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

ABSTRACT: Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic 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 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 . In vivo delivery of mRNA by LNPs co-administered with AAS by multiple routes enhanced in vivo mRNA expression. Delivery of growth hormone encoding mRNA by LNPs with co-administration of AAS improved the liver GH expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized amino acid supplement as a co-delivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314463 | GEO | 2026/03/11

REPOSITORIES: GEO

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			Action	DRS
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	GSE314463_H441_DE_Analysis.csv.gz	Csv
	GSE314463_H441_TPM.csv.gz	Csv
	GSE314463_HT29_DE_Analysis.csv.gz	Csv
	GSE314463_HT29_TPM.csv.gz	Csv

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