PROTAC-based nanoassemblies targeting BRD4 for potentiate FLASH radiosensitization therapy.

Authors

Ruiling Xu, Xiaowen Han, Yunfei Sun, Chaofan Ma, Shuqing Liao, Ruo Tang, Yinquan Pu, Xueting Zheng, Jie Zhang, Wen Yang, Xiaoan Li, Zhi Yang

Published in

Materials today. Bio. Volume 39. Pages 103422. Epub Jul 01, 2026.

Abstract

Ultrahigh dose-rate radiotherapy (FLASH-RT) represents a rapidly emerging radiotherapy modality with improved normal tissue protection. However, tumor radioresistance remains a major obstacle limiting its clinical potential. To address this, we developed a novel redox-responsive, PROTAC-based nanoplatform (APF) formed by the self-assembly of folate-conjugated PEG₂₀₀₀-ARV-771 (FA-PEG₂₀₀₀-ARV-771). Following FA-mediated targeting and endocytic uptake by tumor cells, APF nanoparticles underwent glutathione-triggered cleavage in the reductive tumor microenvironment, releasing ARV-771 which promoted the proteasomal degradation of BRD4. The reduction of BRD4 disrupted the BRD4-c-Myc-RAD51AP1 signaling pathway and damaged the DNA repair pathway that resulting in a significant sensitizing effect of FLASH radiotherapy using Petal Accelerator platform. Both in vitro and in vivo experiments demonstrated that APF-assisted FLASH-RT markedly induced tumor cell apoptosis and necrosis, effectively inhibiting the malignant progression of tumors. Additionally, APF significantly enhanced FLASH-RT-induced tumor cell killing by promoting intracellular reactive oxygen species (ROS) generation and exacerbating DNA double-strand breaks. Transcriptomic analysis further revealed that APF-mediated BRD4 degradation suppressed key DNA repair-related genes. As a result, the APF@FLASH-RT combination achieved superior tumor inhibition in vivo with minimal systemic toxicity. This work provides a promising nanomedicine strategy for enhancing FLASH radiotherapy efficacy through targeted protein degradation.

PMID:
42436803
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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