Dendritic PtFe@RuRhMo Self-Amplifying Oxidative Nanocatalysis via Metabolic Hijacking Overcoming Hypoxia−Glutathione Resistance in Triple-Negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) therapy faces a paradox: Reactive oxygen species (ROS)-generating nanozyme depletes oxygen (O2) and triggers glutathione (GSH) defense, reducing efficacy in hypoxic tumors. To resolve this problem, we developed an enzyme by coupling glucose oxidase (GOx)-mediated glucose depletion with ROS generation and GSH consumption. Dendritic core−shell PtFe@RuRhMo nanocrystals were synthesized, integrating catalase-, peroxidase-, and glutathione oxidase-like activities, accompanied by functionalization with GOx and doxorubicin (DOX). The nanozyme exhibited a threefold lower Michaelis constant for H2O2 than horseradish peroxidase (Km = 0.186 mM), depleted 95.87% of GSH in a cell-free solution within 15 min, and induced 62.3% apoptosis in 4T1 cells under high-glucose conditions. In vivo, the nanodrug achieved marked tumor suppression in all treated mice while exhibiting minimal toxicity. This design precisely modulates the tumor microenvironment in aggressive cancers. The cascade informs multienzyme-based cancer therapy. Future work will optimize the PEGylation density and evaluate long-term biodistribution in larger animal models.