H2S-releasing versatile hydrogel dressing with potent antimicrobial, anti-inflammatory, epithelialization and angiogenic capabilities for diabetic wound healing

•A novel H2S-releasing versatile hydrogel was developed.•DATS@PFC&CMC has good injectability, tissue adhesion, and self-healing.•PHMG and DATS confer DATS@PFC&CMC excellent antimicrobial effects.•H2S inhibits p-ERK and p-STAT3 expression and promotes M2 macrophage polarization.•H2S promotes re-epithelialization and angiogenesis of endothelial cells. Smart hydrogel dressings capable of simultaneously highly effective antimicrobial, anti-inflammatory, and promoting re-epithelialization and angiogenesis are urgently needed for the management of diabetic wounds. Herein, a H2S-releasing multifunctional hydrogel was developed by utilizing the dynamic Schiff base reaction between carboxymethyl chitosan (CMC) and polyhexamethylene guanidine (PHMG)-modified aldehyde F108 (PFC). Diallyl trisulfide (DATS) was encapsulated into the PFC nanoparticles. Apart from possessing the essential properties necessary for an idealized hydrogel dressing, such as excellent injectability, tissue adhesion, self-healing, and stimulus–response degradation, the DATS@PFC&CMC also utilized the synergistic effect of the PHMG and DATS to provide an efficient antimicrobial effect; the H2S was slowly released from the DATS under the action of GSH and exerted excellent anti-inflammatory effects, by inhibiting the expression of p-ERK and p-STAT3 in activated macrophages, and promoting macrophage polarization to the M2 phenotype. Strikingly, following the completion of the efficient antimicrobial and anti-inflammatory effects, the continuously generated H2S further significantly accelerated the proliferation, migration, and vascularization of endothelial cells by extending the activation of the p-p38 and p-ERK1/2. Owing to superior performances, DATS@PFC&CMC significantly promoted the healing of diabetic wounds induced by streptozotocin with good biocompatibility. This study demonstrates that DATS@PFC&CMC is a versatile hydrogel dressing with great potential for the management of diabetic wounds.