PROTAC Prodrug‐Integrated Nanosensitizer for Potentiating Radiation Therapy of Cancer

Abstract Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, the crucial role of bromodomain‐containing protein 4 (BRD4)‐RAD51 associated protein 1 (RAD51AP1) axis in sensitizing RT of HNSCC is revealed. A versatile nanosensitizer (RPB7H) is thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) and hafnium dioxide (HfO₂) nanoparticles to downregulate BRD4‐RAD51AP1 pathway and sensitize HNSCC tumor to RT. Upon intravenous administration, the RPB7H nanoparticles selectively accumulate at the tumor tissue and internalize into tumor cells by recognizing neuropilin‐1 overexpressed in the tumor mass. HfO₂ nanoparticles enhance RT effectiveness by amplifying X‐ray deposition, intensifying DNA damage, and boosting oxidative stress. Meanwhile, BPA771 can be activated by RT‐induced H₂O₂ secretion to degrade BRD4 and inactivate RAD51AP1, thus impeding RT‐induced DNA damage repair. This versatile nanosensitizer, combined with X‐ray irradiation, effectively regresses HNSCC tumor growth in a mouse model. The findings introduce a PROTAC prodrug‐based radiosensitization strategy by targeting the BRD4‐RAD51AP1 axis, may offer a promising avenue to augment RT and more effective HNSCC therapy.