A γ-Ray-Responsive Dynamic Covalent Polymeric Radioprotectant for Efficient Radiation Injury Treatment

The increasing risk of radiation exposure has intensified the demand for advanced radioprotective strategies to counteract radiation injury. Here, a γ-ray-responsive dynamic covalent polymeric radioprotectant, engineered by integrating phenylboronic acid (PBA)-functionalized polymeric micelles with the potent antioxidants epigallocatechin-3-gallate (EGCG) and curcumin (Cur), is developed to provide efficient systemic protection. The architecture of this dynamic covalent polymeric radioprotectant is stabilized by reversible dynamic covalent linkages between the PBA moieties and the catechol groups of EGCG, ensuring robust persistence during systemic circulation and precise release within the radiation-triggered microenvironment. Furthermore, the structural affinity between EGCG and Cur facilitates efficient π-π stacking interactions, enabling the synchronized encapsulation and triggered release of the dual-drug cargo. Compared to individual antioxidant treatments, this dynamic covalent system exhibits superior efficacy in scavenging reactive oxygen species (ROS), promoting cell proliferation, and inhibiting apoptosis. In vivo assessments further confirm that this radioprotectant affords comprehensive systemic protection, effectively mitigating radiation-related physiological damage and enhancing overall survival by orchestrating endogenous antioxidant responses. Given that numerous molecules with radioprotective potential possess diol or catechol motifs, this modular and responsive design offers a versatile framework for on-demand radioprotection, greatly promising for clinical translation.