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 C_Ar-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 <i>N</i>-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.