Nanozyme engineered ROS-tolerant cysteine active-site for upstream deubiquitylation therapy of inflammatory bowel disease

Abstract

Deubiquitinase (DUB)-based upstream regulation of inflammatory pathway has emerged as a promising strategy for inflammatory bowel disease (IBD) compared to clinical biological therapies that block downstream inflammatory mediators. Unfortunately, excessive reactive oxygen species (ROS) in the inflammatory microenvironment usually induces irreversible oxidation of the cysteine active-site of therapeutic DUB, resulting in the rapid fading of deubiquitylation activity and inferior anti-inflammatory efficacy. Herein, a redox active nanozyme boosted deubiquitylation strategy based on the natural-artificial dual catalytic nanodrug (NADCN) is designed for protecting the vulnerable catalytic active center of anti-inflammatory DUB. Benefiting from the nanozyme-enabled protection of DUB’s cysteine active-site, the NADCN exhibits far superior anti-inflammatory activity to that of its counterparts based on the conventional delivery system. Moreover, the redox nanozyme in NADCN confers efficient modulation of the oxidative and hypoxia inflammatory microenvironment, further unleashing the potential of DUB for treatment of IBD. Therefore, the NADCN opens a new avenue to protect the cysteine active-site of therapeutic DUB, providing an attractive opportunity for developing ROS-tolerant deubiquitylation therapy.