A fluorescent hydrogen sulfide donor featuring hydroxyl radical responsiveness promotes diabetic wound healing through the regulation of macrophage polarization.

Hydroxyl radicals are among the most reactive and destructive reactive oxygen species, capable of inducing severe oxidative damage to critical biomolecules-including proteins, DNA, and lipids-thereby contributing to cellular dysfunction, senescence, apoptosis, and the pathogenesis of numerous diseases. In contrast, hydrogen sulfide (H2S) has emerged as a key endogenous signaling molecule with well-documented antioxidant, anti-inflammatory, and tissue-repair properties, prompting growing interest in its therapeutic applications. This study developed a novel hydroxyl radical-responsive hydrogen sulfide donor (HSD-FA-OH), which can release carbonyl sulfide (COS) in environments with elevated hydroxyl radical levels. The COS is rapidly converted by intracellular carbonic anhydrase to release hydrogen sulfide, thereby achieving targeted physiological modulation. Accumulating evidence indicates that H2S exerts anti-inflammatory effects through the regulation of macrophage polarization. To enhance specificity and minimize off-target toxicity, we incorporated a folic acid moiety into the donor system, facilitating selective recognition and uptake by macrophages via folate receptor-mediated endocytosis. In a diabetic wound healing model, treatment with this donor significantly promoted M2 macrophage polarization, suppressed M1 polarization, enhanced collagen deposition and neovascularization, and accelerated wound closure. These findings demonstrate the therapeutic potential of redox-responsive, macrophage-targeted H2S donors and provide a rational strategy for the precise modulation of inflammatory microenvironments.