Architectural modulation of polymeric hydrogen sulfide donors: Structure-responsive materials for controlled therapeutics.

Hydrogen sulfide (H2S), once regarded merely as a malodorous and toxic gas, has emerged as a vital endogenous signaling molecule with multifaceted physiological roles, encompassing neuromodulation, vasorelaxation, cytoprotection, and the regulation of inflammatory responses. Despite this growing recognition of its biological significance, the therapeutic translation of H2S remains impeded by its physicochemical limitations as volatility, poor aqueous solubility, and rapid metabolic clearance. Addressing these challenges has stimulated the development of polymeric hydrogen sulfide (H2S) donors engineered macromolecular systems capable of releasing H2S in a temporally and spatially controlled manner. These structure-responsive materials offer a powerful platform wherein molecular architecture, donor chemistry, and supramolecular organization can be finely tuned to regulate release kinetics and responsiveness to physiological stimuli such as pH variations, redox gradients, and reactive oxygen species (ROS). This review consolidates recent advances in the design and application of polymeric and macromolecular H2S donors, emphasizing the mechanistic relationships between structural parameters polymer topology, donor incorporation strategy, linker chemistry, hydrophilicity, and crosslinking density and their resultant release behaviors. Furthermore, it highlights the expanding biomedical landscape of these materials, discussing their therapeutic potential, translational challenges, and emerging strategies for precision engineering. By bridging molecular-level design with macroscopic functionality, this review aims to inform the rational development of next-generation polymeric H2S donors that enable finely controlled spatiotemporal delivery and enhanced therapeutic efficacy.