TDGs (Fig. ). The lower durability of these second-genera=on Tz limits their bioorthogonal applica=on to rather short-term in vitro studies. Further refinement of the Tz architecture faces the nontrivial task of integra=ng impacts on reac=vity, cleavage efficiency, stability, and scissors design into the already densely tuned Tz structure. The result has been a serial focus on narrow aspects of func=on, op=mizing one parameter at a =me and restric=ng the development of advanced applica=ons. To tackle this key challenge, a conceptual leap to next-level molecular tools is required.