DNA Nanostructures for Modular Growth Factor Delivery and Peripheral Nerve Repair.

Severe peripheral nerve injuries cause significant functional impairments due to limited regenerative capacity. Growth factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor promote neuronal differentiation and regeneration, but their controlled and efficient delivery remains challenging. Here, we present square block DNA nanostructures (SQBs) as a modular platform for the spatially controlled presentation of growth-factor-mimicking peptides. SQBs displaying 38 BDNF-mimicking peptides at 5 nm intervals enhanced the neuronal differentiation of human mesenchymal stem cells. Dual-ligand presentation was validated using fluorescein isothiocyanate and cyanine5.5, demonstrating ratio-controlled conjugation and colocalized delivery within single cells. In a sciatic nerve injury model, BDNF-functionalized SQBs modestly improved functional recovery, reduced muscle atrophy, and enhanced remyelination compared to the untreated crush group. Histological analysis revealed increased myelin sheath thickness and improved axonal integrity. These findings underscore potential SQBs as programmable and spatially precise delivery systems for neuroregenerative therapies and broader tissue repair strategies.