Mn3O4 Nanozymes Regulate Inflammatory Microenvironment and Restore Intestinal Barrier Function Via Scavenging ROS and Enhancing SOD2 Activity in Ulcerative Colitis

The overproduction of reactive oxygen species (ROS) and the reduction of body’s ability to scavenge ROS play a critical role in the progress of ulcerative colitis (UC). In this study, inspired by the traditional Chinese medical treatment strategy of “Fuzheng Guben”, we prepared the ultrasmall biocompatible Mn3O4 nanozyme (PEG-Mn3O4) for the treatment of UC by scavenging ROS while enhancing superoxide dismutase 2 (SOD2) activity. The ex vivo experiments showed that PEG-Mn3O4 exhibited great scavenging activities against multiple ROS. Benefiting from multienzyme activities against ROS, PEG-Mn3O4 effectively protected intestinal epithelial cells from ROS-induced damage and suppressed the expression of proinflammatory cytokines (TNF-α, IL-1β) in activated macrophages. Moreover, PEG-Mn3O4 repaired damaged intestinal mucosal barrier by promoting intestinal epithelial cell migration and inhibiting oxidative stress-mediated intestinal epithelial cell apoptosis. The in vivo study applying a mouse model with colitis also revealed that PEG-Mn3O4 could inhibit activation of proinflammatory macrophages and repair damaged intestinal barrier with good biocompatibility. The therapeutic effect of PEG-Mn3O4 on UC was attributed to its excellent ROS scavenging ability, while promoting SOD2 activity and restoring the body’s ability to scavenge ROS through releasing manganese ions into the inflammatory microenvironment. Together, the better therapeutic effects and biological safety of PEG-Mn3O4 have proven this therapeutic potential on ROS-related diseases.