The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene-linked payloads has strong potential in click-to-release drug delivery, however, an inverse correlation between click reactivity and payload release yield is hampering their clinical translation. Here, the authors develop ortho-substituted bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups for efficient tautomerization and payload elimination, achieving release yields of 96% with 18-fold more reactive tetrazines.
- Ron M. Versteegen
- Raffaella Rossin
- Marc S. Robillard
