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To address these challenges, we crafted a biomimetic hydrogel to carry and gently release MSC\u2010derived exosomes. We engineered a biocompatible, dextran\u2010based composite hydrogel (carboxymethyl chitosan\u2010oxidized dextran\/tannic acid\u2010iron complex, CMC\u2010OD\/TA\u2010Fe(III)) for the encapsulation and sustained release of human umbilical cord MSC\u2010derived exosomes. We systematically compared the organ biodistribution of exosomes delivered via this hydrogel platform using three distinct local routes: intraperitoneal injection, oral (intragastric) administration, and rectal administration, employing in vivo imaging and tissue immunofluorescence analyses in C57BL\/6J mice. Following a single intraperitoneal dose, released exosomes accumulated primarily in the liver and spleen, with minimal brain enrichment. Notably, both oral and rectal administration\u2014non\u2010invasive alternatives to injection\u2014facilitated considerable exosome dissemination to multiple organs. The significant distribution observed via the oral route specifically challenges the prevailing assumption regarding the inefficacy of gastrointestinal delivery for exosome\u2010based therapeutics. This study provides critical insights into administration\u2010route\u2010dependent biodistribution patterns and proposes novel, non\u2010invasive delivery strategies to enhance the therapeutic efficacy and application scenarios of exosomes.<\/jats:p>","DOI":"10.1002\/adhm.71210","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T08:48:27Z","timestamp":1778402907000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Hydrogel\u2010Mediated Sustained\u2010Release Platform Alters the Biodistribution of Umbilical Cord Mesenchymal Stem Cell\u2010Derived Extracellular Vesicles in Mice"],"prefix":"10.1002","volume":"15","author":[{"given":"Zongbin","family":"Sun","sequence":"first","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"},{"name":"General Surgery Department First Hospital of Lanzhou University Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2415-7064","authenticated-orcid":false,"given":"Qiuxia","family":"Zheng","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongyang","family":"Bai","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0476-7157","authenticated-orcid":false,"given":"Desheng","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Solid Lubrication Lanzhou Institute of Chemical Physics Chinese Academy of Sciences  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanghong","family":"Wang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"},{"name":"General Surgery Department First Hospital of Lanzhou University Lanzhou University  Lanzhou China"},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine First Hospital of Lanzhou University Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0811-8287","authenticated-orcid":false,"given":"Jia","family":"Yao","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine First Hospital of Lanzhou University Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6862-7692","authenticated-orcid":false,"given":"Xun","family":"Li","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Lanzhou University  Lanzhou China"},{"name":"General Surgery Department First Hospital of Lanzhou University Lanzhou University  Lanzhou China"},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine First Hospital of Lanzhou University Lanzhou University  Lanzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"1","volume-title":"Advances in Experimental Medicine and Biology","author":"Ratajczak M. 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