Synergistic promotion of Schwann cell remyelination in diabetic peripheral neuropathy via NT3 mimetic–loaded peptide-engineered DNA nanoframework combined with electrical stimulation

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes, characterized by impaired Schwann cell migration and remyelination. Effective therapeutic strategies that simultaneously address molecular dysfunction and regenerative insufficiency remain limited. A peptide-modified DNA hexahedral nanoframework encapsulating an NT3 mimetic compound (Pep-DNA-Hex@NT3) was constructed and characterized using transmission electron microscopy, dynamic light scattering, and high-performance liquid chromatography. Its stability and nuclease resistance were evaluated. Therapeutic efficacy was assessed in a streptozotocin-induced DPN rat model combined with low-frequency electrical stimulation (ES), using gait analysis, nerve conduction velocity measurements, and histological examinations. In vitro studies employed high-glucose–induced RSC96 Schwann cell injury models to evaluate cell viability, migration, inflammation, and oxidative stress. Multi-omics analyses were conducted to elucidate underlying mechanisms. Pep-DNA-Hex@NT3 exhibited high biocompatibility and targeting efficiency. When combined with low-frequency ES in vivo, it improved functional recovery and remyelination in DPN rats. The combined treatment enhanced Schwann cell migration and survival, reduced inflammatory and oxidative stress responses, and strongly activated the Rarres1/integrin β1/FAK signaling axis. Multi-omics analyses revealed coordinated remodeling of lipid metabolism and integrin-mediated adhesion pathways. This study demonstrates a synergistic nanobiotechnology-based strategy integrating DNA nanoframeworks with electrical stimulation to promote Schwann cell–mediated remyelination, providing a promising precision therapeutic approach for DPN.