A Core–Shell Nanotherapeutic Platform Reprograms the Infected Wound Microenvironment through Dual Bactericidal and Immunomodulatory Actions for Accelerated Healing

Abstract The treatment of wounds caused by drug-resistant bacteria is a significant challenge in clinical medicine. Silver (Ag) nanoparticles have attracted considerable attention due to their ability to inhibit drug-resistant bacteria. Nevertheless, the propensity of Ag nanoparticles to aggregate as well as their elevated toxicity have restricted their practical application. To address this issue, this study involved the design of a core–shell-type ZnO@ZIF-8/Ag nanocomposite material that combines high antibacterial activity with excellent biocompatibility. The mean diameter of the Ag nanoparticles in this material was approximately 2.4 nm, and they were highly dispersed. Within the wound microenvironment, antibacterial factors, such as hydroxyl radicals (·OH), singlet oxygen (1O2), Zn2+, and Ag+, were generated. The material induced bacterial death by altering the structure of the cell wall of drug-resistant bacteria, thereby inhibiting respiration, lysing phospholipid layers, and causing cellular content leakage. The introduction of zinc oxide (ZnO) significantly reduced the toxicity of the Ag nanoparticles and regulated macrophage polarization, which inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by M1-type macrophages (M1) while concomitantly promoting the secretion of interleukin-10 (IL-10) and vascular endothelial growth factor by M2-type macrophages (M2). The expression of platelet-endothelial cell adhesion molecule-1 (CD31), type I collagen/fibronectin (COL-I/FN), and proliferating cell nuclear antigen (PCNA) was significantly promoted, which significantly enhanced wound healing in infected wounds. This study thus offers a strategy for developing therapies against drug-resistant bacterial infections with the potential for clinical application.