On-demand therapeutic delivery of hydrogen sulfide aided by biomolecules

Hydrogen sulfide (H₂S), known as the third gasotransmitter, exerts various physiological functions including cardiac protection, angiogenesis, anti-inflammatory, and anti-cancer capability. Given its promising therapeutic potential as well as severe perniciousness if improper use, the sustained and tunable H₂S delivery systems are highly required for H₂S-based gas therapy with enhanced bioactivity and reduced side effects. To this end, a series of stimuli-responsive compounds capable of releasing H₂S (termed H₂S donors) have been designed over the past two decades to mimic the endogenous generation of H₂S and elucidate the biological functions. Further to improve the stability of H₂S donors and achieve the targeted delivery, various delivery systems have been constructed. In this review, we focus on the recent advances of an emerging subset, biomolecular-based H₂S delivery systems, which combine H₂S donors with biomolecular vectors including polysaccharide, peptide, and protein. We demonstrated their basic structures, building strategies, and therapeutic applications respectively to unfold their inherent merits endued by biomolecules including biocompatibility, biodegradability as well as expansibility. The varied development potentials of biomolecular-based H₂S delivery systems based on their specific properties are also discussed. At the end, brief future outlooks and upcoming challenges are presented as well.