An Innovative Sprayable Mg-MOF Hydrogel Enhances Healing of Chronic Wounds with Multifaceted Pathologies in a Porcine Model

Chronic wounds are characterized by unsatisfactory clinical outcomes due to persistent inflammation, excessive oxidative stress, and impaired neurovascular function, which conventional dressings cannot adequately address. This study presents a promising strategy for sequentially reversing these multifactorial wound conditions. We engineered a sprayable Mg-ZIF-8@TP@Alg hydrogel by integrating a Mg-Zn bimetallic metal-organic framework (Mg-ZIF-8) with tea polyphenol (TP), achieving differential release and pH-responsive therapeutic kinetics. In vitro assays demonstrated that Mg-ZIF-8@TP exerted synergistic ROS-scavenging activity, promoted M2 macrophage polarization, and enhanced angiogenic and neurogenic outcomes. These effects are attributed to TP-mediated attenuation of oxidative stress, together with activation of Mg2+/Zn2+-driven cellular behaviors. In a clinically relevant porcine model, the Mg-ZIF-8@TP@Alg hydrogel significantly accelerated wound healing. It sequentially remodelled the immune microenvironment by decreasing pro-inflammatory iNOS+ cells and increasing reparative CD163+ macrophages. Moreover, it enhanced CD31+ vascular neogenesis and β3-tubulin+ peripheral nerve regeneration. Transcriptomic analysis revealed that the hydrogel orchestrated chronic wound repair by modulating key pathways associated with ion transport, immune response suppression, and skin development. Overall, this work presents an innovative sprayable Mg-MOF hydrogel with synergistic, stage-specific therapeutic functionality, offering a potential strategy for chronic wound management.