Biomimetic cascade "four-in-one" Nanozyme for remodeling the redox tumor microenvironment and disrupting energy homeostasis to enhance ferroptosis against triple-negative breast cancer.

Abstract

Ferroptosis, a promising therapeutic strategy for triple-negative breast cancer (TNBC), faces significant challenges due to intrinsic tumor defense mechanisms. To enhance ferroptosis against TNBC, a biomimetic "four-in-one' cascade nanozyme AuPd/Cu₂O@Cancer cell membrane (APCM) was engineered to remodel tumoral redox microenvironment and disrupt cancer cell energy metabolism. APCM nanozyme integrates four enzyme-mimicking activities into a single nanoplatform, including peroxidase-like, glucose oxidase-like, catalase-like, and glutathione peroxidase-like. This synergistic cascade converts endogenous H₂O₂ to cytotoxic ·OH, depletes glucose to block energy supply while self-supplying H₂O₂, alleviates hypoxia, and depletes glutathione to suppress antioxidant defense, collectively triggering lethal reactive oxygen species (ROS) accumulation for ferroptosis. APCM further enables photothermal therapy (PTT), inducing direct thermal ablation and providing localized heat to augment nanocatalytic efficacy. Coating with tumor-derived membrane facilitates homologous targeting and immune evasion. Transcriptomic analysis confirmed profound APCM-mediated modulation of ferroptosis, metabolic, and redox-associated gene signatures. Notably, the APCM nanozyme enables dual-mode imaging, offering visualization of the location of TNBC and precise guidance for treatment. Collectively, this "four-in-one' biomimetic nanozyme, which integrates multiple enzyme-mimicking activities and tumor-cell-membrane camouflage, effectively disrupts redox and metabolic homeostasis to potentiate ferroptosis, establishing a promising therapeutic paradigm for TNBC.