Since we were designing irreversible-release probes, we first considered kinetic aspects on the path to cargo release, as relevant to selectivity. We consider that the same topology restrictions apply as in the disulfide series: i.e. that linear dichalcogenides are likely to be nonselective due to irreversibility of triggering under monothiol challenge. We note that two linear (non-disulfide) dichalcogenide-trigger probes have been published as selective (Fig. ); but according to our analysis, selectivity in the cellular context was not shown (see Supporting Note 2). We instead proceeded with cyclic-topology designs. We also considered that the same geometric factors would apply as for disulfides, ruling out strained dichalcogenides from being cellularly selective. In support of this view, Matile has shown the lability of cyclic 5-membered diselenide probes to nonspecific thiol exchange, mirroring that of the corresponding disulfides (Fig. ).