Liu Chenguang, Guo Lingxiao, Cheng Yuying, Gao Jingjie, Pan Hanling, Zhu Jiayi, Li Danting, Jiao Liqing, Fu Caiyun
College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310018, P. R. China.
Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Zhejiang Sci-Tech University, Hangzhou, 310018, P. R. China.
Adv Sci (Weinh). 2025 Jun 25:e17616. doi: 10.1002/advs.202417616.
Transition metal-based nanotherapeutics, such as chemodynamic therapy and ferroptosis- or cuproptosis-induced strategies, hold great potential for cancer treatment. Copper- and iron-based nanozymes enhance reactive oxygen species (ROS) generation and regulate metal ion homeostasis, driving ferroptosis and cuproptosis. However, simultaneous delivery of copper and iron ions and the role of mitochondria-targeted copper in inducing cuproptosis remain underexplored. Here, a dual-functional nano-heterojunction platform, MIL-CuS-TPP/FA, is reproted, integrating iron- and copper-based components for synergistic ferroptosis and cuproptosis induction. Mitochondria-targeted CuS nanodots demonstrated high biocompatibility and efficiently induced cuproptosis by disrupting mitochondrial iron-sulfur proteins. Combined with MIL-88B, the iron-based metal-organic framework, the MIL-CuS heterojunction exhibited enhanced ROS catalytic activity, confirmed by density functional theory (DFT) analysis, with improved HO adsorption and lower energy barriers for peroxidase (POD)-like reactions. The dual-targeting MIL-CuS-TPP/FA nanoplatform effectively delivered copper ions to mitochondria and iron ions to tumor cells, modulating key ferroptosis- and cuproptosis-related markers, such as GPX4, GSH, FDX-1, and HSP70. The platform synergistically combined photothermal effects with multi-pathway cell death mechanisms, achieving significant anti-tumor efficacy in vitro and in vivo. This study underscores the therapeutic potential of synchronously delivering copper and iron ions and highlights mitochondria-targeted strategies in advancing multi-modal cancer therapies.
基于过渡金属的纳米疗法，如化学动力学疗法以及铁死亡或铜死亡诱导策略，在癌症治疗方面具有巨大潜力。基于铜和铁的纳米酶可增强活性氧（ROS）的生成并调节金属离子稳态，从而驱动铁死亡和铜死亡。然而，铜离子和铁离子的同时递送以及线粒体靶向铜在诱导铜死亡中的作用仍未得到充分探索。在此，报道了一种双功能纳米异质结平台MIL-CuS-TPP/FA，它整合了铁基和铜基成分以协同诱导铁死亡和铜死亡。线粒体靶向的CuS纳米点表现出高生物相容性，并通过破坏线粒体铁硫蛋白有效地诱导了铜死亡。与铁基金属有机框架MIL-88B相结合，MIL-CuS异质结表现出增强的ROS催化活性，密度泛函理论（DFT）分析证实了这一点，其对HO的吸附得到改善，过氧化物酶（POD）样反应的能垒降低。双靶向MIL-CuS-TPP/FA纳米平台有效地将铜离子递送至线粒体，将铁离子递送至肿瘤细胞，调节关键的铁死亡和铜死亡相关标志物，如GPX4、GSH、FDX-1和HSP70。该平台将光热效应与多途径细胞死亡机制协同结合，在体外和体内均实现了显著的抗肿瘤疗效。这项研究强调了同步递送铜离子和铁离子的治疗潜力，并突出了线粒体靶向策略在推进多模态癌症治疗中的作用。
