A SIRT1-stabilizing nanofibrous platform via suppression of ubiquitination for enhanced diabetic wound healing: synergistic therapy with saracatinib and MOF-818.

Chronic diabetic wounds, characterized by persistent oxidative stress, dysregulated inflammation, impaired angiogenesis, and susceptibility to bacterial infection, present a significant clinical challenge due to delayed tissue repair. This study reports the development of a multifunctional nanofibrous dressing, termed P-GMOF-818@Sec, engineered by incorporating saracatinib (Sec)-loaded MOF-818 into an electrospun gelatin/polycaprolactone (P-G) membrane. The P-G nanofibrous matrix provides essential wound adhesion, local retention, and mechanical support. MOF-818 confers reactive oxygen species (ROS)-responsive degradation, nanozyme-mimetic ROS scavenging capabilities, and intrinsic antibacterial activity. The platform exhibited H2O2 concentration-dependent release of Sec, confirming its pathophysiology-guided responsiveness to the diabetic wound microenvironment. The released Sec inhibited Fyn kinase-mediated ubiquitination of SIRT1, thereby stabilizing SIRT1 protein levels and activating the downstream SIRT1/FOXO3a/SOD2 antioxidant pathway. In vitro, P-GMOF-818@Sec effectively reduced intracellular ROS, protected endothelial cells, fibroblasts, and keratinocytes from oxidative injury, and promoted cell migration, proliferation, and VEGF secretion. The dressing demonstrated broad-spectrum antibacterial activity against both antibiotic-sensitive and drug-resistant strains, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Escherichia coli (MDR E. coli). In a diabetic rat wound model, P-GMOF-818@Sec significantly accelerated wound closure, enhancing angiogenesis, collagen deposition, re-epithelialization, and facilitating a shift from M1 to M2 macrophage polarization. Comprehensive evaluations of mechanical properties, Cu/Zr biodistribution, and serum biochemistry supported the structural applicability and favorable preliminary biosafety of the platform. Collectively, P-GMOF-818@Sec represents a pathophysiology-guided therapeutic strategy that uniquely integrates extracellular microenvironment regulation with intracellular stabilization of a key cytoprotective protein, SIRT1, for enhanced diabetic wound healing.