A Multifunctional Ginseng Polysaccharide Hydrogel Loaded With Rg3 Microspheres Enhances Wound Healing via Antioxidant, Antibacterial, and Microbiota‐Modulating Effects

ABSTRACT Wound healing is a complex physiological process involving inflammation, tissue regeneration, and remodeling. Designing wound dressings that integrate antioxidant, antibacterial, and hemostatic functions while promoting tissue repair remains a significant challenge. In this study, a multifunctional hydrogel (Rg3@HMS‐Gel) was developed by embedding Rg3‐loaded gelatin microspheres into a dynamic Schiff base‐cross‐linked hydrogel composed of oxidized ginseng polysaccharide (OGSP) and carboxymethyl chitosan (CMCS). The physicochemical properties, drug release behavior, biocompatibility, and therapeutic performance of the hydrogel were systematically evaluated through in vitro and in vivo experiments. The Rg3@HMS‐Gel demonstrated excellent injectability, self‐healing ability, and sustained Rg3 release. It exhibited potent antioxidant and antibacterial activity, promoted HaCaT cell proliferation and migration, and significantly accelerated wound healing in a full‐thickness mouse skin defect model. Histological analyses revealed enhanced collagen deposition, reepithelialization, and upregulation of VEGF‐A and TGF‐β1. Moreover, 16S rRNA sequencing and LEfSe analysis showed that the hydrogel modulated the skin microbiota by increasing beneficial genera (e.g., Lactobacillus ) and reducing pro‐inflammatory taxa (e.g., Sphingomonas ). The Rg3@HMS‐Gel hydrogel effectively integrates therapeutic delivery, tissue regeneration, and microbiota modulation, offering a promising strategy for advanced wound management. In conclusion, this work provides new insights into the design of bioactive, multifunctional wound dressings with synergistic healing mechanisms.