Advances in nitric oxide donors for myocardial protection: From traditional molecules to smart responsive delivery...

Nitric oxide (NO) is a key regulator of cardiovascular homeostasis, and reduced endogenous NO bioavailability contributes to endothelial dysfunction, myocardial injury, inflammation, and adverse cardiac remodeling. Although conventional NO donors have established the therapeutic value of exogenous nitrogen oxide delivery, their clinical application remains limited by systemic vasodilation, the development of tolerance, insufficient tissue selectivity, and inadequate control over release profiles. This review systematically examines the historical and chemical evolution of nitrogen oxide donors, ranging from classical organic nitrates and sodium nitroprusside to S-nitrosothiols, sydnonimines, diazeniumdiolates (NONOates), furoxans, metal nitrosyl complexes, and nitroxyl (HNO) donors, and further extends to contemporary stimuli-responsive delivery systems. Particular emphasis is placed on current cardioprotective strategies, including pharmacophore-NO hybrids, NO/H₂S co-delivery systems, hypoxia- and enzyme-activated prodrugs, bioorthogonal enzyme-prodrug systems, hydrogels, nanocarriers, nanomotors, and implantable biomaterials. The structural design, release mechanisms, biological activities, and major limitations of these systems are critically discussed, with the aim of providing guidance and inspiration for the development of more advanced and clinically relevant therapeutic strategies.