Microenvironment-Responsive Xanthotoxol–Copper Nanozyme for MRSA-Infected Wound Healing

Methicillin-resistant <i>Staphylococcus aureus</i> (<i>MRSA</i>) infections, oxidative stress, and excessive inflammation present significant challenges for wound healing. The natural product xanthotoxol (XT) demonstrates strong antibacterial and anti-inflammatory properties; however, its therapeutic efficacy is limited by poor water solubility. To address this limitation, we have modified XT using polyethylenimine (PEI) to enhance its solubility and have developed a Cu-based composite material, XT-PEI-Cu, which possesses glutathione lyase (GSH-X)-like activity and is specifically designed to respond to the wound microenvironment. During the initial bacterial infection phase, the acidic wound microenvironment activates the glutathione lyase (GSH-X)-like activity of XT-PEI-Cu, significantly depleting bacterial intracellular glutathione (GSH) to achieve potent antibacterial efficacy. As healing progresses to the remodeling phase, the neutralized microenvironment triggers a functional shift, where XT-PEI-Cu scavenges excess reactive oxygen species (ROS) efficiency, polarizes macrophages toward an anti-inflammatory phenotype, reduces the secretion of inflammatory cytokines, and promotes angiogenesis and collagen deposition, thereby facilitating the healing of infected wounds. This study presents a strategy for enhancing the use of natural products in the treatment of <i>MRSA</i>-related wound healing.