Ion-paired asiatic acid hydrogel facilitates high-quality wound healing through diverse synergistic effects

High-quality wound healing is a primary clinical goal, yet it remains difficult to achieve reliably with current treatments. For this purpose, this study developed an ion-paired asiatic acid (AA) hydrogel specially for wound healing and systematically evaluated its pharmacodynamic efficacy both in vitro and in vivo. The formulation strategy involved screening organic amines as counter-ions using an ex vivo stratum corneum-removed skin model. Triethanolamine was identified as the optimal counterion, maximizing AA penetration into local tissue while minimizing systemic permeation via the formation of an ion-pair as confirmed by Nuclear Magnetic Resonance. The resulting hydrogel exhibited ideal properties for wound application, as characterized by its water vapor transmission rate, swelling ratio, degradability ratio, and water retention. In vitro , the hydrogel accelerated wound closure by stimulating cellular proliferation and migration, promoting vascular differentiation, and exhibiting selective antibacterial efficacy against S. aureus . In a rat full-thickness skin defect model, the hydrogel effectively facilitated scarless healing, which was mechanistically linked to collagen remodeling (indicated by a higher proportion of type III relative to type I collagen), suppression of TNF-α-mediated inflammation, and downregulation of TGF-β-driven fibrosis. Collectively, this work establishes a strategically designed ion-pair hydrogel system that coordinates key healing processes, offering a promising strategy for achieving reliable, high-quality wound regeneration.