Targeted delivery of microRNAs by microparticles to inflamed endothelium ameliorates endothelial inflammation and atherosclerosis

Abstract

Listen

Translate article

RationaleThe E‐selectin in endothelium promotes the growth of atherosclerotic plaques. We identified an E‐selectin‐targeting thioaptamer (ESTA) and conjugated it onto a multistage vector (MSV) to form an ESTA‐MSV microparticle. We tested E‐selectin‐targeted delivery of microRNAs (miRs) for the treatment of atherosclerosis.Methods and ResultsThe E‐selectin was up‐regulated, while the miR‐146a and miR‐181b were down‐regulated, in TNF‐α‐treated human microvascular endothelial cells (HMVECs). MiR‐146a and miR‐181b mimics were packaged into the ESTA‐MSV. Both miR‐146a and miR‐181b attenuated TNF‐α‐induced endothelial inflammation. Moreover, the monocyte adhesion to HMVECs was also attenuated by miR‐146a or miR‐181b. The ApoE‐/‐ mice were injected with ESTA‐MSV‐packaged miR‐146a or miR‐181b biweekly through tail vein for 12 weeks. Injection of miR mimics resulted in a 4.7‐ and 5.7‐fold overexpression of miRs in mouse aortas. The immunofluorescence staining showed the co‐localization of E‐selectin and miRs in aortic endothelium. MiR‐146a and miR‐181b significantly inhibited atherosclerotic lesion size, lipids deposition, macrophage and lymphocyte infiltration in plaques, and expression of adhesion molecules in aortas.ConclusionsE‐selectin‐targeting delivery of miR‐146a and miR‐181b to inflamed endothelium inhibits atherosclerosis. These findings provide a novel delivery system for miR‐based therapy of atherosclerosis.