Cuproptosis shows good application prospects in tumor therapy. However, the copper efflux mechanism and highly expressed intracellular reducing substances can inhibit the cuproptosis effects. In this study, a platelet vesicle (PV) coated cuprous oxide nanoparticle (Cu2O)/TBP-2 cuproptosis sensitization system (PTC) was constructed for multiple induction of tumor cuproptosis. PTC was prepared by physical extrusion of AIE photosensitizer (TBP-2), Cu2O, and PV. After the biomimetic modification, PTC can enhance its long-term blood circulation and tumor targeting ability. Subsequently, PTC was rapidly degraded to release copper ions under acid conditions and hydrogen peroxides in tumor cells. Then, under light irradiation, TBP-2 quickly enters the cell membrane and generates hydroxyl radicals to consume glutathione and inhibit copper efflux. Accumulated copper can cause lipoylated protein aggregation and iron-sulfur protein loss, which result in proteotoxic stress and ultimately cuproptosis. PTC treatment can target and induce cuproptosis in tumor cells in vitro and in vivo, significantly inhibit lung metastasis of breast cancer, increase the number of central memory T cells in peripheral blood, and prevent tumor rechallenge. It provides an idea for the design of nanomedicine based on cuproptosis.
Keywords: copper efflux inhibition; cuproptosis; glutathione depletion; tumor metastasis and rechallenge; type-I AIE photosensitizer.