Photoactivatable hydrogen sulfide donors for visualizing H₂S controlled release in accelerated chronic wound healing

Hydrogen sulfide (H₂S) is a pivotal endogenous gaseous signalling molecule involved in various physiological processes. Although H₂S exhibits significant anti-inflammatory effects at physiological concentrations, its clinical utility is hindered by the challenges associated with its high activity and difficulties in controlled release. We designed three photoactivatable H₂S donors, HSDs (HSD1, HSD2, and HSD3), by integrating an H₂S-releasing 1,4,2-dioxazole-5-thione scaffold with three fluorophores spanning the ultraviolet to red spectral range. Upon photo-irradiation, each donor induces a pronounced turn-on fluorescence (>58-fold), accompanied by efficient H₂S release (over 30 %) without the formation of electrophilic by-products. Moreover, HSDs enable real-time quantitatively photo-triggered H₂S-release in both live cells and murine models, and present anti-inflammatory and antioxidant effects in vivo. In a full-thickness cutaneous wound model, HSDs markedly accelerated wound healing, highlighting their potential as precision therapeutic agents for wound management. Collectively, we provide a translatable strategy to overcome the limitations of conventional H₂S delivery systems and highlight the therapeutic promise of controlled H₂S release in clinical application.