From Passive Cargo to Active Skeleton: A pH-Responsive Polysaccharide Hydrogel Integrating Dipotassium Glycyrrhizinate as a Dynamic Cross-Linking Node for Scarless Wound Healing

Abstract

Traditional herbal-based wound dressings are often limited by low drug-loading capacity, inadequate infection control, and passive drug delivery. Here, we address these challenges by transforming dipotassium glycyrrhizinate (DG)─a natural herbal anti-inflammatory agent─from a conventional “passive cargo” into an active structural component of a polysaccharide hydrogel network. We developed a dynamically cross-linked hydrogel (HCC-DG-Cu) by integrating DG with hyaluronic acid (HA), chitosan (CS), and carboxymethyl cellulose (CMC) via hydrogen bonding, electrostatic interactions, and dynamic Cu2+ coordination. This design paradigm shift yields three key advances: (1) ultrahigh drug loading (∼55%, ≈30% higher than conventional polysaccharide hydrogels) by incorporating DG as a network-integrated building block rather than a physically loaded additive; (2) pH-responsive release (≈95% at pH 9.0 vs ≈54% at pH 5.5) leveraging Cu2+ coordination dynamics; (3) synergistic antibacterial activity (>90% inhibition against S. aureus and E. coli) and potent anti-inflammatory effects without conventional antibiotics. In an E. coli-infected full-thickness wound model, the HCC-DG-Cu hydrogel significantly accelerated wound closure, promoted orderly collagen deposition, enhanced angiogenesis (CD31+/VEGF+), and minimized scar formation─outcomes attributed to the sustained, microenvironment-modulating release of DG from the dynamic network. This work establishes a clear structure–function–therapeutic efficacy correlation and presents a generalizable strategy to upgrade passive herbal-loaded dressings into active, multifunctional regenerative platforms.