Abstract
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.
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