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Although biologics can effectively control inflammation, efficient delivery to the colon and colon epithelial cells remains challenging. Milk\u2010derived extracellular vesicles (EV) show promise as an oral delivery tool, however, the ability to load biologics into EV presents challenges to therapeutic applications. Here, we demonstrate that fusing cell\u2010penetrating peptide (TAT) to green fluorescent protein (GFP) enabled biologics loading into EV and protected against degradation in the gastrointestinal environment in vitro and in vivo after oral delivery. Oral administration of EV loaded with anti\u2010tumour necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) nanobody (VHHm3F) (EV<jats:sub>VHH<\/jats:sub>) via TAT significantly reduced tissue TNF\u2010\u03b1 levels and alleviated pathologies in mice with acute UC, compared to VHH alone. In mice with chronic UC, simultaneously introducing VHH and an antimicrobial peptide LL37 into EV (EV<jats:sub>LV<\/jats:sub>), then administering orally improved intestinal barrier, inflammation and microbiota balance, resulted in relief of UC\u2010induced depression and anxiety. Collectively, we demonstrated that oral delivery of EV<jats:sub>LV<\/jats:sub> effectively alleviated UC in mice and TAT efficiently loaded biologics into EV to confer protection from degradation in the gastrointestinal tract. This therapeutic strategy is promising for UC and is a simple and generalizable approach towards drug\u2010loaded orally\u2010administrable EV treatment for other diseases.<\/jats:p>","DOI":"10.1002\/jev2.12462","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T01:20:18Z","timestamp":1717636818000},"source":"Crossref","is-referenced-by-count":44,"title":["Milk\u2010derived extracellular vesicles functionalized with anti\u2010tumour necrosis factor\u2010\u03b1 nanobody and anti\u2010microbial peptide alleviate ulcerative colitis in mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Renwei","family":"Jing","sequence":"first","affiliation":[{"name":"State Key Laboratory of Experimental Hematology &amp; The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics &amp; Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) &amp; School of Basic Medical Sciences &amp; School of Medical 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of Medical Technology Tianjin Medical University  Tianjin China"},{"name":"Department of Clinical Laboratory Tianjin Medical University General Hospital  Tianjin 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