Smart Silk‐Based In Situ Sol‐Gel Modulates Rectal Microenvironment for Effective Ulcerative Colitis Alleviation

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease, with untreated cases often progressing to colorectal cancer. 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‐based fucoidan (SFU) in situ rectal gel, with sol‐gel 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 ± 1.52%. The gel efficiently reduces reactive oxygen species (ROS) and nitric oxide (NO) production, demonstrating its reliable antioxidant effects. In a DSS‐induced 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‐inflammatory M2 phenotypes, significantly lowering IL‐6 and TNF‐α levels, suggesting anti‐inflammatory properties. Furthermore, SFU increased tight junction proteins Occludin‐1 and ZO‐1, 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.