A biodegradable nanomedicine for potentiated cancer therapy via Ca2+-overload and photothermal dual-amplifying cuproptosis.

Cuproptosis holds promise for breast cancer therapy, yet systemic copper delivery risks off-target toxicity, and intrinsic tumor resistance mechanisms limit its therapeutic efficacy. To overcome this obstacle, a biodegradable hybrid nanomedicine (designated CaO2@CuPDA) was designed to dual-amplify cuproptosis through Ca2+-overload and photothermal effects for potent immunotherapy. The nanomedicine comprises a calcium peroxide (CaO2) core encapsulated within a copper-polydopamine shell, which stabilizes CaO2 against premature hydrolysis and confers tumor microenvironment-responsive behavior, photothermal capability, and controlled Cu2+ release. Upon exposure to the acidic, glutathione (GSH)-rich tumor microenvironment, CaO2@CuPDA disintegrates, concurrently releaseing Cu2+/Ca2+ and generating H2O2. The Fenton-like reaction catalyzed by GSH-reduced Cu+converts H2O2into hydroxyl radicals, elevating intracellular oxidative stress. Simultaneously, FDX1-mediated reduction of excess Cu2+to Cu+inhibits the synthesis of iron‑sulfur cluster proteins to trigger cuproptosis. Critically, this cuproptosis degree is dramatically potentiated by Ca2+-overload, increased ROS, and photothermal effects. The amplified cuproptosis elicits robust releasing damage-associated molecular patterns (DAMPs) that activate dendritic cells and recruit cytotoxic T lymphocytes, leading to potent antitumor immunity and suppressed tumor growth in vivo. This work presents a safe and efficient nanoplatform for cuproptosis potentiation, providing a novel strategy for breast cancer treatment.