Efficient mRNA delivery using lipid nanoparticles modified with fusogenic coiled-coil peptides

Nanoscale, vol. 15, pp. 15206–15218

Abstract

Gene delivery has great potential in modulating protein expression in specific cells to treat diseases. Such therapeutic gene delivery demands sufficient cellular internalization and endosomal escape. Of various nonviral nucleic acid delivery systems, lipid nanoparticles (LNPs) are the most advanced, but still, are very inefficient as the majority are unable to escape from endosomes/lysosomes. Here, we develop a highly efficient gene delivery system using fusogenic coiled-coil peptides. We modified LNPs, carrying EGFP-mRNA, and cells with complementary coiled-coil lipopeptides. Coiled-coil formation between these lipopeptides induced fast nucleic acid uptake and enhanced GFP expression. The cellular uptake of coiled-coil modified LNPs is likely driven by membrane fusion thereby omitting typical endocytosis pathways. This direct cytosolic delivery circumvents the problems commonly observed with the limited endosomal escape of mRNA. Therefore fusogenic coiled-coil peptide modification of existing LNP formulations to enhance nucleic acid delivery efficiency could be beneficial for several gene therapy applications.

Authors 9

1. Ye Zeng Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

2. Mengjie Shen Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

3. Roy Pattipeiluhu Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

4. Xuequan Zhou Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

5. Yun Zhang Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

6. Thomas Bakkum Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

7. Thomas Harry Sharp Aachen Department of Cell and Chemical Biology Section Electron Microscopy

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Cell and Chemical Biology, Section Electron Microscopy, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

8. Aimee L. Boyle Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands

9. Alexander Kros corresponding Aachen Department of Supramolecular and Biomaterials Chemistry

   Leiden University

   Affiliation as printed

   Department of Supramolecular & Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands