Abstract

Probiotics represents a significant strategy for managing inflammatory bowel disease (IBD), however, the inflammatory gut microenvironment rich in reactive oxygen species (ROS) compromises the viability and colonization of probiotics. Here, we innovatively developed a ROS-responsive probiotic delivery system based on milk exosomes (mExo@DSPE-PEG-PBA@AKK). The ROS-sensitive borate ester bond in mExo@DSPE-PEG-PBA@AKK underwent oxidation and cleavage at inflammatory sites, which simultaneously scavenged excessive ROS and achieved targeted release of the probiotics. Consequently, mExo@DSPE-PEG-PBA@AKK exhibited enhanced activity and prolonged retention within the inflamed intestine. In dextran sulfate sodium (DSS)-induced colitis mice, mExo@DSPE-PEG-PBA@AKK showed superior therapeutic efficacy compared to treatment with milk exosomes or probiotics alone. Furthermore, mExo@DSPE-PEG-PBA@AKK treatment reduced pro-inflammatory factor levels, restored intestinal barrier integrity, and effectively modulated the abundance and diversity of the gut microbiota in DSS-induced mice. The proposed mExo@DSPE-PEG-PBA@AKK system incorporates multiple functions including probiotic protection, delivery, and targeted release, offering a novel “clear-release-regulate” therapeutic approach for the treatment of IBD.