Flow-responsive nanodisks target PTGS2 to stabilise atherosclerotic plaques
C Zhang, Y ChenAbstract
Background
Disturbed flow drives endothelial inflammation and atherosclerosis. PTGS2 is a hub gene and is downregulated under disturbed flow with potential atheroprotective effects, whereas systemic activation causes off-target toxicity. We developed Rebamipide-loaded mesoporous silica nanodisks (MSND-Cy7-Rebamipide) for flow-mediated, site-specific PTGS2 activation and evaluated their anti-atherosclerotic efficacy.
Methods
Atherosclerosis was induced by partial carotid ligation and high-fat diet in Apoe-/- mice. Disk-shaped (MSND) and spherical (MSNS) Cy7-Rebamipide nanoparticles were administered via tail vein every three days starting from day 1 post-ligation. Biosafety was assessed by CCK-8 and organ histology. Targeting and biodistribution were analyzed by in vivo and ex vivo fluorescence imaging (n=4). Plaque area, necrotic core and composition were quantified histologically, including Picrosirius red staining for collagen (n=6).
Results
MSND-Cy7-Rebamipide showed no cytotoxicity at 0–200 μg/mL and favourable in vivo biosafety. Fluorescence imaging demonstrated greater accumulation at ligated carotid arteries versus MSNS-Cy7-Rebamipide from 12–192 h (in vivo: 6.30×10⁶±1.73×10⁶ vs. 5.08×10⁶±1.48×10⁶ [p/s/cm²/sr] / [µW/cm2]; ex vivo: 2.69×10⁶±9.46×10⁴ vs. 2.03×10⁶±2.23×10⁵ [p/s/cm²/sr] / [µW/cm²]), confirming flow-mediated targeting.MSND-Cy7-Rebamipide reduced necrotic core area by 54.84% (45.42% vs. 20.51%, p=0.001) and increased collagen content by 40.22% (30.61% vs. 42.92%, p=0.0068), indicating improved plaque stabilization.
Conclusions
MSND-Cy7-Rebamipide could attenuate atherosclerosis by targeted activation of PTGS2 in disturbed flow.