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2 years 2 monthsNucleic acid therapies have advanced over the last decade with the FDA approval of the first siRNA drug in 2018 and the recent approval of COVID vaccines leveraging mRNA technology. While surface receptors and endocytosis genes have been shown to influence the effectiveness of RNA drug delivery with lipid nanoparticles (LNPs), the effect of the metabolic state of a cell upon therapies seeking to produce or silence proteins remains understudied. This project therefore aims to (i) understand whether metabolic perturbations to the mTOR pathway upon PIP3 extracellular administration affect LNP-mediated mRNA delivery, (ii) develop cell- and mouse-agnostic high throughput LNP screening systems for siRNA and DNA drugs that will allow scientists to perform mechanistic studies on functional delivery with genetic knockout mice, and (iii) leverage these platforms to study whether mice exhibiting different levels of activity across the mTOR signaling pathway are more or less receptive to different nucleic acid drugs. This work will constitute early steps toward two equally important goals: (a) exploiting natural differences in cell signaling to improve cell type–specific nanoparticle delivery and (b) understanding how different physiological states can lead to different delivery potencies of nucleic acid therapeutics.