以线粒体靶向富集的金属铜消耗正在成为一种有吸引力的抗癌策略。然而，现有铜分子螯合剂无特异性、有毒且无效。本文报道了一种多功能纳米颗粒（MSN-TPP/BNA-DPA），其不仅可以通过在介孔二氧化硅纳米颗粒（MSN）表面上结合荧光染料4-溴-1,8-萘酐（BNA）、铜消耗基元二甲基吡啶胺（DPA）和线粒体靶向配体三苯基膦（TPP），将荧光探针和铜消耗基元集成至一体以靶向线粒体来诱导铜消耗疗法，还可作为纳米载体用于运输抗癌药物进行化疗。BNA和荧光探针BNA-DPA的内部电荷转移使得MSN-TPP/BNA-DPA在紫外激发下发出绿色荧光，可用于监测纳米颗粒的细胞摄取。当铜离子与DPA结合时，荧光熄灭，提供了对铜消耗的可视化反馈。治疗方面，以线粒体靶向富集的铜消耗可有效引起线粒体损伤、增强氧化压力和减少三磷酸腺苷（ATP）的生产，诱导癌细胞凋亡。此外，介孔结构使得MSN-TPP/BNA-DPA能够将柔红霉素输送到线粒体，以进行化疗，并通过产生H2O2来增强铜消耗疗法。总之，增强的铜消耗疗法和柔红霉素介导的化疗的协同疗效在4T1移植瘤小鼠中实现了显著的癌细胞杀伤作用和明显的肿瘤生长抑制。本研究为基于铜消耗的协同抗癌疗法提供了一种有效的策略。

Mitochondria-targeted copper-depletion is emerging as an attractive strategy to combat cancer. However, existing copper molecular chelators are non-specific, toxic and ineffective. Here, it is reported that multifunctional nanoparticles (MSN-TPP/BNA-DPA) can not only target mitochondria to deprive copper ions to trigger copper-depletion therapy, but also serve as nanocarriers to deliver anticancer drugs for chemotherapy, which are engineered by conjugating a fluorophore 4-bromo-1,8-naphthalicanhydride (BNA), a copper-depriving moiety dimethylpyridinamine (DPA) and a mitochondrial targeting ligand triphenylphosphonium (TPP) on the surface of mesoporous silica nanoparticles (MSN). BNA and the internal charge transfer of compound BNA-DPA endow MSN-TPP/BNA-DPA with green fluorescence emission upon UV excitation, which can be used to monitor the cellular uptake of nanoparticles. When copper ions bind to DPA, green fluorescence is quenched, providing visualization feedback of copper-depletion. Therapeutically, mitochondria-targeted copper-depletion effectively causes mitochondria damage, elevated oxidative stress and reduced ATP production to induce intensive cancer cell death. Moreover, the mesoporous structure enables MSN-TPP/BNA-DPA to deliver doxorubicin to mitochondria for chemotherapy and enhances copper-depletion therapy through H2O2 production. Together, the synergistic therapeutic effect of enhanced copper-depletion therapy and doxorubicin-mediated chemotherapy achieves a remarkable cancer cell-killing effect and significant tumor growth inhibition in 4T1 tumor-bearing mice. This work provides an efficacious strategy for copper-depletion based synergistic cancer therapy.