Tumor‐Microenvironment‐Responsive Cerium‐Enriched Copper Nanozyme with O2 Supply and Oxidative Stress Amplification for In Situ Disulfiram Chemotherapy and Chemodynamic Therapy Intensification

Traditional chemotherapy has faced tough challenges of systemic toxicity, hypoxia resistance, and inadequacy of monotherapy. Developing the tumor-specific O₂-supply-enhanced chemotherapy without toxic drugs while combing other precise treatments can substantially improve therapeutic efficacy. Herein, a CeO₂-enriched CuO nanozyme with O₂ supply and oxidative stress amplification for tumor-specific disulfiram (DSF) chemotherapy and intensified chemodynamic therapy by synergistic in situ "nontoxicity-toxicity" activation is developed. Notably, CeO₂ can not only act as a morphological "regulator," but also serve as a cascaded enzyme-mimetic catalyst via tumor-microenvironment-responsive cascaded-logical programmable valence conversion. Once internalized inside tumor cells, the nanozyme can be degraded by lysosomal acidity to release nontoxic DSF and Cu²⁺, which can trigger in situ "Cu²⁺-DSF" chelation, generating a highly toxic Cu(DTC)₂ for in situ chemotherapy. Moreover, the enriched CeO₂ with catalase-mimetic activity can decompose the endogenous H₂O₂ into O₂, which can relieve the hypoxia to enhance the chemotherapeutic efficacy. Furthermore, the simultaneously generated Ce³⁺ can exert peroxidase-mimetic activity to catalyze H₂O₂ into hydroxyl radicals (•OH) for chemodynamic therapy. This Fenton-like chemistry is accompanied by the regeneration of Ce⁴⁺, which can deplete the intracellular overproduced GSH to amplify the oxidative stress. Therefore, this nanozyme can provide an alternative to precise cancer treatment.