Mn₃O₄ Nanozymes Regulate Inflammatory Microenvironment and Restore Intestinal Barrier Function for Treating Inflammatory Bowel Disease

An imbalance between excessive reactive oxygen species (ROS) production and impaired endogenous ROS scavenging capacity is central to the pathogenesis of inflammatory bowel disease (IBD). Inspired by the treatment principle of “Quxie Fuzheng” in traditional Chinese medicine, ultrasmall Mn3O4 nanozymes (PEG-Mn3O4) were prepared in this study to treat experimental colitis, which functioned through direct ROS scavenging and upregulation of superoxide dismutase 2 (SOD2) activity. In vitro experiments showed that PEG-Mn3O4 exhibitedexcellent ROS scavenging activities and could release manganese ions in the inflammatory microenvironment to enhance cellular SOD2 activity, thus inhibiting oxidative stress-induced apoptosis of intestinal epithelial cells and promoting the migration of intestinal epithelial cells; and they could inhibit the expression of pro-inflammatory factors secreted by M1 macrophages. PEG-Mn3O4 effectively attenuated intestinal inflammation and restored the mucosal barrier in experimental colitis by suppressing epithelial cell apoptosis and enhancing tight junction protein expression, demonstrating significant therapeutic efficacy. In addition, PEG-Mn3O4 had good biocompatibility. This study utilized the multienzyme activity of PEG-Mn3O4 to directly scavenge ROS to “Quxie”, and utilized its release of Mn ions to enhance the activity of cellular SOD2 in the inflammatory microenvironment to “Fuzheng”, for the treatment of colitis. The ROS-scavenging and SOD2 activity-enhancing properties of PEG-Mn3O4 offer the possibility to treat other oxidative stress-related diseases.