铜对于生物体是不可或缺的，而其稳态失衡可能会干扰正常的细胞生理过程，甚至诱发细胞死亡。人工调节细胞铜含量提供了激活抗肿瘤作用的可行策略。鉴于此，报道了一种采用肉桂醛（Cin）包装和热敏脂质体涂层的铜离子稳态扰动剂（CuP-CL）。激光照射后，聚多巴胺中掺杂的 Cu2 启动增强光热疗法 (PTT) 并解锁脂质体外层，导致铜离子和 Cin 在弱酸性和高谷胱甘肽 (GSH) 水平的肿瘤微环境中释放。释放的 Cu2 可以引起铜凋亡和化学动力学治疗 (CDT)。同时，利用 H2O2 供应和 GSH 消耗的优点，Cin 作为肿瘤微环境调节剂来放大 Cu2 介导的铜凋亡和 CDT。此外，“激光触发PTT，PTT加速活性氧（ROS）生成，ROS放大脂质过氧化物（LPO）积累，LPO介导热休克蛋白（HSP）清除，下调HSP促进PTT”的正反馈效应对治疗结果的总体益处。体外和体内结果均证实了 CuP-CL 通过铜凋亡/CDT/PTT 的协同作用而具有显着的抗肿瘤性能。总的来说，基于三管齐下的方法，这项工作制定了一种可行的癌症治疗多模式方案。© 2024 Wiley‐VCH GmbH。

Copper is indispensable to organisms, while its homeostatic imbalance may interference normal cellular physiological processes and even induce cell death. Artificially regulating cellular copper content provides a viable strategy to activate antineoplastic effect. In light of this, a copper ions homeostasis perturbator (CuP-CL) with cinnamaldehyde (Cin) packaging and thermosensitive liposome coating is reported. Following laser exposure, the doping of Cu2+ in polydopamine initiates enhanced photothermal therapy (PTT) and unlocks the outer layer of liposome, leading to the release of copper ions and Cin in tumor microenvironment with mild acidity and high glutathione (GSH) levels. The liberative Cu2+ can evoke cuproptosis and chemodynamic therapy (CDT). Meanwhile, leveraging the merits of H2O2 supply and GSH consumption, Cin serves as a tumor microenvironment regulator to amplify Cu2+ mediated cuproptosis and CDT. Additionally, the positive feedback effects of "laser-triggered PTT, PTT accelerates reactive oxygen species (ROS) generation, ROS amplifies lipid peroxide (LPO) accumulation, LPO mediates heat shock proteins (HSPs) clearance, down-regulated HSPs promote PTT" entailed the overall benefit to therapeutic outcomes. Both in vitro and in vivo results corroborate the remarkable antineoplastic performance of CuP-CL by the synergy of cuproptosis/CDT/PTT. Collectively, based on the three-pronged approach, this work plots a viable multimodal regimen for cancer therapy.© 2024 Wiley‐VCH GmbH.