Engineered Transition Metal Oxide (TMO)-Encapsulated Salmon Skin-Based Bioadhesive Hydrogel Promotes Repair, Immuneregulation, and Neovascularization in MRSA-Infected Wounds

Despite success in promoting tissue regeneration, the abundant nutrients in the decellularized extracellular matrix (dECM) are easily prone to environmental bacteria <i>in vitro</i>. Additionally, these dECM-based materials suffer from weak mechanical strength and rapid biodegradation, significantly limiting their potential for wound healing applications. To overcome these aspects, an innovative biohydrogel platform based on transition metal oxides (TMOs)-encapsulated salmon fish skin-derived dECM (FdECM) was developed to promote subsequent antibacterial activity and wound healing. The decellularization-assisted FdECM was initially grafted with photoresponsive methacrylic anhydride (MA) groups through amidation and then encapsulated with silver (Ag) nanodots-decorated manganese dioxide (MnO₂) nanoflowers (ζ value of -20 mV and size of 300 nm) to form FdECM-MA-Ag-MnO₂ (shortly denoted as Fd-AM) composites. Meanwhile, the Fd-AM demonstrated excellent adhesion, biocompatibility, and improved mechanical properties. FdECM and Ag-MnO₂ nanoparticles work synergistically to effectively reduce oxidative stress in cells and promote the formation of tube-like structures by endothelial cells. Both <i>in vitro</i> and <i>in vivo</i> studies showed that the degradation of biocompatible Fd-AM biohydrogel released Ag-MnO₂, improving the hypoxic environment via MnO₂ and significantly combating methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) through silver nanodots. The Fd-AM biohydrogel promoted the effective transformation of macrophages into M2 type, as evidenced by increased IL-10, decreased IL-6, higher CD206 (an M2 macrophage marker), and lower iNOS (an M1 macrophage marker). Additionally, these composites enhanced collagen deposition, exhibited antioxidant properties, and increased CD31 content. Overall, the TMO-encapsulated Fd-AM biohydrogel successfully delivered both antibacterial and antioxidant effects, supporting tissue regeneration (angiogenesis) in MRSA-infected wounds.