Self-Sustained Nanozyme Triggers Dual-Pronged Ferroptosis via ROS Storm and Barrier Collapse in a Remodeled Tumor Microenvironment

Ferroptosis is a reactive oxygen species (ROS)-dependent cell death pathway. The synergistic integration of multimodal ROS-based therapies, such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), to amplify lipid peroxidation represents a potential approach for enhancing ferroptosis-mediated antitumor effects. However, the tumor microenvironment (TME), where insufficient endogenous substrates (e.g., H 2 O 2, O 2 ) and elevated antioxidant defenses (e.g., glutathione, GSH), undermines the efficacy of most ROS-based therapies, thereby limiting ferroptosis-driven tumor eradication. To address this challenge, we developed a multifunctional nanoreactor ZnO 2 @ZnPc@Fe 3+ -tannic acid that orchestrates a ferroptosis-inducing cascade through self-sustained H 2 O 2 supply, GSH depletion-mediated TME modulation, and combined PDT/CDT with mitochondrial dysfunction induction. Under the acidic and GSH-rich TME, the metal-phenolic network shell of ZPFT degraded, releasing Fe 3+ that was subsequently reduced to Fe 2+ . Meanwhile, the exposed ZnO 2 decomposed to generate H 2 O 2, which fueled Fe 2+ -mediated Fenton reactions to produce abundant • OH radicals. These radicals synergize with 1 O 2 generated by ZnPc to collectively trigger a ROS storm. Concurrently, ZnO 2 -derived Zn 2+ induced intracellular zinc overload, which cooperated with PDT/CDT to exacerbate mitochondrial dysfunction, and consequently disrupt the tumor’s antioxidant defenses. This cascade led to significant downregulation of key ferroptosis markers, GPX4 and SLC7A11. This study developed a therapeutic strategy against drug-resistant tumors by remodeling the TME limitations to simultaneously induce a ROS storm and dismantle antioxidant barriers, achieving highly efficient ferroptosis activation.