Project Summary Nanomedicine is a research field centered around applying materials in the nanoscale size range (i.e. nanoparticles) as therapeutics and diagnostics. However, a major challenge is the safe, efficient, and effective delivery of nanoparticles to biological systems, such as cells, tissues, and organs. In this project, we will introduce and explore a novel framework for nanomedicine development with the ultimate goal of efficiently delivering non- viral nanoparticles to cells and tissues for safe and effective applications. Our proposed research program has three main strands: (i) we will develop novel nanoparticles for the safe, efficient, and effective delivery of small molecules and nucleic acid payloads to skeletal muscle cells; (ii) we will develop novel methods for super- resolution bioimaging to study the mechanisms and kinetics of nanoparticle spatiotemporal transport in biological systems; (iii) we will quantify safety, efficiency, and effectiveness of nanoparticle in vivo delivery. Using this novel framework, our long-term scientific goal is to create a major breakthrough in nanomedicine by developing safer, more efficient, and more effective nanoparticles for the non-viral delivery of small molecule-based drugs and nucleic acid payloads to enable therapeutic applications in skeletal muscle disorders.