Plasmonically Reinforced Self-Sufficient Nanozymes Dysregulating Redox Homeostasis for Augmented Cascade Catalytic...

Tumor nanocatalytic therapy represents a promising transformative technology for treating malignant tumors, yet is often limited by insufficient catalytic activity and adaptive tumor microenvironment (TME) resistance. Herein, we develop a plasmonic Pt-CuO₂ nanozyme that integrates plasmonic enhancement with self-sufficient H₂O₂ supply for augmented cascade catalytic therapy. The nanozyme comprises Pt nanoparticles (NPs) and CuO₂ nanodots co-deposited on Au nanostars and encapsulated within PEGylated ZIF-8 metal-organic frameworks (MOFs). It exhibits strong near-infrared localized surface plasmon resonance, enables intrinsic H₂O₂ generation, and depletes glutathione, effectively disrupting intratumoral redox homeostasis. Under acidic TME conditions, the MOFs degrade, releasing Pt NPs and CuO₂ nanodots to produce ∙OH via peroxidase-like and Fenton-like catalytic reactions. Plasmonic heating and "hot electron" injection under 808 nm laser irradiation further promote ∙OH generation. This process induces mitochondrial dysfunction, suppresses adenosine triphosphate biosynthesis and downregulates heat shock proteins, thereby increasing thermal sensitivity of cancer cells and enhancing the efficacy of mild plasmonic hyperthermia therapy (PHT). In a triple-negative breast cancer murine model, the nanozyme demonstrates superior anticancer performance through the synergy of plasmon-enhanced catalysis, self-supplied H₂O₂, redox homeostasis disruption, and mild PHT. This study provides a novel strategy for efficient nanocatalytic therapy with substantial potential for clinical translation.