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While lipid nanoparticle (LNP) formulations influence biodistribution, cellular uptake, and therapeutic efficacy, underlying mechanisms remain incompletely understood. This study develops potent mRNA\u2010LNP formulations and investigates determinants of liver tropism using ornithine transcarbamylase (OTC) deficiency as a protein replacement therapy model. Systematic screening of ionizable and helper lipids, optimization of composition and process, and biophysical characterization identify a liver\u2010tropic helper lipid\u20131,2\u2010dierucoyl\u2010sn\u2010glycero\u20103\u2010phosphoethanolamine (DEPE) that modulates LNP structure and apolipoprotein E (ApoE) binding, enhancing liver\u2010specific delivery. 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