PROJECT ABSTRACT Appropriate functioning of the nervous system is tremendously important to our quality of life. The nerves within our body branch from the spinal column and can extend up to one meter away. Peripheral nerve injuries are a common occurrence and can readily heal in most cases. However, end-organs beyond ~18 inches away from the nerve body, are highly susceptible to poor reinnervation outcomes and long-term detriments. A main reason for this being the slow growth rate of the axons (1-2mm/day or 1 inch/month). Some tissues, such as skeletal muscle, can remain ready for reinnervation for 18-24 months. However, current intervention strategies are limited, and most injuries are left to resolve naturally. This application aims to develop a strategy capable of promoting quicker neurite outgrowth and preserving the muscle in a healthy state until reinnervation can occur. This application focuses on tissue-nanotransfection mediated delivery of non-viral gene cargo to induce molecular changes and to reprogram cells. The ability to deliver cargos locally to the site of injury opens avenues beyond nerve injury for gene and cell-based therapeutics with a precision medicine approach. Completion of the F99 phase sets a strong intellectual, technical and professional foundation for the postdoctoral (K00) phase of this award. During the K00 phase, training in understanding how cell and gene- based therapies impact neurodevelopmental and neurodegenerative conditions will develop knowledge, expertise, and skills essential to becoming an independent investigator.