Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation

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…

• CF
  Cystic Fibrosis Foundation

  Award: SAHAY 19XX0
• NH
  National Heart, Lung, and Blood Institute

  Award: 1R01HL146736-01