Disturbed flow induced targeting of nanomedicine to endothelial cells for effective atherosclerosis therapy

Atherosclerotic plaques preferentially form at the vascular bifurcations and inner curvature of the aortic arch, where oscillatory shear stress (OSS) induces endothelial cell (EC) inflammation, which is a key driver of disease progression. Given that endothelial cell inflammation is the primary initiating factor, using nanoparticles for site-specific drug delivery may facilitate precise therapeutic intervention. We aimed to determine whether use of a STRN3-derived Hippo-activating peptide (SHAP) laden silicasome (SLS) nanocarrier (SHAP-SLS) possessed the ability to inhibit EC activation and protect against atherosclerosis induced by disturbed flow.

In a mouse model of partial left carotid artery ligation, we identified the ability of SLS nanocarrier, i.e. a lipid bilayer-coated mesoporous silica nanoparticle (MSNP), that specifically targeted inflammatory regions. We loaded the mammalian sterile 20-like kinase 1 (MST1) activator SHAP into the MSNP core of SLS. SHAP-SLS significantly inhibited EC inflammation and atherosclerosis progression by upregulating the phosphorylation of MST1. To further investigate the mechanism by which SHAP-SLS inhibits endothelial activation, we immunoprecipitated biotin-labelled SLS and performed proteomic analysis. We found that the endocytic adaptor proteins NUMB isoforms 1 and 2 bind to membrane-associated SLS and mediate the internalization of SHAP-SLS into endothelial cells.

SHAP-SLS represents a promising nanomedicine approach for inhibiting endothelial inflammation and limiting atherosclerosis progression.