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

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: SHAP-SLS represents a promising nanomedicine approach for inhibiting endothelial inflammation and limiting atherosclerosis progression.