Exosome-loaded hydrogel promotes tissue repair in Staphylococcus aureus-infected cutaneous wounds: Histological and immunohistochemical evidence of enhanced regeneration.

Skin wound infections caused by Staphylococcus aureus remain a major clinical challenge because persistent bacterial contamination and excessive inflammation impair tissue repair. This study investigated the therapeutic efficacy of mesenchymal stem cell (MSC)-derived exosome-loaded hydrogel (Exo-HG) compared with hydrogel alone (HG) in a rat model of S. aureus-infected full-thickness skin wounds, with particular emphasis on histopathological regeneration and immunohistochemical markers of tissue repair. Eighty adult male Wistar rats were randomly assigned to four groups: healthy control, infected untreated, infected treated with HG, and infected treated with Exo-HG. Histopathological assessment focused on inflammatory infiltration, re-epithelialization, collagen organization, granulation tissue formation, and neovascularization, while immunohistochemistry evaluated epidermal growth factor receptor (EGFR) and α-smooth muscle actin (α-SMA) expression. Macroscopic wound healing, bacterial burden, oxidative stress (MDA and NO), antioxidant status (GSH, SOD, and CAT), and inflammatory cytokines (TNF-α and IL-6) were additionally assessed. S. aureus infection markedly impaired tissue repair, with persistent inflammation, delayed re-epithelialization, disorganized collagen, and limited neovascularization, accompanied by increased bacterial burden, oxidative stress, and inflammatory cytokines. HG produced partial improvement, whereas Exo-HG resulted in significantly greater histopathological healing than HG at days 14 and 21, with improved re-epithelialization, collagen organization, granulation tissue, and neovascularization. Exo-HG also produced temporally coordinated EGFR and α-SMA immunoreactivity, accelerated wound closure, reduced bacterial counts, restored antioxidant defenses, and decreased MDA, NO, TNF-α, and IL-6. In conclusion, MSC-derived Exo-HG enhanced structural regeneration beyond HG alone, accompanied by favorable antimicrobial, antioxidant, and anti-inflammatory changes. These findings support further investigation of Exo-HG for infected cutaneous wound repair.