External stimuli-responsive gasotransmitter prodrugs: Chemistry and spatiotemporal release

Gasotransmitters like nitric oxide, carbon monoxide, and hydrogen sulfide with unique pleiotropic pharmacological effects in mammals are an emerging therapeutic modality for different human diseases including cancer, infection, ischemia-reperfusion injuries, and inflammation; however, their clinical translation is hampered by the lack of a reliable delivery form, which delivers such gasotransmitters to the action site with precisely controlled dosage. The external stimuli-responsive prodrug strategy has shown tremendous potential in developing gasotransmitter prodrugs, which affords precise temporospatial control and better dose control compared with endogenous stimuli-sensitive prodrugs. The promising external stimuli employed for gasotransmitter activation range from photo, ultrasound, and bioorthogonal click chemistry to exogenous enzymes. Herein, we highlight the recent development of external stimuli-mediated decaging chemistry for the temporospatial delivery of gasotransmitters including nitric oxide, carbon monoxide, hydrogen sulfide and sulfur dioxide, and discuss the pros and cons of different designs.