Nature Communications, Published online: 24 August 2026; doi:10.1038/s41467-026-76960-z Hydrogen cyanide (HCN) is traditionally regarded as a highly toxic industrial pollutant, but growing evidence suggests that, at low concentrations, it can act as an endogenous signaling molecule with gasotransmitter-like properties. Here, the authors develop a series of esterase-activated cyanide donors featuring tunable release kinetics and concomitant fluorophore generation, enabling self-reporting cyanide delivery through fluorescence. As a key result, the optimized donor Et-1 displayed therapeutic activity in a mouse ischemia–reperfusion model, achieving efficacy at doses as low as 0.3 mg kg⁻¹.