Zinc‐Based ROS Amplifiers Trigger Cancer Chemodynamic/Ion Interference Therapy Through Self‐Cascade Catalysis
Yun Sun, Liting Qin, Yuhan Yang, Jingzhe Gao, Yudi Zhang, Hongyu Wang, Qingyuan Wu, Bolong Xu, Huiyu Liu
Abstract
Abstract Nanozyme‐mediated chemodynamic therapy has emerged as a promising strategy due to its tumor specificity and controlled catalytic activity. However, the poor efficacy caused by low hydrogen peroxide (H 2 O 2 ) levels in the tumor microenvironment (TME) poses challenges. Herein, an H 2 O 2 self‐supplying nanozyme is constructed through loading peroxide‐like active platinum nanoparticles (Pt NPs) on zinc peroxide (ZnO 2 ) (denoted as ZnO 2 @Pt). ZnO 2 releases H 2 O 2 in response to the acidic TME. Pt NPs catalyze the hydroxyl radical generation from H 2 O 2 while reducing the mitigation of oxidative stress by glutathione, serving as a reactive oxygen (ROS) amplifier through self‐cascade catalysis. In addition, Zn 2+ released from ZnO 2 interferes with tumor cell energy supply and metabolism, enabling ion interference therapy to synergize with chemodynamic therapy. In vitro studies demonstrate that ZnO 2 @Pt induces cellular oxidative stress injury through enhanced ROS generation and Zn 2+ release, downregulating ATP and NAD + levels. In vivo assessment of anticancer effects showed that ZnO 2 @Pt could generate ROS at tumor sites to induce apoptosis and downregulate energy supply pathways associated with glycolysis, resulting in an 89.7% reduction in tumor cell growth. This study presents a TME‐responsive nanozyme capable of H 2 O 2 self‐supply and ion interference therapy, providing a paradigm for tumor‐specific nanozyme design.