Delivered baicalein immunomodulatory hydrogel with dual properties of pH-responsive and anti-infection orchestrates pro-regenerative response of macrophages for enhanced hypertrophic scars therapy.

Antibioticresistant bacterial infections in skin wounds can cause persistent inflammatory responses, which may lead to severe hypertrophic scarring. In this study, a pH-responsive antibacterial hydrogel composed of phenylboronic acid-grafted chitosan (PBCS) and tannic acid (TA) was developed to achieve controlled and long-lasting release of baicalein (BA) to address the critical challenges of bacterial infection, wound healing, and scarring. The composite hydrogel (BA@PBCS-TA) not only demonstrates excellent injectability, self-healing properties, and robust mechanical performance but also exhibits favorable biological characteristics. Through pH-responsive release of BA, it effectively eliminates Methicillin-resistant (MRSA). experiments further confirm its ability to significantly inhibit fibroblast activation and reduce abnormal collagen deposition, effectively preventing excessive scar formation. Additionally, network pharmacology has identified Glycogen Synthase Kinase 3 Beta (GSK3β) as a key target for BA in inhibiting hypertrophic scar formation. Cellular experiments further demonstrate that the BA@PBCS-TA hydrogel can suppress GSK3β expression, activate the Wnt/β-catenin signaling pathway to repolarize macrophages into the M2 phenotype, and exhibit significant immunomodulatory effects. These results highlight the BA@PBCS-TA hydrogel's ability to harness the excellent properties of biomaterials and optimize BA's pharmacological effects, ultimately promoting wound healing and offering a strategic solution for scar reduction.