Orally Delivered Tolerogenic Nanotherapeutic for Targeted Colitis Therapy via ROS Scavenging and Treg/Th17 Modulation.

Despite compelling progression of current inflammatory bowel disease (IBD) therapy, restoring immune homeostasis in the gut has been a critically important issue. Here, we report a prebiotic-integrated, reactive oxygen species (ROS)-scavenging nanotherapeutic for the targeted treatment of acute colonic inflammation. Porous polydopamine nanoparticles (PNPs), exhibiting inherent antioxidant properties, were attached with the immunomodulatory drug metformin (Met) and subsequently coated with prebiotic tannic acid (TA), forming TA-Met-PNPs. In a dextran sulfate sodium (DSS)-induced colitis mouse model, orally administered TA-Met-PNPs strongly adhered to the inflamed colonic lesions and exhibited high cellular uptake by colon-resident macrophages and dendritic cells, subsequently ameliorating their inflammatory immune responses. Moreover, their prolonged residence in colitis lesions enhanced accumulation in mesenteric lymph nodes (MLNs) and further induction of tolerogenic dendritic cells via intracellular ROS scavenging. Finally, TA-Met-PNPs prominently enhanced butyrate production in the gut, which recovered immune tolerance by increasing the regulatory T (Treg) to T-helper 17 (Th17) cell ratio in MLNs. Our work highlights that the prebiotic-combined ROS-scavenging treatment can remodel the inflammatory gut microenvironment to an immunosuppressive state, offering a promising strategy for treating IBD.