摘要
Cuproptosis has gained significant attention in cancer therapy. Use of copper-overloaded combination therapy that employs a variety of cell death mechanisms has emerged as a promising avenue in the treatment of cancer. However, integrating different modes in a system with optimal synergy and minimal side effects remains a challenge. In this study, a multifunctional copper ion-overloaded nanoparticle was fabricated via one-pot self-assembly for enhanced cuproptosis, chemo- and phototherapy. Molecular dynamics simulation was performed to study the self-assembly mechanism, demonstrating they assembled into stable nanoparticles (NPs) in 50 ns. The NPs possess dual-targeting capabilities towards tumor cells and mitochondria, and exhibit excellent stability in neutral PBS, while showing responsive payload release under acidic conditions or NIR laser irradiation. Upon reaching the mitochondria, the NPs release their payloads, where accumulated copper ions trigger aggregation of lipoylated proteins, etc. Released disulfiram chelates excessive copper ion to form toxic Cu(DTC) 2 , which induces apoptosis combining with hydroxycamptothecin. Meanwhile, indocyanine green-generated ROS and photothermal effects further enhance cuproptosis for synergistic therapy. In vitro results revealed potent cytotoxicity of the NPs against CT26 cells while negligible effects on normal cells. Furthermore, significant reactive oxygen species generation, mitochondrial membrane potential alteration, increased apoptosis, and modulated protein mRNA expression levels, confirmed the synergistic combination of chemotherapy, cuproptosis, and photothermal/photodynamic therapies. Notably, in vivo experiments demonstrated selective tumor accumulation and outstanding antitumor efficacy (89.5% inhibition rate) with excellent biosafety profile. The NPs provide a novel strategy for cuproptosis-based combination cancer therapy and shows significant clinical translation potential.
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