Targeted LNP-mediated delivery of VE-cadherin mRNA reduces vascular hyperpermeability in vivo

Blood vessel hyperpermeability underlies a wide spectrum of potentially fatal diseases, ranging from acute pulmonary edema to brain injuries such as ischemic stroke. However, effective strategies for rapid rehabilitation of the vascular endothelium to restore vascular homeostasis remain lacking. Here, we developed a messenger RNA (mRNA) therapeutic encoding the vascular membrane structural protein vascular endothelial-cadherin (VEc), delivered via an anti-CD31 targeted lipid nanoparticle (aCD31/tLNP-VEc) directly to CD31+ vascular endothelial cells, for the rapid restoration of vascular integrity. We showed that administration of a single dose of aCD31/tLNP-VEc significantly ameliorates pathological onset in multiple mouse models of vascular hyperpermeability. In a bleomycin-induced lung edema model, we found aCD31/tLNP-VEc treatment significantly reduced fluid extravasation and decreased macrophage infiltration. In a transient middle cerebral artery occlusion-induced ischemic stroke model, aCD31/tLNP-VEc delivered postinjury diminished plasma protein leakage associated with brain edema by 50%. Targeted LNP-mediated delivery of VEc mRNA to the vascular network presents a promising platform for treating clinically relevant conditions involving vascular disruption.