1. 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
-
Thomas G. Uhler, Steven Tuyishime, Vladimir V. Shuvaev, Norbert Pardi, Ying K. Tam, Hamideh Parhiz, Michael J. Hope, Barbara L. Mui, Vladimir R. Muzykantov, Jacob S. Brenner, Drew Weissman, Raisa Yu Kiseleva, Thomas D. Madden, and Makan Khoshnejad
- Subjects
0301 basic medicine ,Apolipoprotein E ,Immunoconjugates ,Apolipoprotein B ,Pharmaceutical Science ,Inflammation ,Pharmacology ,Protein expression ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Drug Delivery Systems ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Tissue Distribution ,RNA, Messenger ,Messenger RNA ,Drug Carriers ,biology ,Chemistry ,Cell adhesion molecule ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Systemic administration ,Nanoparticles ,Administration, Intravenous ,Endothelium, Vascular ,medicine.symptom ,Antibody - 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.
- Published
- 2018