Vasculogenic tissue nanotransfection accelerates functional recovery after peripheral nerve injury

Peripheral nerve injuries (PNI) often result in persistent sensory, motor, and functional deficits, even after surgical reconstruction. While gene and cell therapies offer promise for enhancing regenerative outcomes, effective and targeted delivery remains a significant challenge. Here, we explored vasculogenic Tissue Nano-Transfection (TNT) as a novel, non-viral, reprogramming-based cell therapy to improve outcomes following graft reconstruction surgery. TNT aims to improve nerve regeneration by inducing vasculogenic reprogramming and promoting neovascularization to support axonal growth. Through a combination of in vitro screening and in vivo testing in a nerve crush model, we identified an optimal formulation of the vasculogenic genes, Etv2, Fli1, and Foxc2 (EFF), for enhancing reprogramming and axonal repair. TNT-based deployment EFF in a long segmental nerve defect reconstructed with isografts resulted in significant improvements in functional recovery, including grip strength and muscle contractility. Histological analyses demonstrated increased vascular density and myelinated axon counts. These findings support the therapeutic potential of TNT-mediated vasculogenic reprogramming as an adjunct to surgical repair of complex PNI offering a promising strategy to improve nerve regeneration and functional outcomes.