Zinc‐Based ROS Amplifiers Trigger Cancer Chemodynamic/Ion Interference Therapy Through Self‐Cascade Catalysis

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.