Multifunctional Cu₃BiS₃-BP@PEI Radiosensitizer with Enhanced Reactive Oxygen Species Activity for Multimodal Synergistic Therapy

Development of radiosensitizers with high-energy deposition efficiency, electron transfer, and oxidative stress amplification will help to improve the efficiency of radiotherapy. To overcome the drawbacks of radiotherapy alone, it is also crucial to design a multifunctional radiosensitizer that simultaneously realizes multimodal treatment and tumor microenvironment modulation. Herein, a multifunctional radiosensitizer based on the Cu 3 BiS 3 -BP@PEI nanoheterostructure (NHS) for multimodal cancer treatment is designed. Cu 3 BiS 3 -BP@PEI NHS is able to deposit a high radiation dose into cancer cells, enhancing the radiotherapy effect. Due to the heterostructure and the synergistic effect of Cu 3 BiS 3 and black phosphorus (BP), significantly boosted 1 O 2 and •OH generation is obtained under X-ray irradiation, which is promising for extremely efficient radiodynamic therapy. More importantly, the acidic tumor microenvironment (TME) can induce the cycle conversion of Cu 2+ to Cu +, oxidizing glutathione (GSH) and catalyzing intracellular overproduction of H 2 O 2 into highly toxic •OH, which thus further enhances reactive oxygen species (ROS) production and reduces GSH-associated radioresistance. Furthermore, Cu 3 BiS 3 -BP@PEI NHS has an excellent photothermal effect and can effectively transform light into heat. The outcomes of the in vitro and in vivo research confirm that the as-prepared Cu 3 BiS 3 -BP@PEI NHS has a high synergistic therapeutic efficacy at a low radiation dose. This work provides a viable approach to constructing a multifunctional radiosensitizer for deep tumor treatment with TME-triggered multiple synergistic therapies.