Nanoparticle-Aided Characterization of Arterial Endothelial Architecture during Atherosclerosis Progression and Metabolic Therapy

Abstract

Atherosclerosis is associated with a compromised endothelial barrier, facilitating the accumulation of immune cells and macromolecules in atherosclerotic lesions. In this study, we investigate endothelial barrier integrity and the enhanced permeability and retention (EPR) effect during atherosclerosis progression and therapy in Apoe–/– mice using hyaluronan nanoparticles (HA-NPs). Utilizing ultrastructural and en face plaque imaging, we uncover a significantly decreased junction continuity in the atherosclerotic plaque-covering endothelium compared to the normal vessel wall, indicative of disrupted endothelial barrier. Intriguingly, the plaque advancement had a positive effect on junction stabilization, which correlated with a 3-fold lower accumulation of in vivo administrated HA-NPs in advanced plaques compared to early counterparts. Furthermore, by using super-resolution and correlative light and electron microscopy, we trace nanoparticles in the plaque microenvironment. We find nanoparticle-enriched endothelial junctions, containing 75% of detected HA-NPs, and a high HA-NP accumulation in the endothelium-underlying extracellular matrix, which suggest an endothelial junctional traffic of HA-NPs to the plague. Finally, we probe the EPR effect by HA-NPs in the context of metabolic therapy with a glycolysis inhibitor, 3PO, proposed as a vascular normalizing strategy. The observed trend of attenuated HA-NP uptake in aortas of 3PO-treated mice coincides with the endothelial silencing activity of 3PO, demonstrated in vitro. Interestingly, the therapy also reduced the plaque inflammatory burden, while activating macrophage metabolism. Our findings shed light on natural limitations of nanoparticle accumulation in atherosclerotic plaques and provide mechanistic insight into nanoparticle trafficking across the atherosclerotic endothelium. Furthermore, our data contribute to the rising field of endothelial barrier modulation in atherosclerosis.

Nrf2 activator-encapsulating polymeric nanoparticles and LDL-like nanoparticles target atherosclerotic plaque

“…Moreover, in vivo we found evidence via immunofluorescence of macrophages with CD11b staining of association of both CDDO-Me-NPs and LDL-OA-NPs with atherosclerotic plaque macrophages. Their accumulation is consistent with the literature which shows that NPs can also accumulate selectively in atherosclerotic plaque simply due to the enhanced permeation and retention (EPR) effect [42][43] . NPs take advantage of a dysfunctional endothelium with larger inter-endothelial junctions to accumulate in sites of vascular inflammation [42][43] .…”

“…Their accumulation is consistent with the literature which shows that NPs can also accumulate selectively in atherosclerotic plaque simply due to the enhanced permeation and retention (EPR) effect [42][43] . NPs take advantage of a dysfunctional endothelium with larger inter-endothelial junctions to accumulate in sites of vascular inflammation [42][43] . Early atherosclerotic events have been shown to be associated with more severe endothelial barrier disruption, whilst advanced stage disease progressions are associated with improved endothelial barrier permeability 42 .…”

“…NPs take advantage of a dysfunctional endothelium with larger inter-endothelial junctions to accumulate in sites of vascular inflammation [42][43] . Early atherosclerotic events have been shown to be associated with more severe endothelial barrier disruption, whilst advanced stage disease progressions are associated with improved endothelial barrier permeability 42 . Previous pre-clinical studies have successfully integrated NPs into sites of atherosclerotic plaque, some of which were able to inhibit plaque formation and decreased the number of atherosclerotic lesions in mouse models of atherosclerosis 39,[43][44][45][46][47] .…”

Nanoerythrocyte Membrane–Enveloped ROS‐Responsive 5‐Aminolevulinic Acid Prodrug Nanostructures with Robust Atheroprotection

“…[ 30 ] In atherosclerosis treatment, this biomimetic strategy can be used to accumulate nanocarriers in atherosclerotic plaques via the leaky endothelium driven by the enhanced permeability and retention (EPR) effect. [ 31,32 ]…”

Nanoparticle-mediated microRNA-145 Delivery for Vascular Smooth Muscle Cell Phenotype Modulation and Atherosclerosis Treatment

“…Hence, early intervention of VSMC proliferation and transdifferentiation could induce an amplified effect in inhibiting atherosclerosis plaque development (8). In addition, these results may be explained by the enhanced permeability and retention effect that is more prominent in early, developing atherosclerosis compared to late-stage plaques (35). Interestingly, inclisiran, an investigational siRNA-based therapy in clinical trials as a PCSK9 inhibitor for atherosclerosis, has also shown a single dose to have long-term benefits in humans for up to a year (36).…”