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Despite recent drug developments, novel surgical interventions as well as multidisciplinary treatment approaches, the outcome is dismal, with &gt;50% therapy failure rates. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) offer potential therapeutic benefits for treating fistulizing CD, due to the pro\u2010regenerative paracrine signals. However, a significant obstacle to clinical translation of EV\u2010based therapy is the rapid clearance and short half\u2010life of EVs in vivo. Here, an injectable, biodegradable nanofiber\u2010hydrogel composite (NHC) microgel matrix that serves as a carrier to deliver MSC\u2010derived EVs to a rat model of CD perianal fistula (PAF) is reported. It is found that EV\u2010loaded NHC (EV\u2010NHC) yields the best fistula healing when compared to other treatment arms. The MRI assessment reveals that the EV\u2010NHC reduces inflammation at the fistula site and promotes tissue healing. The enhanced therapeutic outcomes are contributed by extended local retention and sustained release of EVs by NHC. In addition, the EV\u2010NHC effectively reduces inflammation at the fistula site and promotes tissue healing and regeneration via macrophage polarization and neo\u2010vascularization. This EV\u2010NHC platform provides an off\u2010the\u2010shelf solution that facilitates its clinical translation.<\/jats:p>","DOI":"10.1002\/adhm.202402292","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T09:45:45Z","timestamp":1725615945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Extracellular Vesicles Delivered by a Nanofiber\u2010Hydrogel Composite Enhance Healing In Vivo in a Model of Crohn's Disease Perianal Fistula"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4498-9466","authenticated-orcid":false,"given":"Ling","family":"Li","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology School of Medicine Johns Hopkins University  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Yao","sequence":"additional","affiliation":[{"name":"Institute for NanoBioTechnology Johns Hopkins University  Baltimore MD USA"},{"name":"Department of Materials Science and Engineering Whiting School of Engineering Johns Hopkins University  Baltimore MD USA"},{"name":"Translational Tissue Engineering Center Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevan J.","family":"Salimian","sequence":"additional","affiliation":[{"name":"Department of Pathology The Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayuan","family":"Kong","sequence":"additional","affiliation":[{"name":"Institute for NanoBioTechnology Johns Hopkins University  Baltimore MD USA"},{"name":"Department of Materials Science and Engineering Whiting School of Engineering Johns Hopkins University  Baltimore MD USA"},{"name":"Translational Tissue Engineering Center Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atif","family":"Zaheer","sequence":"additional","affiliation":[{"name":"Department of Radiology &amp; Radiological Sciences School of Medicine Johns Hopkins University  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Parian","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology School of Medicine Johns Hopkins University  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Gearhart","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery Department of Surgery Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010Quan","family":"Mao","sequence":"additional","affiliation":[{"name":"Institute for NanoBioTechnology Johns Hopkins University  Baltimore MD USA"},{"name":"Department of Materials Science and Engineering Whiting School of Engineering Johns Hopkins University  Baltimore MD USA"},{"name":"Translational Tissue Engineering Center Johns Hopkins University School of Medicine  Baltimore MD USA"},{"name":"Department of Biomedical Engineering Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7990-8238","authenticated-orcid":false,"given":"Florin M.","family":"Selaru","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology School of Medicine Johns Hopkins University  Baltimore MD USA"},{"name":"Institute for NanoBioTechnology Johns Hopkins University  Baltimore MD USA"},{"name":"Department of Biomedical Engineering Johns Hopkins University School of Medicine  Baltimore MD USA"},{"name":"Department of Oncology Sidney Kimmel Cancer Center School of Medicine Johns Hopkins University  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.24884"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.04.023"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izz056"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa030815"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(99)70414-2"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199905063401804"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmjgast-2021-000702","volume":"8","author":"Brewer G. 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