Aggregation-Induced Emission Nanoassembly with Enhanced Radiosensitization for Boosting Breast Cancer Radiotherapy.

Radiosensitizers are crucial in augmenting the radiosensitivity of tumors, with organic variants showing significant promise because of their enhanced biocompatibility. Nonetheless, their clinical application has been impeded by two primary limitations: the inadequate generation of reactive oxygen species (ROS) upon X-ray irradiation and insufficient penetration into the tumor tissues. Herein, we developed an aggregation-induced emission nanoassembly (TTVP NPs) specifically engineered for enhanced radiotherapy in breast cancer. Benefiting from their ultrasmall particle size and positive surface charge, TTVP NPs showed a rapid tumor penetration and efficient cellular internalization. Comprehensive mechanistic investigations through immunofluorescence staining, Western blot analysis, and transcriptomic profiling revealed that TTVP NPs demonstrate an enhanced therapeutic efficacy under X-ray irradiation via (1) efficient conversion of radiation energy to cytotoxic ROS, (2) induction of DNA breaks, and (3) suppression of DNA damage repair, thereby significantly inhibiting cancer cell proliferation and activating apoptotic pathways. In orthotopic breast cancer models, the combination of TTVP NPs with X-ray irradiation suppressed tumor growth, supporting the radiosensitizing activity of the TTVP NPs. Notably, this efficacy was also observed in patient-derived organoids, where TTVP NPs successfully penetrated the tumor barrier and consistently induced significant DNA strand breaks across clinically derived samples with X-ray irradiation, validating their potential as promising radiosensitizer candidates in precision radiotherapy.