As the bis-pyridyl-Tz scaffold is the prime candidate for iTCO based on its IEDDA reac=vity and release yield, we delineated the release kine=cs of Pyr2 (1) with iTCO (9) and rTCO (8) by serial HPLC analysis in PBS at 37 °C (Fig. ). Selec=ng reac=on condi=ons in which the click reac=on reaches comple=on within one minute, iTCO displayed near instantaneous and quan=ta=ve (>99%) release by the earliest experimental =me point-strikingly different from the marginal release (<4%) observed with rTCO. The speed of the iTCOtriggered events is faster than can be reliably measured by HPLC, requiring alterna=ve techniques to monitor the reac=on (vide infra). Cumula=vely, iTCO affords a striking reversal, turning Pyr2 from the least effec=ve Tz for previously developed cleavable TCOs into the perfect match for fast and efficient release, se{ng a new benchmark that outperforms all exis=ng click-to-release tools by an unprecedented margin.