Mesoporous Nanoplatform That Efficiently Delivers DOX as an H₂O₂ Generator to Trigger Mutual Amplification of Cuproptosis and Chemodynamic Therapy

H₂O₂ in the tumor microenvironment (TME) is a critical mediator for both cuproptosis and chemodynamic therapy (CDT). Enhancing H₂O₂ levels is thus a promising strategy to optimize the efficacy of these therapeutic approaches. Here, utilizing the H₂O₂ generation capacity of doxorubicin (DOX), polyacrylic acid (PAA)/CuMnSe nanospheres (NSs) are designed for efficient delivery of DOX to the TME, promoting cuproptosis and CDT simultaneously. The NSs exhibit high DOX-loading capacity (0.97 mg DOX/mg NSs) and pH-responsiveness. The cations (Cu²⁺/Cu⁺ or Mn⁴⁺/Mn²⁺) endow the NSs with cuproptosis and CDT activity, respectively, while CuMnSe acts as a photothermal agent, rendering the NSs near-infrared (NIR)-responsive. Controlled release of DOX in the TME rapidly elevates H₂O₂ to accelerate two coupled redox reactions underpinning cuproptosis and CDT. Specifically, in cuproptosis, Cu²⁺ is reduced by GSH to Cu⁺, which is re-oxidized to Cu²⁺ by H₂O₂ via a Fenton-like reaction. This accelerates the transformation of the oxidation state of copper ions, maximizing the dihydrolipoamide S-acetyltransferase(DLAT)-aggregation induced cuproptosis effects, while GSH is greatly depleted to sensitize the CDT effect. The efficacy of the NSs is evaluated both in vitro and in vivo, demonstrating overall superior anti-tumor efficacy originating from the mutually amplified cuproptosis/CDT effects and the chemotherapy effects of DOX.