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

Mar 11, 2026Science translational medicine

Amino acid supplements improve lipid nanoparticle delivery of mRNA in animal models

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Coadministration of an optimized amino acid supplement with lipid nanoparticles can enhance mRNA expression by 5- to 20-fold in various cell types in vitro.

Lipid nanoparticles (LNPs) are critical for delivering therapeutic messenger RNA (mRNA), but their efficacy varies across different organs.
Cellular metabolism and the physiologic metabolome can limit the expression of mRNA delivered by LNPs.
In an in vitro system, specific amino acid metabolic programs were down-regulated under simulated physiological conditions.
Supplementation with methionine, arginine, and serine improved LNP uptake and mRNA expression in epithelial cells.
Using LNPs with the amino acid supplement led to enhanced mRNA expression and therapeutic outcomes in preclinical models of liver damage.
Intratracheal delivery of gene editing materials with LNPs and amino acid supplements improved gene editing efficiency in the lungs.

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Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic messenger RNA (mRNA). 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 down-regulation of certain amino acid metabolic programs. Supplementation with an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Coadministration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro by promoting clathrin-independent carrier-mediated endocytosis. Delivery of mRNA by LNPs coadministered with AAS by multiple routes enhanced in vivo mRNA expression in preclinical models. Delivery of mRNA encoding growth hormone by LNPs with coadministration of AAS improved the liver growth hormone expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through an intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized AAS as a codelivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.