Drug-Loaded Nanospheres with “Triple-Pronged” Strategy for Triple-Negative Breast Cancer Radiotherapy

Abstract Radiotherapy (RT) is crucial in the treatment of triple-negative breast cancer (TNBC). However, insufficient deposition of X-ray energy and peripheral tissue destruction usually caused RT failure. To circumvent this problem, herein, a “three-pronged strategy” nano-radiosensitizer (by encapsulating small molecules RSL3 and Gingerenone A (Gin A) in hollow Cu9S8 deposited with gold nanoparticles, RG@CSG) to combine with ferroptosis induction, G2/M arrest, and energy deposition is rationally designed. After passive accumulation of radiosensitizers at the tumor site, Au nanoparticles (Au NPs) grown on the surface can increase the deposition of X-ray energy to amplify the radiation-induced damage. Subsequently, upon X-ray irradiation, RG@CSG disintegrates to release RSL3 and Gin A. Gin A induces cell cycle arrest in the G2/M phase of tumor cells, which compromises DNA damage repair capacity and enhances tumor sensitivity to irradiation. RSL3 inactivates the GPX4-dependent ferroptosis defense system to eliminate residual tumor cells radioresistance. Furthermore, Au NPs can monitor the therapeutic response via activatable photoacoustic (PA) imaging in the NIR-II region (920 nm). Overall, the as-constructed RG@CSG enables a PA imaging-guided X-ray deposition-cell-cycle arrest-ferroptosis amplification cascade network, achieving a “triple-enhanced” RT sensitization strategy for effective TNBC therapy.