Sono‐Responsive Hydrogel for Fractionated PROTAC Release to Alleviate Resistance and Immunosuppression Induced by Multi‐Course Postoperative Radiotherapy

Abstract Radiotherapy (RT) is commonly employed to prevent postoperative recurrence, typically delivered in fractionated doses to mitigate side effects. However, multi‐course RT frequently leads to radiation resistance and immunosuppression. In this study, a sono‐responsive hydrogel that enables fractionated releases of PROteolysis TArgeting Chimeras (PROTAC) in response to ultrasound (US) pulses is presented. This system targets bromodomain‐containing protein 4 (BRD4) and releases the PROTAC at the tumor site before each course of RT. This release inhibits DNA repair mechanisms and reduces myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs), thereby mitigating RT resistance and immune suppression. This strategy significantly improves the therapeutic efficacy of postoperative RT, reducing the risk of tumor recurrence. Overall, this work proposes an easy‐to‐implement strategy for overcoming challenges in resistance and immunosuppression in multi‐course postoperative RT.