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

Cuproptosis, a newly discovered cell death pathway, has shown great potential in cancer treatment. Herein, near-infrared (NIR) light-driven nanomotors (CuSiO3@Au-Pd NMs) are designed for cuproptosis-assisted synergistic therapy with autonomous mobility and improved cellular uptake and tumor penetration. Specifically, the released Cu2+ ions from CuSiO3@Au-Pd NMs can induce the Fenton-like reaction, leading to the generation of hydroxyl radicals (center dot OH), accompanied by the depletion of glutathione within the MCF-7 cells. Additionally, the designed CuSiO3@Au-Pd NMs also exhibit excellent photothermal effects, which can further promote the production of center dot OH, resulting in intensified oxidative stress and cellular apoptosis. Moreover, the enhanced tumor permeation efficiency and cellular uptake of CuSiO3@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 Cu2+ 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 CuSiO3@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. This study reports the fabrication of near-infrared light-driven and directionally controllable nanomotor (CuSiO3@Au-Pd) that not only enhances cellular uptake and tumor tissue penetration but also facilitates chemodynamic and photothermal therapy, thereby promoting cell apoptosis. Furthermore, the designed CuSiO3@Au-Pd can induce the cellular cuproptosis pathway, enabling cuproptosis-assisted synergistic cancer therapy.image