Abstract
Chronic wound healing remains clinically challenging due to insufficient angiogenesis coupled with persistent inflammatory microenvironments. Macrophage M2 polarization plays a pivotal role in resolving inflammation and promoting angiogenesis. Capitalizing on scalability and translational advantages, extracellular vesicles derived from Lactobacillus bulgaricus (Lac-EVs) were employed to activate this mechanism. The anti-inflammatory and pro-angiogenic efficacy of Lac-EVs was initially confirmed through in vitro experiments. To support their delivery and function within the hostile diabetic wound microenvironment, a chitosan (CS)-based hydrogel incorporating haemoglobin (Hb)-polydopamine (PDA) complexes was engineered via Schiff base crosslinking with aldehyde-functionalised polyethylene glycol (CHO-PEG-CHO). This platform enabled stable delivery of Lac-EVs, supplemental oxygen release, and NIR-triggered photothermal functionality. In vitro studies demonstrated that the Lac-EVs-laden hydrogel (PCPH@Lac-EVs) effectively induced M2 macrophage polarization, enhanced endothelial cell migration, and promoted angiogenesis. In murine full-thickness diabetic wounds, PCPH@Lac-EVs combined with NIR irradiation achieved 99.3 % wound closure within 13 days, significantly outperforming untreated controls (72.3 %). Mechanistic analysis indicated that the accelerated healing resulted from synergistic enhancement of Lac-EV-mediated inflammation modulation and functional angiogenesis via oxygen release and mild photothermal stimulation. This study highlights the potential of Lac-EVs, delivered via a functional hydrogel, as a promising therapeutic strategy for diabetic wound treatment.