PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake

J Control Release. 2018 Dec 10:291:106-115. doi: 10.1016/j.jconrel.2018.10.015. Epub 2018 Oct 15.

Abstract

Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.

Keywords: Apolipoprotein E; Endothelial targeting; Inflammation; Vascular targeting; mRNA delivery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Apolipoproteins E / metabolism*
  • Cell Line
  • Drug Carriers / metabolism
  • Drug Delivery Systems* / methods
  • Endothelium, Vascular / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoconjugates / metabolism
  • Mice, Inbred C57BL
  • Nanoparticles / metabolism*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
  • RNA, Messenger / administration & dosage*
  • RNA, Messenger / pharmacokinetics
  • Tissue Distribution

Substances

  • Apolipoproteins E
  • Drug Carriers
  • Immunoconjugates
  • Platelet Endothelial Cell Adhesion Molecule-1
  • RNA, Messenger