Lipid-Modified Aminoglycosides for mRNA Delivery to the Liver

Xueliang Yu, Shuai Liu, Qiang Cheng, Tuo Wei, Sang Lee, Di Zhang, Daniel J. Siegwart

Research output: Contribution to journalArticle

Abstract

Cationic lipid nanoparticles (LNPs) are widely used as carriers for delivery of nucleic acids. Most synthetic routes toward cationic lipids have derived from simple amine cores. Greater chemical diversity can be obtained through starting with natural products containing basic nitrogen atoms, which offers routes to more complex molecules. Natural building blocks are not extensively explored, such as aminoglycosides, which are both structurally and functionally interesting for developing new carriers for nucleic acid delivery. Herein, cationic lipid-modified aminoglycosides (CLAs) are explored as a family of vehicles for messenger RNA (mRNA) delivery. CLAs are synthesized from natural existing aminoglycosides coupling with alkyl epoxides and acrylates. The top hit (GT-EP10) is able to deliver Luc mRNA to C57BL/6 mice at a dose of 0.05 mg kg−1 to achieve a 107 average luminescence intensity in the liver. The Lox-Stop-Lox tdTomato mouse model is used to further demonstrate that this efficient mRNA delivery system can be potentially used for gene editing. Successful delivery of human erythropoietin mRNA shows that CLA-based LNPs have promising opportunities for delivery of therapeutic nucleic acids in the future.

Original languageEnglish (US)
Article number1901487
JournalAdvanced Healthcare Materials
Volume9
Issue number7
DOIs
StatePublished - Apr 1 2020

Keywords

  • aminoglycosides
  • gene delivery
  • gene editing
  • lipid nanoparticles
  • messenger RNA delivery

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

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