PROTAC prodrug-integrated nanosensitizer for potentiating radiation therapy of cancer.

Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, we have revealed the crucial role of bromodomain-containing protein 4 (BRD4)-RAD51 associated protein 1 (RAD51AP1) axis in sensitizing RT of HNSCC. We herein innovatively engineered a versatile nanosensitizer (RPB7H) by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) and hafnium dioxide (HfO 2 ) nanoparticles to downregulate BRD4-RAD51AP1 pathway and sensitize HNSCC tumor to RT. Upon intravenous administration, the RPB7H nanoparticles selectively accumulated at the tumor tissue and internalized into tumor cells by recognizing neuropilin-1 overexpressed in the tumor mass. HfO 2 nanoparticles enhanced RT effectiveness by amplifying X-ray deposition, intensifying DNA damage, and boosting oxidative stress. Meanwhile, BPA771 can be activated by RT-induced H 2 O 2 secretion to degrade BRD4 and inactivate RAD51AP1, thus impeding RT-induced DNA damage repair (DDR). This versatile nanosensitizer, combined with X-ray irradiation, effectively regressed HNSCC tumor growth in a mouse model. Our findings introduce a PROTAC prodrug-based radiosensitization strategy by targeting the BRD4-RAD51AP1 axis, might offer a promising avenue to augment RT and more effective HNSCC therapy. This article is protected by copyright. All rights reserved.