Photothermally Triggered Copper Payload Release for Cuproptosis‐Promoted Cancer Synergistic Therapy

Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper-induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN-Cu/PEG/DSF) to realize on-demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu2+ in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu+ species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano-therapeutic platforms.