2. Academic Validation
  3. Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration

Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration

  • Commun Biol. 2021 Aug 11;4(1):956. doi: 10.1038/s42003-021-02441-2.
Manuel J Carrasco 1,  Suman Alishetty 1,  Mohamad-Gabriel Alameh 2,  Hooda Said 1,  Lacey Wright 1,  Mikell Paige 3,  Ousamah Soliman 2,  Drew Weissman 2,  Thomas E Cleveland 4th 4,  Alexander Grishaev 4,  Michael D Buschmann 5
Affiliations

Affiliations

  • 1 Department of Bioengineering, George Mason University, Fairfax, VA, USA.
  • 2 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Department of Chemistry & Biochemistry, George Mason University, Fairfax, VA, USA.
  • 4 Institute for Bioscience and Biotechnology Research National Institute of Standards and Technology, Rockville, MD, USA.
  • 5 Department of Bioengineering, George Mason University, Fairfax, VA, USA. [email protected].
PMID: 34381159 DOI: 10.1038/s42003-021-02441-2
Abstract

Lipid Nanoparticles (LNPs) are used to deliver siRNA and COVID-19 mRNA vaccines. The main factor known to determine their delivery efficiency is the PKA of the LNP containing an ionizable lipid. Herein, we report a method that can predict the LNP PKA from the structure of the ionizable lipid. We used theoretical, NMR, fluorescent-dye binding, and electrophoretic mobility methods to comprehensively measure protonation of both the ionizable lipid and the formulated LNP. The PKA of the ionizable lipid was 2-3 units higher than the PKA of the LNP primarily due to proton solvation energy differences between the LNP and aqueous medium. We exploited these results to explain a wide range of delivery efficiencies in vitro and in vivo for intramuscular (IM) and intravascular (IV) administration of different ionizable lipids at escalating ionizable lipid-to-mRNA ratios in the LNP. In addition, we determined that more negatively charged LNPs exhibit higher off-target systemic expression of mRNA in the liver following IM administration. This undesirable systemic off-target expression of mRNA-LNP vaccines could be minimized through appropriate design of the ionizable lipid and LNP.

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