Thermosensitive Hydrogel for Controlled Delivery of PAD4 Inhibitor YJ-2 in Diabetic Wound Healing

<b>Background</b>: Diabetic wound healing is hampered by persistent inflammation and excessive neutrophil extracellular traps (NET) formation. Peptidylarginine deiminase 4 (PAD4) is a key enzyme driving this pathology. This study developed a thermosensitive chitosan/β-glycerophosphate hydrogel for the local delivery of a novel PAD4 inhibitor, YJ-2, to promote diabetic wound repair. <b>Methods</b>: A YJ-2-loaded hydrogel (CGY) was synthesized and characterized. <i>In vitro</i> studies used HaCaT cells and macrophages to assess proliferation, migration, NETs (via H3cit), and polarization. Efficacy was evaluated in diabetic C57 mouse wound models. <b>Results</b>: CGY exhibited temperature-sensitive gelation and sustained YJ-2 release. <i>In vitro</i>, YJ-2 inhibited NETs formation, reduced pro-inflammatory markers, promoted HaCaT migration, and induced M2 macrophage polarization. <i>In vivo</i>, CGY treatment significantly accelerated wound closure. <b>Conclusions</b>: Local hydrogel delivery of the PAD4 inhibitor YJ-2 effectively mitigates inflammation and NETs, promoting healing in diabetic wounds. This strategy represents a promising targeted therapy for diabetic wounds.