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Current treatments aim to induce inflammatory remission but often neglect the surrounding microenvironment, which significantly impairs mucosal healing and contributes to treatment failures. This study presents a novel silk fibroin\u2010based fucoidan (SFU) in situ rectal gel, with sol\u2010gel transition confirmed through rheological analysis under physiological pH and temperature conditions. The SFU gel exhibits strong antioxidant activity, achieving a DPPH radical scavenging rate of 73.3 \u00b1 1.52%. The gel efficiently reduces reactive oxygen species (ROS) and nitric oxide (NO) production, demonstrating its reliable antioxidant effects. In a DSS\u2010induced UC mouse model, SFU effectively alleviates colitis symptoms, including weight loss and disease activity index (DAI) reduction, with improved stool consistency and reduced rectal bleeding. Moreover, SFU therapy reprograms macrophages from proinflammatory M1 to anti\u2010inflammatory M2 phenotypes, significantly lowering IL\u20106 and TNF\u2010\u03b1 levels, suggesting anti\u2010inflammatory properties. Furthermore, SFU increased tight junction proteins Occludin\u20101 and ZO\u20101, indicating gut mucosal barrier integrity. SFU treatment restores goblet cells and mucin production while preventing fibrosis, demonstrating its potential as a natural therapy for UC treatment.<\/jats:p>","DOI":"10.1002\/adhm.202500984","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T01:51:42Z","timestamp":1747792302000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Smart Silk\u2010Based In Situ Sol\u2010Gel Modulates Rectal Microenvironment for Effective Ulcerative Colitis Alleviation"],"prefix":"10.1002","volume":"14","author":[{"given":"Perumal Ramesh","family":"Kannan","sequence":"first","affiliation":[{"name":"Institute of Smart Biomedical Materials School of Materials Science and Engineering Zhejiang Sci\u2010Tech University  Hangzhou 310018 P. R. China"},{"name":"Zhejiang\u2010Mauritius Joint Research Center for Biomaterials and Tissue Engineering Zhejiang Sci\u2010Tech University  Hangzhou 310018 P. R. 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