TY - JOUR
T1 - Lipid nanoparticle-mediated mRNA delivery in lung fibrosis
AU - Massaro, Matteo
AU - Wu, Suhong
AU - Baudo, Gherardo
AU - Liu, Haoran
AU - Collum, Scott
AU - Lee, Hyunho
AU - Stigliano, Cinzia
AU - Segura-Ibarra, Victor
AU - Karmouty-Quintana, Harry
AU - Blanco, Elvin
N1 - Funding Information:
This work was supported by funding from the Houston Methodist Research Institute. The authors thank Rachael Whitehead and Matthew G. Landry for assistance with schematics. The authors acknowledge the Baylor College of Medicine Cryo-Electron Microscopy Core Facility for performing cryo-electron microscopy imaging of LNPs. The authors also acknowledge Dr. David Haviland, director of the Houston Methodist Research Institute Flow Cytometry Core, for assistance with flow cytometry. M.M. is grateful for the economic support kindly provided to him by B.S.P Pharmaceuticals (Latina, IT). G.B. and M.M. received funding support from the ANSO Scholarship for Young Talents, University of Chinese Academy of Sciences, College of Material Science and Opto-electronic Technology.
Publisher Copyright:
© 2023
PY - 2023/4/1
Y1 - 2023/4/1
N2 - mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics. eGFP mRNA LNP transfection in human primary cells proved dose- and time-dependent in vitro. In a bleomycin mouse model of lung fibrosis, luciferase mRNA LNPs administered intratracheally led to site-specific lung accumulation. Importantly, bioluminescence signal was detected in lungs as early as 2 h after delivery, with signal still evident at 48 h. Of note, LNPs were found associated with AEC2 and fibroblasts in vivo. Findings highlight the potential for pulmonary delivery of mRNA in IPF, opening therapeutic avenues aimed at halting and potentially reversing disease progression.
AB - mRNA delivery enables the specific synthesis of proteins with therapeutic potential, representing a powerful strategy in diseases lacking efficacious pharmacotherapies. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) deposition and subsequent alveolar remodeling. Alveolar epithelial type 2 cells (AEC2) and fibroblasts represent important targets in IPF given their role in initiating and driving aberrant wound healing responses that lead to excessive ECM deposition. Our objective was to examine a lipid nanoparticle (LNP)-based mRNA construct as a viable strategy to target alveolar epithelial cells and fibroblasts in IPF. mRNA-containing LNPs measuring ∼34 nm had high encapsulation efficiency, protected mRNA from degradation, and exhibited sustained release kinetics. eGFP mRNA LNP transfection in human primary cells proved dose- and time-dependent in vitro. In a bleomycin mouse model of lung fibrosis, luciferase mRNA LNPs administered intratracheally led to site-specific lung accumulation. Importantly, bioluminescence signal was detected in lungs as early as 2 h after delivery, with signal still evident at 48 h. Of note, LNPs were found associated with AEC2 and fibroblasts in vivo. Findings highlight the potential for pulmonary delivery of mRNA in IPF, opening therapeutic avenues aimed at halting and potentially reversing disease progression.
KW - Animals
KW - Mice
KW - Humans
KW - RNA, Messenger/metabolism
KW - Signal Transduction
KW - Lung/metabolism
KW - Idiopathic Pulmonary Fibrosis/metabolism
KW - Bleomycin
KW - Fibroblasts/metabolism
KW - Idiopathic pulmonary fibrosis
KW - Lung fibroblasts
KW - mRNA
KW - Alveolar epithelial cells
KW - Gene delivery
KW - Lipid nanoparticles (LNPs)
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U2 - 10.1016/j.ejps.2023.106370
DO - 10.1016/j.ejps.2023.106370
M3 - Article
C2 - 36642345
SN - 0928-0987
VL - 183
SP - 106370
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
M1 - 106370
ER -