Bridging traditional Chinese medicine theory with advanced MOFs delivery for synergistic drug-resistant infected-chronic wound therapy.

Chronic wounds infected with multidrug-resistant bacteria pose a significant challenge to global health, as traditional monotherapies often fail to eradicate pathogens and restore the damaged wound microenvironment. Engineering innovative nanocomposites that integrate synergistic therapeutics and controlled release is a pivotal strategy for advanced wound management. Here, we developed a novel multi-drug metal-organic framework (MOF) nanocomposite, BBR + FA@UiO, by covalently grafting ferulic acid (FA) onto UiO-66-NH2 and physically loading berberine (BBR). Drawing from "Jun-Chen-Zuo-[Shi]" hierarchy of Traditional Chinese Medicine (TCM), this design used the MOF as a robust porous carrier "[Shi]" for the antibacterial drug "Jun" (BBR) and antioxidant drug "Chen/Zuo" (FA). BBR + FA@UiO exhibits potent, synergistic antibacterial and antibiofilm activity against critical clinical pathogens like MRSA and Pseudomonas aeruginosa, through a pH/ROS-responsive release mechanism in the infected site. Functionally, BBR + FA@UiO activates the Nrf2/Keap1 pathway in macrophages, thereby mitigating oxidative stress and enhancing mitochondrial function. Consequently, proliferation and migration of Human Umbilical Vein Endothelial Cells (HUVECs) are restored through promoting angiogenesis. In vivo, BBR + FA@UiO significantly accelerates healing by eradicating bacteria, enhancing collagen deposition, and improving vascularization, driven by the coordinated activation of the Nrf2/HO-1 antioxidant axis and pro-regenerative Wnt/β-catenin and TGF-β signaling pathways. Demonstrating excellent biocompatibility and no systemic toxicity, this work establishes BBR + FA@UiO as a new therapeutic approach that merges TCM with advanced MOFs for comprehensive wound care.