Encapsulation of 211 At(Ø) + into a Nanoscale Covalent Organic Framework Prevents Deastatination In Vivo

Astatine-211 (211At) is a highly promising α-emitter for targeted alpha therapy (TAT), combining near-100% α-emission with an optimal 7.21-h half-life. Yet clinical translation of 211At-based radiopharmaceuticals is hindered by oxidative cleavage of labile CAr-At bonds in conventional covalent constructs, leading to notable off-target and radiation hazards to normal tissues during therapy. Here, we propose a paradigm-shifting radiolabeling strategy within a preorganized zwitterionic covalent organic framework (ZVCOF, ZV = zwitterionic vinylene-linked) that stably immobilizes cationic 211At species (At(Ø)+) via synergistic multiple noncovalent interactions. The resulting dynamically reversible radiolabeling pathway in ZVCOFs achieves high labeling efficiency (RCY ≥ 90% and radiolabeling kinetics ≤ 2 min) and enhanced in vivo stability against deastatination, surpassing molecular organo-astatine complexes represented by N-succinimidyl 3-[211At]astatobenzoate, a gold standard in clinical trials. Theoretical studies provide fundamental insights into the coordination chemistry and dynamic behavior of At(Ø)+ in the ZVCOF, while cellular and in vivo experiments validate the practical potential of this strategy. This work establishes a robust, deastatination-resistant platform for next-generation α-therapeutics, providing pivotal hints for unlocking the full potential of 211At in precision oncology.