CO‐Releasing Polyoxometalates Nanozyme with Gut Mucosal Immunity and Microbiota Homeostasis Remodeling Effects for Restoring Intestinal Barrier Integrity

Abstract Disruption of the intestinal epithelial barrier, driven by imbalances in gut mucosal immunity and microbial homeostasis, is central to the onset and progression of inflammatory bowel disease (IBD). This study introduces a CO‐releasing polyoxometalates (POMs) nanozyme (PMC), synthesized by coordinating pentacarbonyl manganese bromide with molybdenum‐based POM nanoclusters. PMC demonstrates targeted accumulation at IBD‐affected sites, efficient scavenging of reactive oxygen species (ROS), and responsive CO release, resulting in multiple therapeutic effects. Extensive in vitro and in vivo studies have validated the exceptional capacity of PMC to repair intestinal barrier, attributed to their potent antioxidant and anti‐inflammatory properties, thereby achieving significant therapeutic efficacy in ulcerative colitis treatment. 16S rRNA sequencing indicated that PMC efficiently remodeled the gut microbiota composition. Single‐cell RNA sequencing indicates a reduction in pro‐inflammatory M1 macrophages, alongside suppressed ROS and inflammatory signaling pathways. Concurrently, an increase in reparative M2 macrophages and intestinal stem cells is observed, in addition to significant activation of the VEGF signaling pathway in macrophages and the NOTCH pathway in stem cells, underscoring the potential of PMC to restore immune balance and promote tissue repair. This study positions PMC as a promising, multifunctional therapeutic agent for IBD treatment owing to its robust intestinal barrier‐restoring capability.