Anticancer nanomedicines used for ferroptosis therapy generally rely on the direct delivery of Fenton catalysts to drive lipid peroxidation in cancer cells. However, the therapeutic efficacy is limited by the ferroptosis resistance caused by the intracellular anti-ferroptotic signals. Herein, we report the intrinsic ATPase-mimicking activity of a vanadium carbide MXene nanozyme (PVCMs) to pharmacologically modulate the nuclear factor erythroid 2-related factor 2 (Nrf2) program, which is the master anti-ferroptotic mediator in the ironclad defense system in triple-negative breast cancer (TNBC) cells. The PVCMs perform high ATPase-like activity that can effectively and selectively catalyze the dephosphorylation of ATP to generate ADP. Through a cascade mechanism initiated by falling energy status, PVCMs can powerfully hinder the Nrf2 program to selectively drive ferroptosis in TNBC cells in response to PVCMs-induced glutathione depletion. This study provides a paradigm for the use of pharmacologically active nanozymes to moderate specific cellular signals and elicit desirable pharmacological activities for therapeutic applications.

中文翻译：

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一种模拟 ATP 酶的 MXene 纳米酶在药理学上打破了铁死亡癌症治疗的铁定防御系统


用于铁死亡治疗的抗癌纳米药物通常依赖芬顿催化剂的直接传递来驱动癌细胞中的脂质过氧化。然而，治疗效果受到细胞内抗铁死亡信号引起的铁死亡抵抗的限制。在此，我们报告了碳化钒 MXene 纳米酶 (PVCM) 的内在 ATP 酶模拟活性，可通过药理学调节核因子红细胞 2 相关因子 2 (Nrf2) 程序，该程序是铁甲防御系统中的主要抗铁死亡介质。三阴性乳腺癌（TNBC）细胞。 PVCM具有较高的类ATP酶活性，可以有效、选择性地催化ATP去磷酸化生成ADP。通过能量状态下降引发的级联机制，PVCM 可以强有力地阻碍 Nrf2 程序，选择性地驱动 TNBC 细胞中的铁死亡，以响应 PVCM 诱导的谷胱甘肽耗尽。这项研究提供了使用药理活性纳米酶来调节特定细胞信号并引发治疗应用所需的药理活性的范例。