Restoration of dysregulated intestinal barrier and inflammatory regulation through synergistically ameliorating hypoxia and scavenging reactive oxygen species using ceria nanozymes in ulcerative colitis

Abstract

Abstract Background Reactive oxygen species (ROS) overproduction and excessive hypoxia play pivotal roles in the initiation and progression of ulcerative colitis (UC). Synergistic ROS scavenging and generating O2 could be a promising strategy for UC treatment. Methods Ceria nanozymes (CNPs) are fabricated using a modified reverse micelle method. We investigate hypoxia attenuating and ROS scavenging of CNPs in intestinal epithelial cells and RAW 264.7 macrophages. We also study the effect of CNPs on pro-inflammatory macrophages activation. Colitis mice induced by administration of 2,4,6-trinitrobenzenesulfonic acid are then given intravenous injection of CNPs to evaluate anti-inflammatory activities, mucosal healing properties and biosafety in UC. Results CNPs with multi-enzymatic activity can synergistically scavenge ROS and generate O2 to treat UC by restoring dysregulated intestinal barriers and inhibiting the pro-inflammatory macrophages activation. CNPs are found to reduce hypoxia-induced factor-1α expression in intestinal epithelial cells by generating O2 based on catalase-mimicking activity, thus further promoting disrupted intestinal mucosal barrier restoration. Meanwhile, CNPs can effectively relieve colonic macrophage hypoxia and scavenge ROS in impaired colon tissues to suppress the pro-inflammatory macrophages activation, thereby preventing UC occurrence and development. Conclusion This study has provided a paradigm to utilize metallic nanozymes, and suggests that further materials engineering investigations could yield a facile method based on the pathological characteristics of UC for clinically managing UC.