Recent advances beyond classical bioorthogonal chemistry

Bioorthogonal chemistry was originally developed for fast and selective ligation of small molecules onto biomolecules in complex biological environments. Over time, the field has grown significantly beyond just clicking molecules together. It now includes reactions that can form or break chemical bonds and control how reactive substances are generated within living organisms. The field is continuing to develop strategies that allow reactions to be turned on when needed, exhibit greater compatibility in biological environments, and enable multi-step transformations to achieve complex operations. In this review, we summarize these new developments, including new click reactions and reagents, inducible and enzyme-activated click systems, click-induced bond dissociation reactions, bioorthogonal chemical operations, and bioorthogonally activated reactive species.