Nebulized Lipid Nanoparticles Deliver mRNA to the Liver for Treatment of Metabolic Diseases.

Abstract

An optimal administration approach is critical for effective mRNA delivery and treatment. Nebulizer inhalation offers a mild, convenient, and noninvasive strategy with high translational potential but primarily focused on lung delivery. In this study, we found that surface charges influence tissue targeting of mRNA lipid nanoparticle (mRNA-LNP) postnebulization. Charged mRNA-LNPs showed lung tropism, while neutral ones targeted the liver when administered via a microsprayer aerosolizer. Using nebulized liver-targeted LNPs (NebuLi LNPs), we successfully delivered therapeutic mRNAs for the treatment of metabolic diseases. In a Hereditary Tyrosinemia Type 1 model, fumarylacetoacetate hydrolase mRNA was effectively delivered to the liver, which helped to maintain mouse body weight, preserve liver function, and delay liver fibrosis. In a Type 2 diabetes model, dulaglutide mRNA was effectively expressed in the liver and exhibited good hypoglycemic effects. Overall, the NebuLi LNPs delivery platform offers a promising noninvasive strategy for metabolic disease treatment.