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

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.

Author information

1
Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: parhizh@pennmedicine.upenn.edu.
2
Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
3
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada.
5
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dreww@upenn.edu.
6
Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: muzykant@mail.med.upenn.edu.

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

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