Ferroptosis-Mediated Synergistic Therapy of Hypertrophic Scarring Based on Metal-Organic Framework Microneedle Patch

Hypertrophic scarring, an abnormal fibroproliferative wound-healing disease, has brought tremendous burden for global healthcare systems. To date, no satisfactory treatment of hypertrophic scarring is available yet. Ferroptosis, an iron-dependent form of cell death, has attracted much attention recently for the therapy of diseases featuring iron addiction. Intriguingly, myofibroblasts derived from hypertrophic scarring are found to exhibit a high iron state which appears to be sensitive to trigger ferroptosis for scarring treatment. Accordingly, in this study, a pH responsive self-assembly nanoplatform is designed by encapsulating silver nanoclusters (AgNCs) and Chinese herbal medicine trigonelline (TRG) into zeolitic imidazolate framework-8 (ZIF-8) for synergistic ferroptosis therapy against hypertrophic scarring. The fabricated AgNC/TRG/ZIF-8 composites exhibit good biocompatibility and pH responsive-degradation inside myofibroblasts. The ZIF-8 precursors can increase the generation of lipid reactive oxygen species and deplete intracellular glutathione (GSH). Also, AgNCs have the capability to consume GSH, while TRG can inhibit the activity of glutathione peroxidase. Consequently, the synergistic ferroptosis anti-scarring therapy can be effectively achieved. Furthermore, AgNC/TRG/ZIF-8-loaded microneedle patches made of gelatin methacrylate show remarkable therapeutic effect against hypertrophic scarring on a rabbit ear model. This study suggests the great potential of ferroptosis-mediated strategy for treating fibrotic skin diseases in future clinical application.