In summary, we show that DMEDA can be applied as a minimal self-immolative linker for the design of bis(carbamate)-linked TCO-caged phenols that can be cleaved and thereby activated by bioorthogonal reaction with tetrazines. The mechanism of the overall bond-cleavage process upon IEDDA-ligation with selected symmetrical and unsymmetrical Tz was investigated in detail, with emphasis on Tz-substituents modified with directing groups (CO2H, NH3 + ) and their effect on post-click tautomerization and 1,4-elimination. We achieved >95% release of the phenolic drug CA4 upon Tz-triggered cleavage of prodrug 12 in PBS within 2 hours. Notably, we have observed a 700-fold lower cytotoxicity of the prodrug compared to CA4, also demonstrating high stability of TCO-DMEDA-phenol conjugates. In situ reaction of 12 with Tz confirmed efficient bioorthogonal release of CA4 resulting in a substantially (up to 220-fold) increased cytotoxicity. Based on these results we aim to combine TCO-DMEDA-caging with nextlevel chemical tools for bioorthogonal bond-cleavage to further accelerate the initial Tz/TCO click reaction while achieving fast and complete release of phenolic drugs.