Reactive Oxygen Species‐Activated CO Versatile Nanomedicine with Innate Gut Immune and Microbiome Remodeling Effects for Treating Inflammatory Bowel Disease

Abstract Abnormal activation of the gut mucosal immune system and a highly dysregulated gut microbiota play essential roles in the progression of inflammatory bowel disease (IBD). The clinical treatment of IBD remains highly challenging, with first‐line drugs showing limited efficacy and significant side effects. A reactive oxygen species (ROS)‐activated CO versatile nanomedicine (CMPs) capable of remodeling the gut immune‐microbiota microenvironment via potent anti‐oxidant, anti‐inflammatory, and antimicrobial effects is developed. CORM‐401‐loaded mannose‐modified peptide dendrimer nanogel: CMPs preferentially congregate on the surface of damaged colon mucosa after rectal administration and are subsequently internalized by activated immune cells. CORM‐401 can release numerous CO molecules in response to high ROS levels in cells and at the site of IBD, resulting in multiple therapeutic effects. In vitro and in vivo studies have demonstrated that CMPs scavenge ROS, suppress inflammatory responses, eliminate pathogens, and alleviate colitis in mouse models. RNA sequencing reveals that CMPs successfully remodel gut mucosal immune homeostasis by scavenging ROS, inhibiting NF‐κB/p38MAPK, activating PI3K‐Akt, and inhibiting HIF‐1‐induced glycolysis. 16S ribosomal RNA sequencing shows that CMPs can remodel the gut flora composition by restraining detrimental bacteria and augmenting beneficial bacteria. This study develops a promising and versatile nanomedicine for the management of IBD.