Pomegranate Peel Extracellular Vesicle-Incorporated GelMA Hydrogel Targets <i>Staphylococcus aureus</i> Infection and Accelerates Wound Healing

Infectious wound healing remains a significant medical challenge due to <i>Staphylococcus aureus</i> (<i>S. aureus</i>) colonization. The development of nano-Chinese herbal medicines has provided new approaches for the application of nanomedicines. Extracellular vesicles (EVs) play an important role as mediators of bacterial communication. However, the roles of Chinese herbal medicine-derived EV in <i>S. aureus</i> physiology and ecology have not been characterized. Furthermore, developing effective CHM-EV-based therapies for managing bacteria-infected wounds remains challenging. In this study, we found that <i>S. aureus</i> was specifically killed by EV derived from the traditional Chinese medicine pomegranate peel (PTP-EV). Furthermore, PTP-EV was taken up into <i>S. aureus</i> and could alter the expression of approximately 46.53% of all genes in the <i>S. aureus</i> genome, influencing diverse functions such as replication, division, and metabolism. Notably, PTP-EV downregulated the genes of key virulence factors, including <i>saeS</i>, <i>saeR</i>, and <i>psmB</i>. Incorporating PTP-EV into the GelMA (PEV-GM) hydrogel effectively promoted sustained slow release of EV. Furthermore, the PEV-GM hydrogel demonstrated strong antibacterial activity against <i>S. aureus</i>, thereby accelerating the wound healing process. Our findings offer information about the physiological and ecological significance of PEV-GM-bacterial interactions and the therapeutic potential of PEV-GM hydrogel as a promising and biocompatible dressing for managing biofilm-associated chronic wounds.