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

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 (PEG-CNPs) are fabricated using a modified reverse micelle method. We investigate hypoxia attenuating and ROS scavenging of PEG-CNPs in intestinal epithelial cells and RAW 264.7 macrophages and their effects on pro-inflammatory macrophages activation. Subsequently, we investigate the biodistribution, pharmacokinetic properties and long-term toxicity of PEG-CNPs in mice. PEG-CNPs are administered intravenously to mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis to test their colonic tissue targeting and assess their anti-inflammatory activity and mucosal healing properties in UC. Results: PEG-CNPs exhibit multi-enzymatic activity that can scavenge ROS and generate O2, promote intestinal epithelial cell healing and inhibit pro-inflammatory macrophage activation, and have good biocompatibility. After intravenous administration of PEG-CNPs to colitis mice, they can enrich at the site of colonic inflammation, and reduce hypoxia-induced factor-1α expression in intestinal epithelial cells by scavenging ROS to generate O2, thus further promoting disrupted intestinal mucosal barrier restoration. Meanwhile, PEG-CNPs can effectively scavenge ROS in impaired colon tissues and relieve colonic macrophage hypoxia 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. Graphical Abstract: [Figure not available: see fulltext.]