Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation

Jeonghwan Kim, Antony Jozic, Yuxin Lin, Yulia Eygeris, Elissa Bloom, Xiaochen Tan, Christopher Acosta, Kelvin D. MacDonald, Kevin D. Welsher, Gaurav Sahay

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)14792-14806
Number of pages15
JournalACS Nano
Issue number9
StatePublished - Sep 27 2022


  • cystic fibrosis
  • inhalation
  • lung delivery
  • mRNA therapy
  • nebulization
  • pulmonary delivery
  • β-sitosterol

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)


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