STAT3-Mediated wound repair Enabled by a Carrier-Free GA/GLA@Zn supramolecular hydrogel for treating MRSA-Infected skin wounds

• A carrier-free supramolecular hydrogel is developed for infected wound healing. • GA/GLA@Zn exhibits potent anti-MRSA, anti-inflammatory and antioxidant activities. • STAT3 is a key molecular target validated by simulations and in vivo assays. • GA/GLA@Zn accelerates angiogenesis and tissue regeneration via the STAT3 axis. Drug-resistant bacterial infection severely impedes skin wound healing, highlighting the urgent need for effective non-antibiotic therapies. Herein, we develop a carrier-free injectable supramolecular hydrogel (GA-GLA@Zn) through the co-assembly of gallic acid (GA) and glycyrrhizic acid (GLA) reinforced by Zn 2+ coordination. The hydrogel exhibits excellent injectability, mechanical stability, and sustained Zn 2+ release, providing a functional platform for infected wound treatment. GA-GLA@Zn shows potent antibacterial and antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) by disrupting bacterial membranes, while maintaining favorable biocompatibility and blood compatibility. In vitro studies demonstrate effective reactive oxygen species scavenging, suppression of inflammatory responses, and promotion of fibroblast proliferation and migration. In a MRSA-infected full-thickness wound model, GA-GLA@Zn markedly accelerates wound closure, reduces bacterial burden, alleviates excessive inflammation, and enhances collagen deposition and tissue remodeling. Mechanistically, integrated network pharmacology and molecular simulations identify signal transducer and activator of transcription 3 (STAT3) as a key molecular target of GA and GLA. In vivo results further reveal activation of STAT3 signaling and its downstream effectors Cyclin D1 and SOCS3, accompanied by enhanced angiogenesis via the HIF-1α/VEGF pathway. Overall, this study elucidates a STAT3-centered mechanism and highlights GA-GLA@Zn as a promising antibiotic-free strategy for treating drug-resistant infected wounds.