Proceedings of the National Academy of Sciences of the United States of AmericaFeb 11, 2026

Using lipid nanoparticles to deliver GM-CSF for autoimmune lung disease causing protein buildup

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Nebulized GM-CSF mRNA lipid nanoparticles may restore macrophage surfactant clearance in a preclinical aPAP model.

Evidence

Preclinical lipid nanoparticle design and disease-model experiments tested NLD2 delivery of GM-CSF mRNA to alveolar macrophages and surfactant lipoprotein clearance.

Caveat

The evidence remains preclinical, with no patient safety, dosing, durability, or clinical outcome data for nebulized NLD2 GM-CSF mRNA.

Simplified

Granulocyte-macrophage colony-stimulating factor (GM-CSF) deficiency drives autoimmune pulmonary alveolar proteinosis (aPAP), a disease characterized by impaired macrophage-mediated clearance of pulmonary surfactants. Clinical data suggest that inhaled recombinant GM-CSF reduces symptoms in aPAP patients, providing a rationale for mRNA-based GM-CSF replacement therapies. However, these require effective mRNA delivery after nebulization. Here, we report the iterative in vivo design of a lipid nanoparticle, named nebulized lung delivery 2 (NLD2), that efficiently delivers mRNA after nebulization. NLD2 carrying GM-CSF mRNA transfected alveolar macrophages in vivo, leading to interleukin-10 pathway activation and subsequent surfactant lipoprotein clearance. In a preclinical disease model of aPAP, GM-CSF mRNA delivery reduced surfactant protein thickness more than recombinant GM-CSF. These data support continued exploration of nebulized lipid nanoparticle therapies for aPAP.