While gene therapy with mRNA offers tremendous potential to transform the management of genetic diseases, delivering mRNA outside the reticuloendothelial system (e.g. liver and spleen) remains challenging. Without carriers that can reach organs such as the lungs, heart, brain, or pancreas, the potential of mRNA to treat diseases of those organs, such as asthma, coronary artery disease, multiple sclerosis, and diabetes, will remain untapped. This research will establish the protein corona as a new lipid nanoparticle design element that can be engineered to achieve mRNA delivery outside the reticuloendothelial system. Upon injection into the body, lipid nanoparticles are immediately coated in local proteins, forming a protein corona that interfaces with cells and tissues. The composition of that natural corona has been shown to strongly influence nanoparticle fate in vivo. This work will develop “smart” protein coronas by pre-coating mRNA lipid nanoparticles with proteins that localize to organs outside the reticuloendothelial system prior to administration. In Aim 1, a small library of naturally-occurring proteins will be evaluated for their ability to direct mRNA delivery to non-reticuloendothelial organs, including the lungs, heart, brain, and pancreas, in C57BL/6 mice. Imaging and flow cytometry will be used to identify organ and cellular targets of smart corona-coated mRNA lipid nanoparticles. Aim 2 will elucidate the mechanisms by which smart corona-coated lipid nanoparticles enable differential organ targeting. Smart coronas may enable differential targeting by altering circulation time, by recruiting additional serum proteins that serve as active targeting agents, or by binding specific cell surface receptors via the smart corona itself or via additionally adsorbed proteins. Proteomic analysis will determine what proteins adsorb coated-lipid nanoparticles upon intravenous injection, and cell receptor blocking studies will identify cellular targets that facilitate effective mRNA delivery. This work is innovative in that it will establish the protein corona as a previously-unappreciated nanoparticle design element that can be engineered to enable mRNA delivery to challenging organ targets. While efficacious smart coronas will provide researchers with new tools to advance drug targeting, mechanistic insights will inform future smart corona design. This research is significant because it will contribute a paradigm-shifting targeting strategy to accelerate the clinical translation of mRNA therapeutics for extrahepatocellular diseases. Further, the results obtained by this research will advance the delivery of nucleic acids, small molecules, and proteins from diverse drug carriers, such nanoparticles, drug conjugates, and implantable devices. Ultimately, the knowledge generated by this work has the potential to transform and accelerate the development of targeted drug carriers.