Engineered nanodendritic sonosensitizers empower sonodynamic-elicited ferroptosis and PANoptosis against platinum-resistant breast cancer

Cisplatin-resistant breast cancer continues to pose a major clinical challenge, largely due to sophisticated cellular defense mechanisms that compromise the effectiveness of conventional chemotherapy. Ferroptosis and PANoptosis, as programmed cell death pathways, have emerged as promising strategies to circumvent treatment resistance. In this study, Pt56Mn44 nanodendrites have been designed and engineered as high-performance ultrasound-activatable sonosensitizers for efficient sonodynamic therapy of cisplatin-resistant breast cancer. The nanodendrites feature a narrow bandgap structure that facilitates enhanced electron-hole separation under ultrasound irradiation, leading to highly efficient reactive oxygen species (ROS) generation. Importantly, the resulting nanodendrites effectively suppressed the growth of cisplatin-resistant breast tumors through a coordinated multi-mechanistic action. The released Pt(II) ions induced DNA damage and promoted apoptosis while evading common resistance pathways. Concurrently, Mn(II) ions depleted intracellular glutathione and downregulated glutathione peroxidase 4, precipitating ferroptotic cell death. The sonodynamic effect further disrupted mitochondrial integrity, elevated ROS levels, and activated PANoptosis. A synergistic interaction between metal ion-mediated effects and sonodynamic radical oxidation enabled simultaneous induction of multiple cell death programs, collectively overcoming cisplatin resistance of cancer cells. The engineered nanodendrites also exhibited favorable biocompatibility, supporting their high potential as a translatable therapeutic strategy for cisplatin-resistant breast cancer and other treatment-refractory malignancies.