Carrier-Free H₂ O₂ Self-Supplier for Amplified Synergistic Tumor Therapy

Chemodynamic therapy (CDT) utilizes Fenton or Fenton-like reactions to convert hydrogen peroxide (H₂ O₂ ) into cytotoxic hydroxyl radicals (•OH) and draws extensive interest in tumor therapy. Nevertheless, high concentrations of glutathione (GSH) and insufficient endogenous H₂ O₂ often cause unsatisfactory therapeutic efficacy. Herein, a GSH-depleting and H₂ O₂ self-providing carrier-free nanomedicine that can efficiently load indocyanine green (ICG), β-lapachone (LAP), and copper ion (Cu²⁺ ) (ICG-Cu²⁺ -LAP, LICN) to mediate synergetic photothermal and chemotherapy in enhanced chemodynamic therapy is designed. The results show that  LICNs successfully enter tumors owing to the enhanced permeability and retention effect. Through the reductive intracellular environment, Cu²⁺ in LICN can react with intracellular GSH, alleviate the antioxidant capacity of tumor tissues, and trigger the release of drugs. When LICN is subjected to near-infrared (NIR) irradiation, enhanced photothermal effect and upregulated expression of NAD(P)H quinone oxidoreductase-1 (NQO1) are observed. Meanwhile, the released LAP not only supports chemotherapy but also catalyzes NQO1 and produces sufficient endogenous H₂ O₂ , thereby increasing the efficiency of Cu⁺ -based Fenton-like reaction. Notably, GSH depletion and H₂ O₂ self-sufficiency generate sufficient •OH and kill tumor cells with high specificity. Overall, the study provides an innovative strategy to self-regulate GSH and H₂ O₂ levels for effective anticancer therapy.