Prebiotic-Combined ROS-Scavenging Nanotherapeutics for Gut Microenvironment Remodeling and Targeted Therapy of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a dysregulated gut-associated autoimmune disease resulting from inappropriate and continuous immune response, leading to excessive inflammatory molecules generation, including reactive oxygen species (ROS) and pro-inflammatory cytokines, collapsed gut epithelial tissues, and imbalanced immunity. Current IBD treatments have focused on directly blocking inflammatory cytokines. However, these treatments have not been able to restore balanced immunity against colonic inflammation. Therefore, strategies to restore gut immune homeostasis have come into the spotlight for IBD treatments. In this study, prebiotic-combined ROS-scavenging nanotherapeutic was proposed to restore gut immune homeostasis in IBD. The nanotherapeutic consisted of ROS-scavenging polydopamine nanoparticles (PNP) loaded with metformin (Met), an immunomodulatory drug, and subsequently coated with tannic acid (TA) as a potential phytochemical prebiotic (PNP-Met-TA). In <i>in vitro</i> sets, PNP-Met-TA could effectively scavenge intracellular ROS in LPS-treated macrophages, resulting in decreased production of inflammatory cytokines (TNF-α, IL-6). When PNP-Met-TA was orally delivered to dextran sulfate sodium (DSS)-induced IBD murine model, the nanotherapeutics exhibited extended resident time in inflamed lesions and enhanced accumulation in mesenteric lymph nodes with high cellular uptake by innate immune cells (macrophages, dendritic cells). Furthermore, when PNP-Met-TA was orally administered to the DSS-induced IBD model, the significant recovery of body weight, the suppression of the pro-inflammatory gut microenvironment, and the restoration of epithelial barriers were simultaneously observed. Most importantly, the elevated production of butyric acid, one of the gut metabolites with anti-inflammatory functions, was found. The downregulation of costimulatory molecules on dendritic cells in mesenteric lymph nodes and the increased ratio of Treg to Th17 suggest that the gut immune homeostasis was recovered. Taken together, our designed prebiotic-combined ROS-scavenging nanotherapeutics shed light on gut microenvironment remodeling for intestinal disease treatment.