Multifunctional DSF/Cu ₃ BiS ₃ @SS Nanoparticles Loaded with Disulfiram Potentiate Breast Cancer Radiosensitivity by Synergistically Activating Cuproptosis and Apoptosis

Radiotherapy is an essential method for breast cancer treatment, primarily characterized by directly or indirectly damaging tumor cells. However, owing to the high DNA repair mechanism of tumor cells, the therapeutic efficacy of radiotherapy is frequently affected. To address this dilemma, it is of great significance to develop effective radiosensitizers. Herein, we design DSF/Cu3BiS3@SS nanoparticles (DCBSS NPs) to potentiate radiotherapy efficacy for breast cancer via amplification of cuproptosis and apoptosis. This material exhibits several key features: (1) In the tumor microenvironment, DCBSS NPs have pH-responsive properties. (2) Cu2+ leads to the depletion of glutathione, which facilitates the reduction of Cu2+ to Cu+, collectively inducing intracellular Cu+ overload and triggering cuproptosis. (3) The resultant Cu+ catalyzes Fenton-like reactions, generating abundant reactive oxygen species to intensify oxidative stress. (4) The high-Z (Bi) element can enhance radiation energy deposition, effectively induce DNA damage, and further arrest the cell cycle at the radiosensitive G2/M phase, and Cu2+ reacts with DSF to form CuET, together ultimately amplifying apoptosis. In vivo, DCBSS NPs exhibit effective tumor accumulation via the enhanced permeability and retention effect and achieve an excellent antitumor effect when combined with radiotherapy, with excellent biosafety. This study demonstrates a robust radiosensitization strategy for breast cancer but also introduces an innovative way for cancer therapy based on the regulation of cuproptosis and apoptosis pathways.