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

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. HIGHLIGHTSRobust 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.

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