Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke

Abstract

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke. To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and increase of the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, nanocarriers targeted to VCAM achieved the highest level of brain delivery, nearly 2 orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (IL-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted nanocarriers. Thus, VCAM-targeted lipid nanocarriers represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating acute ischemic stroke.