Amelioration of Vascular Hyperpermeability Mediated by Targeted LNP Delivery of VE-Cadherin mRNA In Vivo

Mar 13, 2026Blood advances

Reducing Blood Vessel Leakiness Using Targeted Delivery of VE-Cadherin mRNA

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Abstract

A single dose of aCD31/tLNP-VEc reduced plasma protein leakage from brain edema by 50% in an ischemic stroke model.

Blood vessel hyperpermeability is linked to serious health issues, including pulmonary edema and ischemic stroke.
An mRNA therapeutic encoding VE-Cadherin was developed and delivered specifically to vascular endothelial cells.
In mouse models, aCD31/tLNP-VEc treatment significantly improved vascular integrity and reduced pathological symptoms.
In a lung edema model, treatment led to decreased fluid extravasation and lower macrophage infiltration.
Targeted delivery of VEc mRNA may offer a new approach for addressing conditions involving vascular disruption.

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Blood vessel hyperpermeability underlies a wide spectrum of potentially fatal diseases ranging from acute pulmonary edema to brain injuries such as ischemic stroke. Yet, effective strategies for rapid rehabilitation of the vascular endothelium to restore vascular homeostasis remain lacking. Here we developed an mRNA therapeutic encoding the vascular membrane structural protein VE-Cadherin (VEc), delivered via an anti-CD31 targeted lipid nanoparticle (aCD31/tLNP-VEc) directly to CD31+ vascular endothelial cells, for the quick restoration of vascular integrity. We showed that administration of a single dose of aCD31/tLNP-VEc significantly ameliorates pathological onsets 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 infiltrations. In a transient middle cerebral artery occlusion (tMCAO)-induced ischemic stroke model, aCD31/tLNP-VEc delivered post-injury diminished plasma protein leakage from 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.