Controlled release of berberine modulates the wound microbiome to accelerate wound healing

The wound microbiome has been shown to play a significant role in influencing the wound healing process. Coptis chinensis, a traditional Chinese medicine (TCM) known for its heat-clearing properties, contains berberine (BER) as major active ingredient, which exhibits notable antibacterial activity. In this study, we investigated the effect of BER on wound healing and wound microbiome through three distinct delivery strategies, including solution form, burst-release scaffolds (PCL/BER), and sustained-release scaffolds (PCL/PLGA/BER), compared with an untreated negative control (NC) group. Drug release studies confirmed that PCL/BER caused a pronounced burst release, while the incorporation of PLGA enabled sustained release of BER for up to 120 h. Further in vivo studies showed that the sustained BER release from the PCL/PLGA/BER resulted in the most effective improvement in wound healing. Microbiome analysis using 16S rRNA sequencing identified Staphylococcus xylosus (S. xylosus) as the key species influencing wound healing outcomes in response to BER delivery. S. xylosus overabundance in the NC group and its depletion in the BER solution and burst BER release groups impaired wound healing. In contrast, sustained BER delivery maintained an optimal S. xylosus abundance that promoted a favorable immune microenvironment by modulating CXCL10 and (IFN-α) expression. Our findings emphasize the importance of coordinating drug release kinetics with microbiome dynamics for optimal wound healing outcomes and provide valuable insights for developing future delivery systems for heat-clearing TCMs, with a focus on microbiome-modulation therapeutic strategies.