We therefore expected that only cyclic 6-membered dichalcogenides might avoid kinetically irreversible, nonspecific triggering in cells, by ensuring that monothiol attack has the potential to be reversible (discussion in ). This is only a partial solution however. Ensuring that highly reducing dithiol proteins e.g. Trx and Grx (10 µM) or GSH (up to 8 mM) do not catalyse cargo release, while only ca. 20 nM TrxR can do so, cannot be feasible by considering thermodynamics alone (e.g. Trx-reducible 1,2-dithianes resist TrxR, see Supporting Note 3). Ensuring this requires specificity either in binding or in the pathway to cargo release; and since TrxR's CU active site is on an unstructured tail, we focused instead on pathways.