A Versatile Bioorthogonal Theranostic Platform Enables Relay Activation of Tumor Cell Imaging and Targeted Protein Degradation

作者：Feilong Sun, Tian Wang, Pengfei Wang, Jiaxin Shi, Yanyan Shen, Guilong Wang, Biyu Yang, Huiwen Li, Qiumeng Zhang, Yi Chen, Xuan Zhang · 发表于：Journal of the American Chemical Society · 年份：2025 · DOI：10.1021/jacs.5c11564 · 被引用次数：7 · 研究领域：Click Chemistry and Applications、Protein Degradation and Inhibitors、Nanoplatforms for cancer theranostics

Targeted protein degradation offers therapeutic promise but often suffers from on-target off-tissue toxicities. To overcome this challenge, we developed a versatile theranostic platform that integrates tumor cell imaging with precisely controlled protein degradation. Central to this platform is XZ2223, a glutathione (GSH)-cleavable bioorthogonal trigger that couples cancer cell labeling with concomitant tetrazine release, thereby activating trans-cyclooctene (TCO)-caged CRBN-recruiting degrader prodrugs, Pro-CC-885 and Pro-dBET6, to induce on-demand degradation of GSPT1 and BET, respectively. Coadministration of XZ2223 with either prodrug afforded robust tumor imaging and efficient protein degradation in xenograft models, while the XZ2223/Pro-dBET6 combination further elicited in vivo antitumor efficacy with reduced systemic toxicity. This innovative platform shows potential as a dual-function approach for precision cancer therapy.