Feng Ye, Xiaofang Zhai, Mingze Xu, Bin Liu, Yanjiao Ding, Yuliang Li
Methicillin-resistant Staphylococcus aureus (MRSA) and its biofilms severely impair wound healing, necessitating therapies that integrate antibacterial activity with tissue repair functions. In this study, we developed a carrier-free injectable supramolecular hydrogel, referred to as the GB gel, through the co-assembly of two natural small molecules, glycyrrhizic acid (GA) and baicalin (BA). The principal design logic of this system lies in the cooperative integration of GA-mediated amphiphilic assembly and BA-mediated antibacterial activity: GA improves the aqueous solubility of BA, drives nanoparticle formation, and facilitates bacterial membrane adsorption and disruption, whereas BA serves as the major bactericidal component. The optimized GB gel exhibited favorable injectability, self-healing behavior, and sustained-release properties. In vitro, the GB gel showed potent anti-MRSA and antibiofilm effects, accompanied by bacterial membrane disruption, increased intracellular reactive oxygen species, and apoptosis-like responses. In a murine MRSA-infected wound model, topical GB gel application accelerated wound closure, reduced bacterial burden, alleviated inflammation, and promoted neovascularization and collagen deposition. Network pharmacology and transcriptomic analyses further suggested that GB gel treatment was associated with broad stress-responsive transcriptional reprogramming in MRSA, involving translation-related processes, central metabolic pathways, and host immune-related regulatory networks. Overall, this carrier-free GA/BA co-assembled hydrogel integrates antibacterial, anti-inflammatory, and pro-regenerative functions, offering a promising therapeutic strategy for MRSA-infected wound repair.