Rational Design of Orally Administered Cascade Nanozyme for Inflammatory Bowel Disease Therapy

Abstract Inflammatory bowel disease (IBD) affects millions of individuals worldwide annually. Enteric reactive oxygen species (ROS) play critical roles in the physiology and pathology of IBD. Nanozymes hold great promise for the treatment of IBD because of their exceptional ability to regulate redox homeostasis during ROS‐related inflammation. However, the rapid development of orally administered, acid‐tolerant, antioxidant nanozymes for IBD therapy is challenging. Here, a nine‐tier high‐throughput screening strategy is established to address the multifaceted IBD treatment demands, including intrinsic stability, radioactivity, solubility, gut microbiome toxicity, biomimetic elements, intermediate frontier molecular orbitals, reaction energy barriers, negative charges, and acid tolerance. Ni 3 S 4 is selected as the best matching material from 146 323 candidates, which exhibits superoxide dismutase‐catalase bienzyme‐like activity and is 3.13‐ and 1.80‐fold more active than natural enzymes. As demonstrated in a mouse model, Ni 3 S 4 is stable in the gastrointestinal tract without toxicity and specifically targets the diseased colon to alleviate oxidative stress. RNA and 16S rRNA sequencing analyses show that Ni 3 S 4 effectively inhibits the cellular pathways of pro‐inflammatory factors and restores the gut microbiota. This study not develops a highly efficient orally administered cascade nanozyme for IBD therapy and offers a next‐generation paradigm for the rational design of nanomedicine through data‐driven approaches.