Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation.

Journal Article (Journal Article)

Despite lipid nanoparticles' (LNPs) success in the effective and safe delivery of mRNA vaccines, an inhalation-based mRNA therapy for lung diseases remains challenging. LNPs tend to disintegrate due to shear stress during aerosolization, leading to ineffective delivery. Therefore, LNPs need to remain stable through the process of nebulization and mucus penetration, yet labile enough for endosomal escape. To meet these opposing needs, we utilized PEG lipid to enhance the surficial stability of LNPs with the inclusion of a cholesterol analog, β-sitosterol, to improve endosomal escape. Increased PEG concentrations in LNPs enhanced the shear resistance and mucus penetration, while β-sitosterol provided LNPs with a polyhedral shape, facilitating endosomal escape. The optimized LNPs exhibited a uniform particle distribution, a polyhedral morphology, and a rapid mucosal diffusion with enhanced gene transfection. Inhaled LNPs led to localized protein production in the mouse lung without pulmonary or systemic toxicity. Repeated administration of these LNPs led to sustained protein production in the lungs. Lastly, mRNA encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was delivered after nebulization to a CFTR-deficient animal model, resulting in the pulmonary expression of this therapeutic protein. This study demonstrated the rational design approach for clinical translation of inhalable LNP-based mRNA therapies.

Full Text

Duke Authors

Cited Authors

  • Kim, J; Jozic, A; Lin, Y; Eygeris, Y; Bloom, E; Tan, X; Acosta, C; MacDonald, KD; Welsher, KD; Sahay, G

Published Date

  • September 2022

Published In

Volume / Issue

  • 16 / 9

Start / End Page

  • 14792 - 14806

PubMed ID

  • 36038136

Pubmed Central ID

  • PMC9939008

Electronic International Standard Serial Number (EISSN)

  • 1936-086X

International Standard Serial Number (ISSN)

  • 1936-0851

Digital Object Identifier (DOI)

  • 10.1021/acsnano.2c05647


  • eng