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

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机构： [1]Jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, China. [2]Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong 637100, China. [3]Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.

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关键词： Breast cancer Nanomedicine Cuproptosis Ca2+-overload Tumor therapy Antitumor immunity

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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.Copyright © 2025 Elsevier Inc. All rights reserved.

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大类 | 1 区

化学

小类 | 2 区物理化学

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大类 | 1 区

化学

小类 | 2 区物理化学

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第一作者机构： [1]Jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, China.

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