Bioorthogonal chemistries for theranostics and radioconjugates

The integration of diagnostic imaging and targeted therapy into unified theranostic platforms represents a paradigm shift in precision medicine. Yet, clinical efficacy is often hampered by suboptimal pharmacokinetics that impair target-specific uptake and increase systemic exposure, representing a persistent obstacle to effective in vivo delivery. Bioorthogonal chemistry provides a complementary strategy to address these limitations by enabling high-fidelity chemical reactions to occur directly within the living subject. By facilitating strategies such as in vivo pretargeting and stimulus-responsive payload release, these distinct chemical tools allow for the temporal decoupling of targeting vectors from cytotoxic radioactivity, and 'click-to-clear' strategies additionally provide selective clearance of circulating radioconjugates to expand the therapeutic window. This capability for on-demand molecular assembly and activation has broadened the scope of nuclear medicine and stimulated growing interest in bioorthogonal-based interventions. This review summarizes the latest advancements in utilizing bioorthogonal chemistry for theranostics and mainly focuses on pretargeted imaging and therapy approaches as well as bioorthogonal cleavage-mediated activation. In addition, we critically examine the translational barriers and clinical prospects of implementing these advanced chemical systems in patient care.