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To overcome these limitations, we developed a bioengineered extracellular vesicle (EV) platform that modulates key immune signaling pathways to efficiently restore the T-cell balance in inflamed intestinal tissues. EVs derived from Wharton\u2019s jelly mesenchymal stem cells were engineered to display PD-L1 on their surface and encapsulate miR-27a-3p. Surface PD-L1 engages the PD-1 checkpoint in activated T cells, attenuating T-cell receptor signaling via SHP2-mediated dephosphorylation of ZAP70 and AKT. In parallel, miR-27a-3p suppresses prohibitin 1 (PHB1), a mitochondrial regulator of Th17 cell bioenergetics and inflammatory function, thereby reducing Th17 polarization and increasing the number of FOXP3\u207a regulatory T cells. These dual-targeting EVs preferentially localized to inflamed intestinal tissues via chemokine (CCR2\/CXCR4) and PD-1-dependent mechanisms. In humanized mouse models of colitis, these EVs attenuated mucosal inflammation, suppressed effector T-cell responses, and preserved epithelial integrity. In IBD patient-derived colonoid cultures, PD-L1\/miR-27a-3p EVs maintained epithelial viability and barrier integrity without inducing cytotoxicity or structural disruption. Transcriptomic and single-cell analyses revealed the downregulation of inflammatory and exhaustion signatures, along with the enrichment of regulatory subsets. Collectively, this study presents a cell-free immunotherapeutic approach that reprograms T cells in inflamed tissues through the PD-1 and mitochondrial signaling pathways while maintaining intestinal epithelial integrity, offering a promising therapeutic strategy for IBD and other T cell-driven inflammatory disorders.<\/jats:p>","DOI":"10.1038\/s41392-025-02516-0","type":"journal-article","created":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:02:47Z","timestamp":1766620967000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Engineered extracellular vesicles reprogram T cells by targeting PD-1 and PHB1 signaling in inflammatory bowel disease"],"prefix":"10.1038","volume":"10","author":[{"given":"Mi-Kyung","family":"Oh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Sung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Hoon","family":"Chae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Han","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyoung","family":"Heo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keonwoo","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiho","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8489-0044","authenticated-orcid":false,"given":"Byeonghwi","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Mo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan E.","family":"Axelrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Ku","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Pil","family":"Im","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong-Joon","family":"Koh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung-Soo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Rok","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"2516_CR1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/nrgastro.2016.208","volume":"14","author":"MF Neurath","year":"2017","unstructured":"Neurath, M. 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