Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder of the alimentary tract without exact etiology. Mitochondrial reactive oxygen species (mtROS) derived from mitochondrial dysfunction impair intestinal barrier function, increase gut permeability, and facilitate immune cell invasion, and, therefore, are considered to have a pivotal role in the pathogenesis of IBD. Here, we reprogrammed regulatory T cell (Treg)-derived exosomes loaded with the antioxidant trace element selenium (Se) and decorated them with the synthetic mitochondria-targeting SS-31 tetrapeptide via a peptide linker. This linker can be cleaved by matrix metalloproteinases (MMPs) in inflammatory lesions. This actively targetable exosome-derived delivery system is protected from intestinal inflammation by scavenging excessive mtROS and preventing immunologically programmed cell death pyroptosis, necroptosis, and apoptosis, known as PANoptosis. Our results suggest that this engineered exosome delivery platform represents a promising targeted therapeutic strategy for the treatment of IBDs.