Nitric Oxide-Delivering High-Density Lipoprotein-like Nanoparticles as a Biomimetic Nanotherapy for Vascular Diseases

Abstract

Disorders of blood vessels cause a range of severe health problems. As a powerful vasodilator and cellular second messenger, nitric oxide (NO) is known to have beneficial vascular functions. However, NO typically has a short half-life and is not specifically targeted. On the other hand, high-density lipoproteins (HDLs) are targeted natural nanoparticles (NPs) that transport cholesterol in the systemic circulation and whose protective effects in vascular homeostasis overlap with those of NO. Evolving the AuNP-templated HDL-like nanoparticles (HDL NPs), a platform of bioinspired HDL, we set up a targeted biomimetic nanotherapy for vascular disease that combines the functions of NO and HDL. A synthetic S-nitrosylated (SNO) phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphonitrosothioethanol) was synthesized and assembled with S-containing phospholipids and the principal protein of HDL, apolipoprotein A-I, to construct NO-delivering HDL-like particles (SNO HDL NPs). SNO HDL NPs self-assemble under mild conditions similar to natural processes, avoiding the complex postassembly modification needed for most synthetic NO-release nanoparticles. In vitro data demonstrate that the SNO HDL NPs merge the functional properties of NO and HDL into a targeted nanocarrier. Also, SNO HDL NPs were demonstrated to reduce ischemia/reperfusion injury in vivo in a mouse kidney transplant model and atherosclerotic plaque burden in a mouse model of atherosclerosis. Thus, the synthesis of SNO HDL NPs provides not only a bioinspired nanotherapy for vascular disease but also a foundation to construct diversified multifunctional platforms based on HDL NPs in the future.

Targeting Scavenger Receptor Type B1 In Cholesterol-Addicted Lymphomas Abolishes Glutathione Peroxidase 4 and Results in Ferroptosis

“…In this study, and in many previous studies using the HDL NP as systemic therapy in animal models, we have noted a lack of toxic side effects (21,24,25,37,43,44). We also reported that HDL NP treatment of primary human hepatocytes and macrophages, the two most abundant normal cell types that express SCARB1, did not result in toxicity and that each of the normal cell types tightly regulated cholesterol homeostasis when treated with the HDL NP or native human HDL (24).…”

“…Here, we verified the requirement of SCARB1 as a target of HDL NP in these lymphoma cells using an anti-SCARB1 blocking antibody and fluorescently labeled HDL NPs. HDL NPs were fluorescently labeled using the intercalating dye DiI, as previously described (21,37). Ramos and SUDHL4 cells were treated with DiI HDL NPs for 2 hours followed by flow cytometric analysis.…”

Advances in HDL: Much More than Lipid Transporters

“…For instance, reduction of miR-92a levels has been shown to reduce infarct size and post-ischemic loos of cardiac function by displaying cell-protective, pro-angiogenic, and anti-inflammatory effects, whereas miR-486 has demonstrated to prevent cardiomyocyte apoptosis execution [60][61][62][63]. These promising experimental data have encouraged the development of synthetic HDL-like formulations containing, within the structural HDL components, locked nucleic acid-modified antisense against a given miRNA or different proportion of these candidate miRNAs [64].…”

High density lipoprotein mimicking nanoparticles for atherosclerosis

“…Lastly, the in vivo study demonstrated that the mice only developed 27.83% of atherosclerotic plaque after treated with SNO HDL-NPs, which was much less than that of the PBS-treated mice (48.13 ± 4.82%) ( Fig. 3e-i) [55].…”