Gao Yun, Han Renlu, Guo Zhen, Zhuang Zekai, Fu Jie, Hou Yafei, Yu Jiancheng, Tang Keqi
Zhejiang Engineering Research Center of Advanced Mass Spectrometry and Clinical Application, Institute of Mass Spectrometry, School of MaterialsScience & Chemical Engineering, Ningbo University, Ningbo 315211, PR China.
Zhejiang Engineering Research Center of Advanced Mass Spectrometry and Clinical Application, Institute of Mass Spectrometry, School of MaterialsScience & Chemical Engineering, Ningbo University, Ningbo 315211, PR China; Zhenhai Institute of Mass Spectrometry, Ningbo 315211, PR China.
Colloids Surf B Biointerfaces. 2025 Aug;252:114682. doi: 10.1016/j.colsurfb.2025.114682. Epub 2025 Apr 9.
Cuproptosis is a currently discovered programmed cell death modality driven by copper (Cu) ions, which shows potential application prospects in overcoming apoptotic resistance in cancer therapy due to its unique mechanism. Nevertheless, the efficiency of cuproptosis is restricted by strict Cu metabolism regulation. Herein, elesclomol (ES) and glucose oxidase (GOx) co-loaded CuFeO (CF) nanoplatform (termed as CFEG) was elaborately engineered to boost cuproptosis through multi-pathway copper metabolisms regulation. After triggered by tumor-overexpressed glutathione (GSH), the released ES continuously chelated and targeted transport Cu ions through a shuttle mechanism to mitochondria where cuproptosis was initiated, which dramatically improved the influx efficiency of Cu. Additionally, GOx-mediated glucose oxidation reaction together with Cu and Fe ions stimulated Fenton reaction simultaneously amplified intracellular oxidative pressure by hydrogen peroxide (HO) self-supply and subsequent hydroxyl radical (•OH) generation, which down-regulated Cu exporter ATP7A expression and inhibited Cu ions efflux, thereby exacerbating cuproptosis. Furthermore, the consumption of GSH simultaneously reduced the chelation of GSH with Cu and promote the •OH generation, further potentiating the occurrence of cuproptosis. Collectively, such the multi-pathway copper metabolisms regulation including improved Cu influx, inhibited Cu efflux and GSH depletion significantly boosted cuproptosis, which synergized with photothermal effect of CF to efficiently repressed the growth of tumor in mice without causing systemic toxicity. This work provides a multivariate mode for enhanced tumor cuproptosis therapy, and may also inspire the design of advanced cuproptosis-related nanomedicine system.
铜死亡是目前发现的一种由铜离子驱动的程序性细胞死亡方式，由于其独特的机制，在克服癌症治疗中的凋亡抗性方面显示出潜在的应用前景。然而，铜死亡的效率受到严格的铜代谢调控的限制。在此，精心构建了负载艾力司莫（ES）和葡萄糖氧化酶（GOx）的铜铁氧化物（CF）纳米平台（称为CFEG），以通过多途径铜代谢调控来促进铜死亡。在被肿瘤过表达的谷胱甘肽（GSH）触发后，释放的ES通过穿梭机制持续螯合并靶向转运铜离子至线粒体，在那里启动铜死亡，这显著提高了铜的流入效率。此外，GOx介导的葡萄糖氧化反应与铜和铁离子同时刺激芬顿反应，通过过氧化氢（HO）的自我供应和随后羟基自由基（•OH）的产生同时放大细胞内氧化压力，下调铜转运蛋白ATP7A的表达并抑制铜离子外流，从而加剧铜死亡。此外，GSH的消耗同时减少了GSH与铜的螯合并促进•OH的产生，进一步增强了铜死亡的发生。总体而言，这种包括改善铜流入、抑制铜外流和消耗GSH在内的多途径铜代谢调控显著促进了铜死亡，其与CF的光热效应协同作用，在不引起全身毒性的情况下有效抑制小鼠肿瘤的生长。这项工作为增强肿瘤铜死亡治疗提供了一种多变量模式，也可能启发先进的铜死亡相关纳米药物系统的设计。
