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

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. [Display omitted] •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.