Single Atom Ru Doped CuTi Nanozyme with Precisely Programmed Cascade Catalysis for Amplified Oral Cancer Therapy

Oral squamous cell carcinoma (OSCC) lacks effective low-toxicity treatments. Chemodynamic therapy (CDT) offers a tumor-specific approach by converting hydrogen peroxide into toxic radicals. However, its efficacy is limited by insufficient H₂O₂, high glutathione (GSH) levels that neutralize the radicals, and reliance on a single cell death pathway. Herein, we report a precisely programmable catalytic platform consisting of Ru single atoms anchored on a CuTi layered double hydroxide (Ru CuTi-LDH) nanozyme. The Ru sites not endow the nanozyme with superoxide dismutase (SOD)-like activity and enable precise control over its catalytic functions, which also include peroxidase (POD), catalase (CAT), and glutathione peroxidase (GPx). Together, these features orchestrate a precise cascade reaction to amplify therapeutic efficacy for OSCC. Light-triggered superoxide radicals (^•O₂^-) are converted to H₂O₂ by Ru sites, fueling Fenton-like reactions at Cu centers that generate cytotoxic hydroxyl radicals (^•OH). Meanwhile, Ru CuTi-LDH depletes GSH and generates O₂ to alleviate tumor hypoxia. This chemical reprogramming amplifies oxidative damage and sensitizes tumor cells to cuproptosis. Additionally, endoplasmic reticulum (ER) stress triggered by the cascade activates paraptosis, establishing three distinct cell death pathways simultaneously. This approach achieved 84.7% tumor inhibition and prolonged survival in an orthotopic OSCC model. This work presents a chemical strategy that addresses fundamental CDT limitations through cascade catalysis with atomic-level tunability.