Co-Delivery of NGF^R100W and VEGFA mRNA enhances Vascular and Neural Repair in Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) poses significant clinical challenges due to progressive nerve degeneration and vascular insufficiency. To address both neural and vascular complications simultaneously, we employed a messenger RNA (mRNA)-based protein replacement therapy. In this study, leveraging mRNA template design, structure-based screening identified NGF^R100W as a variant dissociating neuroprotective and nociceptive functions, demonstrating enhanced neuritogenic activity without pain sensitization. Additionally, transcriptome analysis of NGF mutants versus wild type further reveals the potential mechanism by which NGF^R100W uncouple neuroprotective and nociceptive pathways. We co-transfected chemically modified NGF^R100W-mRNA and vascular endothelial growth factor A (VEGFA) -mRNA, and the conditioned media collected from this transfection promoted endothelial cell migration, tubulogenesis, and neurite outgrowth. In a diabetic mouse model, combination therapy with lipid nanoparticle co-delivery of NGF^R100W and VEGFA mRNA significantly improved blood flow in the plantar region and mitigated nerve function decline compared to monotherapy. Histological analysis showed increased microvessel formation and higher intraepidermal nerve fiber density in treated mice. Our findings highlight the therapeutic potential of NGF^R100W and VEGFA mRNA co-administration for DPN, suggesting that protein supplementation via mRNA could offer a novel strategy for clinical intervention in some chronic medical conditions.