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.