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

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 <i>in vivo</i> antitumor efficacy with reduced systemic toxicity. This innovative platform shows potential as a dual-function approach for precision cancer therapy.