A H2O2-self-supplying and oxygen-evolving nanosystem for amplified chemodynamic therapy of breast cancer

Breast cancer continues to be a prevalent malignancy with high incidence and mortality rates worldwide, urgently calling for more effective treatment options. Chemodynamic therapy (CDT) has gained attention as a novel cancer treatment modality; however, its therapeutic outcome is severely compromised by insufficient intratumoral hydrogen peroxide (H₂O₂), hypoxia conditions, and the glutathione (GSH)-mediated antioxidant defense mechanism. To address these limitations, we developed a multifunctional nanosystem (denoted as HML) composed of hyaluronic acid-coated hollow manganese dioxide nanoparticles loaded with β-lapachone (β-LAP). Upon targeted accumulation at the tumor site, the HML nanoparticles disassemble within acidic and GSH-enriched tumor milieu, triggering the synchronous release of Mn²⁺ and β-LAP. This process effectively depletes GSH and generates oxygen in situ to ameliorate tumor hypoxia. Importantly, the released β-LAP acts as an endogenous H₂O₂ generator, ensuring a continuous supply that is catalyzed by Mn²⁺via Fenton-like reactions to yield extremely cytotoxic hydroxyl radicals. This results in a lethal burst of oxidative stress and robust apoptosis of tumor cells. Extensive in vitro and in vivo evaluations confirmed the HML nanosystem achieves potent tumor suppression with minimal adverse effects. Overall, this study presents an efficient therapeutic approach for enhancing CDT by simultaneously addressing multiple biological barriers.