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Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation
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    Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation
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    • Jeonghwan Kim
      Jeonghwan Kim
      Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon 97201, United States
    • Antony Jozic
      Antony Jozic
      Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon 97201, United States
      More by Antony Jozic
    • Yuxin Lin
      Yuxin Lin
      Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
      More by Yuxin Lin
    • Yulia Eygeris
      Yulia Eygeris
      Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon 97201, United States
    • Elissa Bloom
      Elissa Bloom
      Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon 97201, United States
      More by Elissa Bloom
    • Xiaochen Tan
      Xiaochen Tan
      Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
      More by Xiaochen Tan
    • Christopher Acosta
      Christopher Acosta
      Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon 97201, United States
    • Kelvin D. MacDonald
      Kelvin D. MacDonald
      Department of Pediatrics, School of Medicine, Oregon Health and Science University, Portland, Oregon 97239, United States
    • Kevin D. Welsher
      Kevin D. Welsher
      Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
    • Gaurav Sahay*
      Gaurav Sahay
      Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, Oregon 97201, United States
      Department of Biomedical Engineering, Robertson Life Sciences Building, Oregon Health Science University, Portland, Oregon 97239, United States
      Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97239, United States
      *Email: [email protected]
      More by Gaurav Sahay
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    ACS Nano

    Cite this: ACS Nano 2022, 16, 9, 14792–14806
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    https://doi.org/10.1021/acsnano.2c05647
    Published August 29, 2022
    Copyright © 2022 American Chemical Society

    Abstract

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    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.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.2c05647.

    • Supporting figures, lipid nanoparticle composition and characterization, and additional data demonstrating the efficacy of lipid nanoparticles in vitro and in vivo (PDF)

    • Supporting video, representative trajectories of LNP-Sito with 1.5% and 3.5% PEG lipid (MP4)

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    Published August 29, 2022
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