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.
Parhiz, Hamideh a,*; Shuvaev, Vladimir V. a; Pardi, Norbert b; Khoshnejad, Makan a; Kiseleva, Raisa Yu a; Brenner, Jacob S. a; Uhler, Thomas a; Tuyishime, Steven b; Mui, Barbara L. c; Tam, Ying K. c; Madden, Thomas D. c; Hope, Michael J. c; Weissman, Drew b,*; Muzykantov, Vladimir R. a,*
[Article]
Journal of Controlled Release.
291:106-115, December 10, 2018.
(Format: HTML, PDF)
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.
HIGHLIGHTS:
* Robust pulmonary targeting of mRNA was achieved by endothelial targeted anti-PECAM/LNP-mRNA nanoparticles.
* Delivery of targeted Anti-PECAM/LNP-mRNA nanoparticles is independent of apolipoprotein E pathway.
* Around 200-fold elevation in pulmonary mRNA expression was reached upon IV administration of targeted nanoparticles.
* Rapid, transient, and specific protein expression from reporter mRNA was observed, with limited off-target biodistribution.
(C) 2018Elsevier, Inc.