As we have previously shown, Tz-triggered cleavage of transcyclooctenes, such as widely used release-TCO (rTCO) and the cleavable linker cTCO (Fig. ), strongly depends on post-click reaction mechanisms. In fact, it can be considered a 3-step process: (i) IEDDA click, (ii) tautomerization, and (iii) 1,4elimination. Hence, the overall click-to-release efficiency depends on the rate of the ligation, the tautomerization of the initially formed 4,5-dihydropyridazine (4,5-DHP), and the subsequent elimination of the releasing 1,4-DHP tautomer (Fig. ). Several undesired pathways can compete with the actual release event: intramolecular cyclization leading to formation of a tricyclic dead end (for alkyl-Tz), irreversible formation of the non-releasing 2,5-DHP tautomer (aryl-Tz), and spontaneous oxidation of that tautomer (any Tz) all impede bioorthogonal elimination. We have shown that intramolecular cyclization can be blocked by using secondary (e.g., N-methylated) amines, enabling complete release upon reaction with bis-alkyl-tetrazines, such as 3,6dimethyltetrazine (DMT, 1, Fig. ). However, due to unfavorable kinetics of both the initial IEDDA click reaction and the release step, the overall efficiency of this reagent-set is still limited and unable to achieve fast click-to-release at low concentrations. Release dynamics are markedly enhanced by Tz-acids or ammonium-functionalized Tz (Fig. ). These improved bioorthogonal scissors exploit CO2H and NH3 + as directing groups that act as intramolecular proton donors and acceptors to accelerate both post-click tautomerization and elimination. Nonetheless, the random nature of click orientation handicaps the maximal performance of unsymmetric tetrazines equipped with one directing group and one substituent to increase click reactivity. NH3 + -functionalized heteroaryl-Τz developed by van Kasteren et al., for instance, improve Tz/TCO bond-cleavage but are ultimately limited to ~80% release by the subset of reactions when the aryl group ends up in 'head-to-head' position adjacent to the carbamate. While we recently circumvented the impact of click orientation by the development of a C2-symmetric TCO (C2TCO), enabling highly efficient bioorthogonal turn-off, this cleavable linker does not allow for controlled release of a specific single molecule. Hence, the Tz-diacid PA2 (2, Fig. ) is still the only known Tz that achieves near-complete release of primary amines via bioorthogonal cleavage of rTCO-and cTCOcarbamates. However, the low IEDDA reactivity of 2 (secondorder rate constant k2 < 10 M -1 s -1 in PBS at 22 °C) severely limits further application. Conversely, highly reactive mono-aryl and bis-pyridyl-tetrazines (e.g., 2Pyr2 (3), Fig. ) are commonly used for fast Tz/TCO ligation but limited due to very low release yields. Recent efforts to develop structurally modified, cleavable TCO linkers have yielded improved synthetic strategies and mechanistic insights but did not enable significantly increased IEDDA reaction rates with Tz. To tackle the trade-off between the click reactivity and release efficiency of tetrazines, we aimed to combine the features of aryl-Tz (high IEDDA reactivity) and Tz acids (enhanced release, Fig. ). We hypothesized that OH groups introduced on the aryl substituent (phenyl or pyridyl) vicinal to the Tz could enhance tautomerization and elimination by acting as intramolecular proton donors and acceptors (Fig. ). Herein we show that the transformation of phenyl-and pyridyl-substituted tetrazines into hydroxylated 'bioorthogonal scissors' enables near-quantitative release upon fast click reaction with cleavable TCO-conjugates.