Adhesive cationic hyaluronic acid loading with small extracellular vesicles from IL-6 activated mesenchymal stem cells improves repair of corrosive esophageal injury.

The treatment of corrosive esophageal injury (CEI) remains challenging due to recurrent courses, frequent complications, and severe tissue damage. Enhancing the therapeutic potential of mesenchymal stem cell-derived small extracellular vesicles (sEVs) through cytokine preconditioning has emerged as a promising strategy. In this study, functionally enhanced sEVs (E-sEVs) were generated by pretreating umbilical cord-derived mesenchymal stem cells with interleukin-6 (IL-6). E-sEVs exhibited superior capabilities in promoting fibroblast migration and suppressing macrophage-mediated inflammation compared to naïve sEVs. To improve local retention and therapeutic efficacy, E-sEVs were integrated into a cationic hyaluronic acid (CHA) hydrogel with strong bioadhesive properties, forming a composite system termed E-sEVs@CHA. In vitro assays demonstrated that E-sEVs@CHA effectively promoted endothelial cell invasion, exhibited antioxidant activity, and modulated macrophage polarization toward an anti-inflammatory phenotype. In a rat model of CEI, E-sEVs@CHA significantly reduced esophageal inflammation, oxidative stress, and fibrotic remodeling, leading to improved tissue repair and reduced stricture formation. This study presents a novel cell-free therapeutic strategy with translational potential for the management of corrosive esophageal injury.