Nano lettersSep 8, 2025

Inhaled lipid nanoparticles deliver mRNA to the liver to treat metabolic diseases

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Nebulized neutral lipid nanoparticles may deliver therapeutic mRNA to the liver for metabolic disease models.

Evidence

This preclinical platform study tested charged versus neutral mRNA-LNP targeting after nebulization and therapeutic mRNAs in mouse models of Hereditary Tyrosinemia Type 1 and Type 2 diabetes.

Caveat

The evidence is limited to mouse disease models and delivery-platform endpoints, not human clinical treatment outcomes.

Simplified

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.