Abstract

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.