2. Academic Validation
  3. Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis

Self-homing nanocarriers for mRNA delivery to the activated hepatic stellate cells in liver fibrosis

  • J Control Release. 2023 Jan:353:685-698. doi: 10.1016/j.jconrel.2022.12.020.
Mahmoud A Younis 1,  Yusuke Sato 2,  Yaser H A Elewa 3,  Yasuhiro Kon 4,  Hideyoshi Harashima 5
Affiliations

Affiliations

  • 1 Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: mahmoudyounis@aun.edu.eg.
  • 2 Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
  • 3 Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt; Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18, Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
  • 4 Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-18, Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
  • 5 Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
PMID: 36521688 DOI: 10.1016/j.jconrel.2022.12.020
Abstract

Herein, we report on the development of a platform for the selective delivery of mRNA to the hard-to-transfect Activated Hepatic Stellate Cells (aHSCs), the fundamental player in the progression of liver fibrosis. Using a microfluidic device (iLiNP), we prepared a series of lipid nanoparticles (LNPs) based on a diverse library of pH-sensitive lipids. After an in-depth in vivo optimization of the LNPs, their mRNA delivery efficiency, selectivity, potency, robustness, and biosafety were confirmed. Furthermore, some mechanistic aspects of their selective delivery to aHSCs were investigated. We identified a promising lipid candidate, CL15A6, that has a high affinity to aHSCs. Tweaking the composition and physico-chemical properties of the LNPs enabled the robust and ligand-free mRNA delivery to aHSCs in vivo post intravenous administration, with a high biosafety at mRNA doses of up to 2 mg/Kg, upon either acute or chronic administrations. The mechanistic investigation suggested that CL15A6 LNPs were taken up by aHSCs via Clathrin-mediated endocytosis through the Platelet-derived growth factor receptor beta (PDGFRβ) and showed a pKa-dependent cellular uptake. The novel and scalable platform reported in this study is highly promising for clinical applications.

Keywords

Hepatic stellate cells; Lipid nanoparticles; Liver fibrosis; Microfluidic device; mRNA.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159865
    Ionizable Lipid