Codelivery of NGFR100W and VEGFA mRNA Enhances Vascular and Neural Repair in Diabetic Peripheral Neuropathy

• DOI: 10.2337/db24-0989
• Publication Date: 2025-05-28T18:05:47Z
• Authors: Wenjing Wang; Xiang Yu; Zheng Yang; Yu Zhang; Wen Yang; Yingjie Xu; Wei Xu
• Keywords: Diabetic Neuropathy

Diabetic peripheral neuropathy (DPN) poses significant clinical challenges due to progressive nerve degeneration and vascular insufficiency. To address both neural complications simultaneously, we employed an mRNA-based protein replacement therapy. In this study, leveraging mRNA template design, structure-based screening identified NGFR100W as a variant dissociating neuroprotective 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 uncouples pathways. We cotransfected chemically modified endothelial growth factor A (VEGFA) mRNA, conditioned media collected from transfection promoted cell migration, tubulogenesis, neurite outgrowth. diabetic mouse model, combination therapy with lipid nanoparticle codelivery VEGFA significantly improved blood flow in plantar region mitigated function decline compared monotherapy. Histological showed increased microvessel formation higher intraepidermal fiber density treated mice. Our findings highlight therapeutic coadministration for DPN, suggesting that supplementation via could offer novel strategy intervention some chronic medical conditions. ARTICLE HIGHLIGHTS aimed develop dual-targeted insufficiency neuropathy. mutation enhances sensitization investigated its explore ability uncouple Combination using nanoparticles flow, formation, preserved model. This approach, combines design therapy, offers decoupling functions developing molecules specific functionalities.