver Res. 2025 Mar;9(1): 17-28

Bioengineered extracellular vesicles: The path to precision medicine in liver diseases.

Ashmit Mittal, Vibhuti R Jakhmola, Sukriti Baweja.

Extracellular vesicles (EVs) are membrane-bound entities secreted by each cell, categorized as, exosomes, microvesicles or apoptotic bodies based on their size and biogenesis. They serve as promising vectors for drug delivery due to their capacity to carry diverse molecular signatures reflective of their cell of origin. EV research has significantly advanced since their serendipitous discovery, with recent studies focusing on their roles in various diseases and their potential for targeted therapy. In liver diseases, EVs are particularly promising for precision medicine, providing diagnostic and therapeutic potential in conditions such as metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, hepatocellular carcinoma, alcoholic liver disease, liver fibrosis, and acute liver failure. Despite challenges in isolation and characterization, engineered EVs have shown efficacy in delivering therapeutic agents with improved targeting and reduced side effects. As research progresses, EVs hold great promise to revolutionize precision medicine in liver diseases, offering targeted, efficient, and versatile therapeutic options. In this review, we summarize various techniques for loading EVs with therapeutic cargo including both passive and active methods, and the potential of bioengineered EVs loaded with various molecules, such as miRNAs, proteins, and anti-inflammatory drugs in ameliorating clinical pathologies of liver diseases.

Keywords: Bioengineering; Drug delivery; Exosomes; Extracellular vesicles (EVs); Liver diseases; Microvesicles; Precision medicine; Therapeutic agents

DOI: https://doi.org/10.1016/j.livres.2025.02.002

Front Cell Dev Biol. 2025 ;13 1549096

Mesenchymal stromal/stem cell-derived exosomes as a potential therapeutic approach to osteoarthritis combined with type 2 diabetes mellitus.

Siyi Xie, Meiling Liu, Yajie Kong, Yiming Yang, Ruixue Chen, Yuzhong Wang, Shuxing Cao, Yongzhou Song.

Osteoarthritis (OA) and type 2 diabetes mellitus (T2DM) often coexist due to shared risk factors and high prevalence, but effective treatment methods are currently lacking. Mesenchymal stromal/stem cell-derived exosomes (MSC-Exos) have regenerative properties that can repair cartilage damage, lower blood sugar levels, and improve pancreatic β cell function, showing great potential in tissue repair. This review primarily explores the application of MSC-Exos in the treatment of OA and T2DM, the potential mechanisms of MSC-Exos, and the therapeutic strategies of engineered exosomes. Although MSC-Exo therapy shows promising therapeutic potential, further research is needed to validate its safety and feasibility.

Keywords: diabetic osteoarthritis; engineered exosomes; mesenchymal stromal/stem cell-derived exosomes; microRNAs; osteoarthritis; type 2 diabetes mellitus

DOI: https://doi.org/10.3389/fcell.2025.1549096

ACS Nano. 2025 Apr 06.

Engineered Exosomes Loaded in Intrinsic Immunomodulatory Hydrogels with Promoting Angiogenesis for Programmed Therapy of Diabetic Wounds.

Wei Huang, Qianru Guo, Hongrong Wu, Yaxian Zheng, Tao Xiang, Shaobing Zhou.

Inducing rapid angiogenesis by delivering specific biological cues is critical for diabetic wound healing. Nevertheless, the angiogenesis is hindered by the inflammatory microenvironment, and the immune cells fail to orchestrate immune responses to wound healing. Herein, vascular endothelial growth factor (VEGF) plasmids-loaded macrophage exosomes (Exos) were fabricated and enfolded in injectable self-healing hydrogels for programmed therapy of diabetic wounds through sequentially intrinsically modulating the inflammatory microenvironment and promoting angiogenesis. The hydrogels, formed via dynamical Schiff base reactions using modified polysaccharides, intrinsically regulate the inflammatory microenvironment via broad-spectrum antioxidant activity and macrophage phenotype regulation, restoring tissue redox and immune homeostasis. Furthermore, the hydrogels can stabilize and release the engineered exosomes. By integration of generation and release of VEGF by plasmids-loaded macrophage Exos, VEGF secretion by M2 macrophages, and enhanced binding of VEGF to VEGF receptor 2 by high affinity of sulfated chitosan, the intrinsic immunomodulatory hydrogels effectively promote the angiogenesis and accelerate the diabetic wound healing process.

Keywords: angiogenesis; diabetic wound healing; immunomodulatory hydrogels; inflammatory microenvironment; plasmids-loaded exosomes

DOI: https://doi.org/10.1021/acsnano.5c02896

Clin Transl Med. 2025 Apr;15(4): e70298

MiR-146a engineered extracellular vesicles derived from mesenchymal stromal cells more potently attenuate ischaemia-reperfusion injury in lung transplantation.

Xiucheng Yang, Shanchao Hong, Tao Yan, Mingzhao Liu, Mingyao Liu, Jin Zhao, Bingqing Yue, Di Wu, Jingbo Shao, Man Huang, Jingyu Chen.

BACKGROUND: The limited donor lung pool for lung transplantation (LTx) is largely due to concerns over ischaemia-reperfusion injury (IRI), a major cause of primary graft dysfunction (PGD). NLRP3 inflammasome activation is known to play a pivotal role in the onset of IRI. While human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) have shown potential in reducing acute lung injury, their effects on NLRP3 activation in the context of LTx remain unclear.
METHODS: In this study, engineered hucMSC-EVs were delivered via nebulisation to mitigate IRI in rat LTx models. We utilised both a rat orthotopic LTx model and a cell cold preservation reperfusion model to evaluate the therapeutic efficacy of hucMSC-EVs. Bulk-RNA sequencing, single-cell sequencing analysis, immunofluorescence and Western blot techniques were employed to assess NLRP3 inflammasome activation and inflammation.
RESULTS: Nebulised hucMSC-EVs were efficiently internalised by alveolar macrophages (AMs), significantly reducing lung injury and improving oxygenation in the LTx models. Mechanistically, the engineered hucMSC-EVs, which enhance the expression of miR-146a, can more effectively suppress the activation of the NLRP3 inflammasome by targeting the IRAK1/TRAF6/NF-κB pathway, resulting in decreased levels of IL-1β, IL-18 and other inflammatory cytokines. These findings highlight the potential of miR-146a-modified EVs in modulating innate immune responses to alleviate IRI.
CONCLUSION: Our results demonstrate that nebulised delivery of engineered hucMSC-EVs effectively mitigates IRI in LTx by inhibiting NLRP3 inflammasome activation. This innovative approach presents a promising strategy for enhancing donor lung preservation and improving post-transplant outcomes in LTx.
HIGHLIGHTS: Nebulized Delivery of miR-146a Engineered hucMSC-EVs Mitigates Ischemia-Reperfusion Injury (IRI) in Lung Transplantation. This study demonstrates the therapeutic potential of nebulized, engineered human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) modified with miR-146a to alleviate IRI in rat lung transplantation models. The treatment significantly improved lung oxygenation and reduced inflammation, highlighting the efficacy of this novel approach in enhancing donor lung preservation. Mechanistic Insights: Inhibition of NLRP3 Inflammasome Activation. Engineered hucMSC-EVs efficiently targeted alveolar macrophages and suppressed NLRP3 inflammasome activation through the IRAK1/TRAF6/NF-κB pathway. This modulation of innate immune responses played a crucial role in reducing IRI-induced lung injury and inflammation, offering a promising strategy to manage primary graft dysfunction in lung transplantation. Superior Efficacy of miR-146a-Modified EVs in Reducing Inflammatory Cytokines. The miR-146a modification enhanced the anti-inflammatory properties of hucMSC-EVs, leading to a more significant reduction in pro-inflammatory cytokines (IL-1β, IL-18, and TNF-α) compared to unmodified EVs. This targeted intervention presents a potential therapeutic avenue for improving lung transplant outcomes and mitigating IRI. Innovative Therapeutic Approach: Non-Invasive Nebulization for Direct Lung Delivery. The use of nebulized EVs for direct delivery to donor lungs represents a non-invasive and efficient method for lung-targeted therapy. This strategy could expand the applicability of MSC-EV-based treatments for improving lung transplantation outcomes, particularly in enhancing donor lung preservation during the procurement process.

Keywords: extracellular vesicles; ischaemia–reperfusion injury; lung transplantation; miR‐146a

DOI: https://doi.org/10.1002/ctm2.70298

Bioact Mater. 2025 Jul;49 502-514

Exosomes from young plasma stimulate the osteogenic differentiation and prevent osteoporosis via miR-142-5p.

Zhikun Li, Qifeng Yu, Xiang Cui, Yi Wang, Ruijun Xu, Renjie Lu, Jiahao Chen, Xiaohan Zhou, Chi Zhang, Lanya Li, Wei Xu.

Osteoporosis (OP) is a multifactorial metabolic bone disorder commonly observed in the elderly, particularly prevalent in postmenopausal women. However, many conventional anti-osteoporosis drugs have undesirable side effects, limiting their long-term use. Here, we demonstrated that exosomes derived from both young and old healthy human plasma, which exhibited similar morphology, could significantly enhance the proliferation and migration of mesenchymal stem cells (MSCs). Furthermore, treatment with these exosomes increased alkaline phosphatase (ALP) activity, enhanced the mineralization of MSCs, and decreased the number of osteoclasts in vitro. When intravenously injected into rats, these exosomes accumulated in bone tissue. In vivo experiments demonstrated that both types of exosomes had a beneficial effect on osteoporosis by facilitating bone formation and suppressing osteoclast differentiation in an ovariectomized (OVX)-induced osteoporotic rat model. Strikingly, exosomes derived from young healthy human plasma exhibited stronger anti-osteoporosis effect. The miRNA sequencing analysis showed that miR-142-5p expression was significantly higher in the exosomes from young healthy adult plasma compared to in exosomes from older controls. Importantly, miR-142-5p overexpression exerted similar pro-osteogenic effects to those of exosomes from young healthy human plasma, while miR-142-5p downregulation had the opposite effect on osteogenic differentiation of MSCs. The anti-osteoporosis effect of exosomes from young healthy adult plasma were reversed upon miR-142-5p inhibition. In addition, ZFPM2 was a potential target of miR-142-5p involved in osteoporosis. Therefore, our study reveals the potential anti-osteoporosis effects of plasma exosomes and their underlying mechanisms, thereby providing an effective therapeutic strategy for clinical treatment of osteoporosis.

Keywords: Exosomes; Old human plasma; Osteogenic differentiation; Osteoporosis; Young human plasma; miRNAs

DOI: https://doi.org/10.1016/j.bioactmat.2025.03.012

Oncol Lett. 2025 May;29(5): 255

Bone mesenchymal stem cell‑derived exosome‑encapsulated microRNA‑125b‑5p inhibits ovarian cancer progression via DDX5 downregulation.

Yuxia Wang, Wei Wang, Dan Zheng, Ying Gao.

Exosomes can be used to mediate the delivery of nucleic acids such as microRNA-125b-5p (miR-125b-5p), a tumor-suppressor in certain types of cancer, into tumor cells. The present study investigated the use of bone mesenchymal stem cells-derived exosome (BMSCs-Exo) delivery of miR-125b-5p in ovarian cancer (OC). BMSCs were transfected with miR-125b-5p mimic, from which exosomes termed Exo-miR-125b-5p mimic were extracted. The expression levels of miR-125b-5p in OC tissue samples, BMSCs, exosomes and SKOV3 cells were quantified using reverse transcription-quantitative PCR. The influence of Exo-miR-125b-5p mimic on the biological functions of OC was evaluated through cell proliferation, invasion, migration and apoptosis assays. The targeting relationship between miR-125b-5p and DEAD-box helicase 5 (DDX5) was verified, and the expression levels of DDX5 in OC samples and SKOV3 cells were quantified using western blotting. miR-125b-5p was downregulated in tumor tissue samples from patients with OC. BMSCs-Exo reduced the malignant properties of SKOV3 cells in vitro, and these effects were be advanced by miR-125b-5p upregulation. miR-125b-5p targeted and inhibited DDX5 expression. DDX5 overexpression inhibited Exo-miR-125b-5p-induced suppression of OC development. Overall, this study highlights that BMSCs-Exo-encapsulated miR-125b-5p inhibited OC progression via DDX5 downregulation, providing insight into the molecular mechanisms underlying OC.

Keywords: DEAD-box helicase 5; bone mesenchymal stem cells; exosomes; microRNA-125b-5p; ovarian cancer; tumor

DOI: https://doi.org/10.3892/ol.2025.15001

J Am Chem Soc. 2025 Apr 09.

Ultrasound-Energized OX40L-Expressing Biohybrid for Multidimensional Mobilization of Sustained T Cell-Mediated Antitumor Immunity and Potent Sono-Immunotherapy.

Mengyun Liang, Xiaoying Kang, Hanwen Liu, Lu Zhang, Tianjiao Wang, Mengjie Ye, Wen Li, Ji Qi.

Harnessing immunostimulation to reinvigorate antitumor effector immune cells represents a promising strategy for tumor eradication. However, achieving durable clinical outcomes necessitates multidimensional activation to sustain robust immune responses. Here, we present an ultrasound-empowered living biohybrid that strategically mobilizes T-cell-mediated immunity for potent tumor sono-immunotherapy. Through synthetic biology, we engineer bacteria to express a fusion protein encoding the costimulatory OX40 ligand (OX40L), and further functionalize them with a high-performance polymer sonosensitizer tethered via a reactive oxygen species-cleavable linker. Upon ultrasound irradiation, the sono-activated nanocargoes detach from the bacterial surface, facilitating cellular entry and exposing immune-stimulating OX40L. The potent sonodynamic effects, coupled with the native immunogenicity of bacteria, promotes tumor-associated antigen release, fosters a proinflammatory microenvironment, and drives dendritic cell maturation, thereby priming cytotoxic T-cell activation. The OX40L expressed by the engineered bacteria amplifies and sustains T-cell activity, orchestrating a robust and durable antitumor response. This cascade-amplified immune activation effectively suppresses tumor growth, induces long-lasting immune memory, and provides protection against tumor metastasis and recurrence, significantly enhancing survival outcomes. By integrating ultrasound-energized nanoadjuvants with costimulatory immune boosters, this hybrid living biotherapeutic platform offers a versatile and powerful strategy for multidimensional immune activation, advancing the frontier of cancer sono-immunotherapy.

DOI: https://doi.org/10.1021/jacs.5c02025