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

Antibiotic - resistant 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 Staphylococcus aureus (MRSA). In vivo 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. Schematic illustration of the multifunctional hydrogel dressing system designed to promote wound healing in infected environments and inhibit hypertrophic scar formation through pH-responsive drug release and macrophage repolarization. • By exploiting the interaction between tannic acid and baicalein, efficient loading of baicalein has been achieved, simultaneously resolving issues related to its solubility and bioavailability. This provides valuable insights for expanding the biomedical applications of baicalein. • A multifunctional smart hydrogel was successfully prepared. This hydrogel, based on the crosslinking of phenylboronic acid-modified chitosan, tannic acid, and baicalein to form a three-dimensional network structure, not only exhibits injectability, self-healing properties, and excellent mechanical characteristics but also achieves intelligent controlled release of drugs in the acidic environment caused by bacterial infections. Ultimately, it enables targeted antibacterial action (with an MRSA kill rate exceeding 90%) and modulation of macrophage M2 polarization, overcoming the limitations of traditional dressings with single functionalities. • Based on network pharmacology and experimental validation, effective targets of baicalein in regulating skin immunity and inhibiting hypertrophic scars formation have been identified. This untangles the crucial role of the GSK3β/β-catenin signaling pathway in remodeling the immune microenvironment. • A novel synergistic approach for the treatment of hypertrophic scars utilizing antimicrobial and immunomodulatory methods has been introduced. This drug delivery system simultaneously addresses three primary clinical challenges: antibiotic-resistant bacterial infections, wound regeneration disorders, and pathological scarring. It effectively inhibits the formation of hypertrophic scars, achieving a balance between promoting tissue regeneration and anti-scarring.