Design of Near Infrared Light‐Powered Copper Phyllosilicate Nanomotors for Cuproptosis‐Based Synergistic Cancer Therapy

Abstract Cuproptosis, a newly discovered cell death pathway, has shown great potential in cancer treatment. Herein, near‐infrared (NIR) light‐driven nanomotors (CuSiO 3 @Au‐Pd NMs) are designed for cuproptosis‐assisted synergistic therapy with autonomous mobility and improved cellular uptake and tumor penetration. Specifically, the released Cu 2+ ions from CuSiO 3 @Au‐Pd NMs can induce the Fenton‐like reaction, leading to the generation of hydroxyl radicals (·OH), accompanied by the depletion of glutathione within the MCF‐7 cells. Additionally, the designed CuSiO 3 @Au‐Pd NMs also exhibit excellent photothermal effects, which can further promote the production of ·OH, resulting in intensified oxidative stress and cellular apoptosis. Moreover, the enhanced tumor permeation efficiency and cellular uptake of CuSiO 3 @Au‐Pd NMs via autonomous movement under self‐thermophoretic forces are proved using 2D cellular experiments and 3D multicellular tumor spheroids. The resultant intracellular accumulation of Cu 2+ can induce the oligomerization of lipoylated proteins, leading to cuproptosis, along with the mitochondrial dysfunction pathway. More importantly, both in vitro and in vivo experiments show that CuSiO 3 @Au‐Pd NMs could penetrate deeply into tumors and exhibit great anticancer efficacy through multimodal therapeutic methods. These findings manifest promising potentials of NIR‐powered Cu‐based NMs with high maneuverability for future smart and synergistic cancer therapy.