2D Fe-hxl-UiO-67_SH/Au Nanosheets: Cascaded Nanozyme-Driven Chemodynamic Therapy Enhancement for Triple-Negative Breast Cancer

Abstract

Chemodynamic therapy (CDT) has emerged as a promising strategy for cancer treatment by leveraging Fenton reactions to generate cytotoxic reactive oxygen species (ROS). However, its therapeutic efficacy remains hindered by the limited endogenous H₂O₂ levels in the tumor microenvironment (TME) and the instability of catalytic metal ions. Here, we report the rational design of Fe-hxl-UiO-67_SH/Au nanosheets, a multifunctional nanoplatform that integrates glucose oxidase (GOx)-mimicking activity with peroxidase (POD)-like properties for enhanced CDT. The Fe-hxl-UiO-67_SH/Au nanosheets efficiently catalyze glucose oxidation to produce H₂O₂, which subsequently undergoes a Fenton reaction to generate hydroxyl radicals (^•OH), leading to lipid peroxide (LPO) accumulation and ferroptotic cell death. Furthermore, the incorporation of Au nanoparticles (AuNPs) synergistically amplifies ROS production while stabilizing Fe species within the frameworks, ensuring sustained catalytic activity. In vitro studies demonstrate that Fe-hxl-UiO-67_SH/Au exhibits potent anticancer effects against triple-negative breast cancer (TNBC), inducing mitochondrial dysfunction and ferroptosis through glutathione peroxidase 4 (GPX4) inhibition. This work presents a nanozyme-driven strategy for CDT enhancement, offering a promising approach for overcoming the limitations of traditional Fenton-based therapies and advancing cancer nanomedicine.