Bismuth-Triggered Copper Release From CuS Nanosheets Enables Synergistic Ion-Interference and Chemodynamic/Photothermal Therapy.

Despite the promising potential of Cu-based nanozymes in cancer therapy, the therapeutic efficacy remains limited by the difficulty of achieving controlled Cu-ion release without compromising lattice integrity and catalytic activity. Herein, we developed a therapeutic nanoplatform utilizing bismuth (Bi)-doping techniques to control the release of copper (Cu) ions, enabling synergistic ion interference therapy, chemodynamic therapy (CDT) and photothermal therapy (PTT) for tumor treatment. Based on the instability of Bi-based compounds in the tumor microenvironment (TME), Bi ions are preferentially released from Bi-doped CuS nanosheets (Bi-CuS NSs), exposing more Cu vacancies and facilitating Cu ion release compared to CuS NSs. More importantly, upon cellular internalization, the released copper ions induce ionic homeostasis disruption, leading to cuproptosis in liver cancer cells. Simultaneously, the Cu vacancies generated by ion release enhance the peroxidase-like activity to produce more reactive oxygen species and improve the photothermal conversion efficiency to induce localized hyperthermia, synergistically amplifying tumor cell destruction. Consequently, Bi-CuS NSs exhibit excellent potential for synergistic metal ion interference and photothermal/chemodynamic therapy, enabling the multimodal treatment of hepatocellular carcinoma. This study presents a Bi-mediated strategy for regulating Cu-ion release and catalytic activity in metal-based cancer nanomedicines.