Lipid nanoparticles (LNPs) are a powerful tool to deliver mRNA, however the cellular machinery that regulates LNP-mRNA mediated gene expression are not well characterised. To address this knowledge gap, here we performed a genome-wide CRISPR activation screen to identify factors that enhance mRNA–LNP-mediated gene expression. We selected for CRISPRa transduced cells that show increased cargo expression following mRNA-LNP treatment, and identified genes involved in endocytic trafficking, translation initiation, Rho GTPase cycling, and retinoic acid metabolism and transport. These data suggest that efficient LNP uptake, trafficking, and translation collectively determine mRNA-LNP outcomes. Among the most prominent genes, we identified the phagocytic “eat-me” receptor MEGF10 as a potent enhancer of LNP mRNA delivery. Upregulation of MEGF10 increased the speed of LNP uptake and accelerated mRNA translation, resulting in earlier and stronger gene expression. Together, these findings define new cellular factors that influence mRNA-LNP cargo expression, information that can help us enhance nanomedicine efficacy and improve LNP-based therapeutics.