Immune-instructive baicalin-loaded nanofibrous membranes regulate macrophage polarization via PI3K/AKT/GSK3β signaling for enhanced cutaneous wound healing.

Chronic cutaneous wounds remain a major clinical challenge due to a persistent pro-inflammatory microenvironment characterized by unresolved inflammation and dysregulated macrophage polarization. Emerging "immune-instructive" biomaterials offer a promising strategy to actively modulate host immune responses rather than providing mere structural support. In this study, we performed a comparative screening of representative traditional Chinese medicine (TCM)-derived monomers, identifying baicalin (BAL) as the most potent regulator of macrophage polarization. To ensure localized and sustained bioactivity, BAL was encapsulated into mesoporous silica nanoparticles (MSNs) and subsequently integrated into electrospun poly(ε-caprolactone)/silk fibroin (PCL/SF) nanofibrous membranes to construct a hierarchical bioactive system (BA@MSN/PCL/SF). Mechanistic investigations combining network pharmacology, molecular docking, and pharmacological inhibition revealed that BAL directs macrophage polarization toward a pro-regenerative M2 phenotype via the PI3K/AKT/GSK3β signaling axis. In vitro, the composite membranes exhibited excellent cytocompatibility and effectively modulated inflammatory responses. In a murine full-thickness wound model, BA@MSN/PCL/SF membranes significantly accelerated wound closure, enhanced granulation tissue formation, and promoted high-quality collagen deposition and skin appendage regeneration. These therapeutic effects correlated with a pronounced shift in the local immune microenvironment, evidenced by increased ARG1+ and decreased iNOS+ macrophage populations. Our findings demonstrate that integrating potent natural immunomodulators with controlled-release hierarchical scaffolds provides a sophisticated strategy for engineering immune-instructive wound dressings, offering a mechanistic basis for modernizing traditional therapies in regenerative medicine.