<i>Lactobacillus</i> extracellular vesicle-driven oxygen-releasing photothermal hydrogel reprograms macrophages and promotes angiogenesis to accelerate diabetic wound healing.

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 <i>Lactobacillus bulgaricus</i> (<i>Lac</i>-EVs) were employed to activate this mechanism. The anti-inflammatory and pro-angiogenic efficacy of <i>Lac</i>-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 <i>Lac</i>-EVs, supplemental oxygen release, and NIR-triggered photothermal functionality. In vitro studies demonstrated that the <i>Lac</i>-EVs-laden hydrogel (PCPH@<i>Lac</i>-EVs) effectively induced M2 macrophage polarization, enhanced endothelial cell migration, and promoted angiogenesis. In murine full-thickness diabetic wounds, PCPH@<i>Lac</i>-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 <i>Lac</i>-EV-mediated inflammation modulation and functional angiogenesis via oxygen release and mild photothermal stimulation. This study highlights the potential of <i>Lac</i>-EVs, delivered via a functional hydrogel, as a promising therapeutic strategy for diabetic wound treatment.