Inflammatory bowel disease (IBD) is characterized by excessive generation of reactive oxygen species and reactive nitrogen species (RONS) within the pro-inflammatory microenvironment. Conventional treatments often have serious side effects, making IBD management challenging. Here, a new cerium cluster, Ce12, with a formula of [Ce(12)(mu (3)-O)(8)(mu (3)-OH)(8)(mu (2)-OH)(6)(ADA)(18)]∙3H(2)O∙3CH(3)CN (ADA(-) = 1-adamantanecarboxylate) was prepared and capped with beta-cyclodextrin (beta-CD) through self-assembly process involving the adamantane moiety of Ce12 and beta-CD, resulting in Ce12@CD nanoparticles (NPs). Ce12@CD NPs, with good stability and biocompatibility, exhibit excellent reactive RONS scavenging activities due to the presence of a fraction of Ce(3+) ions, offering potential for treating inflammatory diseases. Treatment significantly alleviated body weight loss, colon length reduction, and pathological injury of colon in mice with dextran sodium sulfate (DSS)-elicited colitis, thereby repairing the intestinal mucosal barrier and reducing inflammation. RNA sequence analysis revealed that the therapeutic effects of Ce12@CD NPs are highly correlated with IL-17 and TNF signaling pathways, thereby reducing inflammatory factors such as IL-1beta and TNF-alpha, and alleviating intestinal inflammation. Additionally, Ce12@CD NPs successfully modulated DSS-induced gut microbiota imbalances. This work highlights the unique catalytic activity of Ce12@CD NPs in removing RONS and mimicking biological enzymes, showcasing their potential therapeutic applications for inflammatory disorders.