Biocompatible metal–organic frameworks for the storage and therapeutic delivery of hydrogen sulfide

Hydrogen sulfide (H(2)S) is an endogenous gasotransmitter with potential therapeutic value for treating a range of disorders, such as ischemia-reperfusion injury resulting from a myocardial infarction or stroke. However, the medicinal delivery of H(2)S is hindered by its corrosive and toxic nature. In addition, small molecule H(2)S donors often generate other reactive and sulfur-containing species upon H(2)S release, leading to unwanted side effects. Here, we demonstrate that H(2)S release from biocompatible porous solids, namely metal–organic frameworks (MOFs), is a promising alternative strategy for H(2)S delivery under physiologically relevant conditions. In particular, through gas adsorption measurements and density functional theory calculations we establish that H(2)S binds strongly and reversibly within the tetrahedral pockets of the fumaric acid-derived framework MOF-801 and the mesaconic acid-derived framework Zr-mes, as well as the new itaconic acid-derived framework CORN-MOF-2. These features make all three frameworks among the best materials identified to date for the capture, storage, and delivery of H(2)S. In addition, these frameworks are non-toxic to HeLa cells and capable of releasing H(2)S under aqueous conditions, as confirmed by fluorescence assays. Last, a cellular ischemia-reperfusion injury model using H9c2 rat cardiomyoblast cells corroborates that H(2)S-loaded MOF-801 is capable of mitigating hypoxia-reoxygenation injury, likely due to the release of H(2)S. Overall, our findings suggest that H(2)S-loaded MOFs represent a new family of easily-handled solid sources of H(2)S that merit further investigation as therapeutic agents. In addition, our findings add Zr-mes and CORN-MOF-2 to the growing lexicon of biocompatible MOFs suitable for drug delivery.