铜磷酸酯（cuproptosis）是一种新认知的细胞死亡方式，在癌症治疗方面展示出巨大的前景。铜磷酸酯的诱导剂在肿瘤治疗中具有更多优势，特别是可以同时触发铜磷酸酯和化学动力学治疗（CDT）。然而，铜磷酸酯受限于细胞内铜离子的缺乏和铜基离子载体的非特异性输送。因此，高水平的输送、响应性释放和利用诱导剂的协同功能成为基于铜磷酸酯的肿瘤治疗的关键。在这项工作中，我们构建了一个级联纳米系统，用于增强铜磷酸酯和CDT。在肿瘤细胞的弱酸性环境中，DNA、锌离子和Cu+可以从纳米系统中释放出来。由于Cu+在介导类Fenton反应和铜磷酸酯方面具有卓越的性能，释放的Cu+能够高效诱导铜磷酸酯和CDT，同时生成Cu2+。然后，Cu2+可以通过谷胱甘肽（GSH）部分转化为Cu+，形成Cu+供应环路并确保协同作用。同时，GSH的消耗也有助于促进铜磷酸酯和CDT的效果。最后，DNA和Zn2+形成DNA酶切割催化酶相关RNA，导致过氧化氢的积累，进一步增强组合治疗效果。这些结果提供了一个有前途的纳米治疗平台，并可能启发基于铜磷酸酯的潜在癌症治疗设计。此文章受版权保护，版权所有。

Cuproptosis, a kind of newly-recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that could trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the non-specific delivery of copper-based ionophores. Therefore, high level delivery, responsive release and utilizing synergistic-function of inducer become the key on cuproptosis-based oncotherapy. In this work, we constructed a cascade nanosystem for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions and Cu+ could release from the nanosystem. Since Cu+ having superior performance in mediating both Fenton-like reaction and cuproptosis, the released Cu+ induced cuproptosis and CDT efficiently, accompanied by Cu2+ generation. Then Cu2+ could be converted into Cu+ partially by glutathione (GSH) to from a Cu+ supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributed to cuproptosis and CDT in return. Finally, DNA and Zn2+ formed DNAzyme to shear catalase-related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nano-therapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.