A cascade catalytic Zr-TCPP(Fe)/cys/Au nanoplatform for ferroptosis-mediated chemodynamic therapy in triple-negative breast cancer.

Chemodynamic therapy (CDT) has emerged as a promising strategy for tumor-selective treatment, however, its therapeutic efficacy is frequently constrained by insufficient endogenous hydrogen peroxide (H2O2) availability and limited catalytic efficiency within the tumor microenvironment. Herein, we report a cascade catalytic nanoplatform, Zr-TCPP(Fe)/cys/Au, constructed by integrating Fe-coordinated tetrakis (4-carboxyphenyl) porphyrin (TCPP)-based metal-organic layers (MOLs) with Au nanoparticles (AuNPs) for the induction of ferroptosis in triple-negative breast cancer (TNBC). AuNPs exhibit glucose oxidase (GOx)-like activity, catalyzing glucose oxidation to generate H2O2, while the Fe centers serve as peroxidase (POD)-like catalysts to convert H2O2 into highly reactive hydroxyl radicals (•OH). This cascade catalytic process results in amplified ROS production, enhanced lipid peroxidation (LPO), and pronounced glutathione (GSH) depletion, thereby disrupting intracellular redox homeostasis. In vitro studies demonstrate that Zr-TCPP(Fe)/cys/Au elevates ROS and LPO levels while suppressing the GPX4-dependent antioxidant system, leading to ferroptosis-dominated cell death. Ferroptosis inhibition assays further confirm the central role of ferroptotic pathways in the observed cytotoxicity. In vivo experiments in 4 T1 tumor-bearing mice reveal that Zr-TCPP(Fe)/cys/Au effectively suppresses tumor growth with negligible systemic toxicity or organ damage. Finally, this work presents a rationally designed cascade catalytic nanoplatform that modulates the tumor redox microenvironment to promote ferroptosis, offering a promising strategy for nanotechnology-enabled cancer therapy.