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

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. Herein, a nine-tier high-throughput screening strategy was 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 S was selected as the best matching material from 146323 candidates, which exhibited superoxide dismutase-catalase bienzyme-like activity and was 3.13- and 1.80-fold more active than natural enzymes. As demonstrated in a mouse model, Ni S is stable in the gastrointestinal tract without toxicity and specifically targets the diseased colon to alleviate oxidative stress. RNA and 16S rRNA sequencing analyses showed that Ni S effectively inhibited the cellular pathways of pro-inflammatory factors and restored the gut microbiota. This study not developed 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. This article is protected by copyright. All rights reserved.