Engineered exosome nanovesicles for delivery of antibodies to treat inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation and impaired immune tolerance, for which current therapies provide only partial and transient relief. Here, we introduce PrEXO-a23, a biomimetic nanotherapeutic engineered by fusing regulatory T cell (Treg)-derived exosomes with platelet membrane vesicles and conjugating interleukin-23 (IL-23) antibodies via a matrix metalloproteinase (MMP)-cleavable linker. This design exploits the inherent homing ability of platelets and Tregs, enabling PrEXO-a23 to preferentially accumulate in inflamed colonic tissues in murine IBD models. At the disease site, elevated MMP activity triggers antibody release to inhibit IL-23-mediated inflammation, while exosomal cargo reprograms dendritic cells and promotes Treg expansion, thereby restoring immune tolerance. This dual-action strategy significantly alleviates IBD, prevents complications like intestinal fibrosis and colitis-associated colorectal cancer, and shows p53-dependent efficacy in carcinogenesis prevention. These findings highlight PrEXO-a23 as a promising nanotherapeutic platform for durable immune reprogramming and long-term IBD management.