Engineered microvesicle-mediated multimodal therapy resolves ulcerative colitis via synergistic immunoregulation, barrier restoration, and microbiota remodeling.

Ulcerative colitis (UC) represents a major global health challenge characterized by immune dysregulation and disruption of the epithelial barrier, with current therapies demonstrating limited efficacy. Microvesicles (MVs) engineered through alternative macrophage activation possess immunomodulatory and restorative cargo. However, their therapeutic potential for UC and the underlying mechanisms remain largely unexplored. Herein, we demonstrate that these engineered MVs significantly mitigate colitis symptoms, including weight loss, rectal bleeding, and colon shortening, while also reducing histopathological damage and restoring barrier function in UC. They suppress pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and upregulate IL-10 by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Furthermore, they reshape gut microbiota, enhance microbial diversity, and rectify dysbiosis. Collectively, our findings establish a multimodal therapy mediated by engineered MVs, which includes the inhibition of inflammatory signaling, repair of the disrupted epithelial barrier and remodeling of dysbiotic microbiota, as a promising strategy for UC, thereby expanding the therapeutic potential of extracellular vesicles for precision management of UC.