Modulating burn wound immunity and vasculature with a photo-crosslinkable glycyrrhizic acid–ginsenoside hydrogel

Abstract Burn injuries create a complex wound microenvironment characterized by a persistent cytokine storm that locks macrophages in a pro-inflammatory (M1) phenotype, while thermally damaged vasculature fails to regenerate, leading to prolonged inflammation and impaired healing. These dual obstacles persist as critical challenges in clinical burn management. Natural bioactive compounds, with their inherent multi-target capabilities and excellent biocompatibility, offer promising therapeutic potential to address these intertwined pathological processes. Here, we engineer an injectable, photo-crosslinkable hydrogel that integrates three natural components-gelatin methacryloyl (GM) as a biocompatible backbone, glycyrrhizic acid (GA) for anti-inflammation, and ginsenoside Rg1 for synergistic immunomodulation and pro-angiogenic signaling, termed GM-GA-Rg1. Upon UV curing, the GM-GA-Rg1 hydrogel instantly conforms to wound geometry, absorbs exudate, and sustains the co-delivery of GA and Rg1. In vitro , the hydrogel effectively shifts macrophages from M1 to M2 phenotype (marked by decreased inducible nitric-oxide synthase and increased CD206 expression), and significantly enhances human umbilical vein endothelial cell migration, with upregulated CD31 and vascular endothelial growth factor. This single-platform strategy simultaneously quells inflammation, promotes neovascularization, and provides a physical barrier, offering a low-cost, translatable dressing that addresses the immune and vascular bottlenecks of burn wound healing.