Lei He, Xijian Chen, Zhuowei Zhang, Long Qiu, Jie Lyu, Ruitong Hou, Lixi Chen, Lixi Chen, Wenqi Zhang, Zhonglin Ma, Fuqiang Zhao, Juan Diwu, Ning Liu, Wei Chen, Long Chen, Long Chen, J H Su, Feize Li, Zhifang Chai, Shuao Wang
Astatine-211 ( 211 At) 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 211 At-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 211 At 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-[ 211 At]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 211 At in precision oncology.