Intelligent sulfur-based delivery systems for controlled hydrogen sulfide therapeutics: Progress and prospects

Hydrogen sulfide (H₂S) is a critical signaling molecule in the gasotransmitter family, with sulfur-based intelligent delivery systems playing a pivotal role in advancing H₂S gas therapy. While the current therapeutic arsenal of these delivery platforms shows great potential in neuromodulation, gastrointestinal control, and cardiovascular regulation, conventional releasing agents are often hindered by premature burst release and insufficient spatiotemporal targeting. With the objective to improve therapeutic outcomes, researchers are developing intelligent sulfur-based delivery systems designed for the stimuli-responsive and regulated release of H₂S. This will enable exact distribution and optimized release kinetics. In this review, a mechanism-based analysis of structure-function relationships and chemical synthesis strategies uniquely integrates across platforms such as MOFs, exosomes, and hydrogels. Based on these insights, we propose a strategic design roadmap that incorporates prospective, AI-assisted perspectives to guide the future transition from molecular engineering to clinical application. Furthermore, it also critically assesses the translational relevance, including pharmacokinetics/pharmacodynamics (PK/PD) considerations and regulatory hurdles, in creating these advanced systems for controlled H₂S release. These analyses provide a strategic foundation for the selection and design of appropriate hydrogen sulfide-releasing agents, thus providing an emerging platform for clinical translation.