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 CaO 2 @CuPDA) was designed to dual-amplify cuproptosis through Ca 2+ -overload and photothermal effects for potent immunotherapy. The nanomedicine comprises a calcium peroxide (CaO 2 ) core encapsulated within a copper–polydopamine shell, which stabilizes CaO 2 against premature hydrolysis and confers tumor microenvironment-responsive behavior, photothermal capability, and controlled Cu 2+ release. Upon exposure to the acidic, glutathione (GSH)-rich tumor microenvironment, CaO 2 @CuPDA disintegrates, concurrently releaseing Cu 2+ /Ca 2+ and generating H 2 O 2 . The Fenton-like reaction catalyzed by GSH-reduced Cu + converts H 2 O 2 into hydroxyl radicals, elevating intracellular oxidative stress. Simultaneously, FDX1-mediated reduction of excess Cu 2+ to Cu + inhibits the synthesis of iron‑sulfur cluster proteins to trigger cuproptosis. Critically , this cuproptosis degree is dramatically potentiated by Ca 2+ -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.