Amino acid supplementation enhances in vivo efficacy of lipid nanoparticle-mediated mRNA delivery in preclinical models

Despite extensive efforts to optimize lipid formulations for in vivo delivery, efficacy of mRNA by LNPs remains suboptimal in many organs. Here, we demonstrate that LNP delivery efficacy is influenced by cellular metabolism, with the physiologic metabolome imposing constraints on mRNA expression from LNPs.

Using an in vitro system, we found that simulated physiologic metabolic conditions led to the downregulation of certain amino acid metabolic programs. Supplementation of an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) which enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Co-administration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro .