2. Academic Validation
  3. Lipid nanoparticle-mediated mRNA delivery in lung fibrosis

Lipid nanoparticle-mediated mRNA delivery in lung fibrosis

  • Eur J Pharm Sci. 2023 Apr 1:183:106370. doi: 10.1016/j.ejps.2023.106370.
Matteo Massaro 1,  Suhong Wu 2,  Gherardo Baudo 1,  Haoran Liu 2,  Scott Collum 3,  Hyunho Lee 2,  Cinzia Stigliano 4,  Victor Segura-Ibarra 2,  Harry Karmouty-Quintana 3,  Elvin Blanco 5
Affiliations

Affiliations

  • 1 Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 United States; College of Materials Sciences and Opto-Electronic Technology, University of Chinese Academy of Sciences, Beijing 100049 China.
  • 2 Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 United States.
  • 3 Department of Biochemistry and Molecular Biology, Divisions of Critical Care, Pulmonary and Sleep Medicine, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, United States.
  • 4 Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX 77030 United States.
  • 5 Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 United States; Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, TX 77030 United States; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, United States. Electronic address: eblanco@houstonmethodist.org.
PMID: 36642345 DOI: 10.1016/j.ejps.2023.106370
Abstract

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.

Keywords

Alveolar epithelial cells; Gene delivery; Idiopathic pulmonary fibrosis; Lipid nanoparticles (LNPs); Lung fibroblasts; mRNA.

Figures
Products