IL ‐10‐secreting engineered macrophages alleviate DSS ‐induced colitis with macrophage phenotypic modulation and gut microbiota remodeling in mice

Abstract Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease characterized by abdominal pain, hematochezia, and weight loss. Although remarkable progress has been made toward understanding the pathogenesis of UC, finding more effective treatments for this disease remains a challenge. Interleukin‐10 (IL‐10) possesses potent anti‐inflammatory properties, yet its therapeutic application in UC has failed clinically due to poor targeting and a short half‐life. In this study, we developed IL‐10‐secreting engineered macrophages (IL‐10M) based on RAW264.7 cells and evaluated their therapeutic effects in a dextran sulfate sodium‐induced colitis model. Intraperitoneal administration of IL‐10M alleviated body weight loss, disease activity, colon shortening, and histological injury. IL‐10M also reduced mucosal damage and improved tight junction‐associated epithelial barrier markers. Flow cytometry further detected engineered macrophage‐associated GFP signals in colonic tissues and revealed an early increase in CD206 + endogenous colonic macrophages. Microbiome profiling showed treatment‐associated compositional changes, including alterations in Bacteroides acidifaciens and Mucispirillum schaedleri , indicating microbiota remodeling after engineered macrophage treatment. Short‐term safety assessment did not reveal overt hematological abnormalities or major histological injury in liver and spleen. Overall, these findings suggest that IL‐10‐secreting engineered macrophages may represent a promising macrophage‐based strategy for mitigating intestinal inflammation in experimental colitis.