ROS-Based Nanoparticles: Comparison
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Atherosclerosis (AS), a chronic arterial disease, is the leading cause of death in western 

 developed countries. Considering its long-term asymptomatic progression and serious complications, 

 the early prevention and effective treatment of AS are particularly important. The unique characteris

tics of nanoparticles (NPs) make them attractive in novel therapeutic and diagnostic applications, 

 providing new options for the treatment of AS. With the assistance of reactive oxygen species (ROS)- 

based NPs, drugs can reach specifific lesion areas, prolong the therapeutic effect, achieve targeted 

 controlled release and reduce adverse side effects. In this article, we reviewed the mechanism of AS 

 and the generation and removal strategy of ROS. We further discussed ROS-based NPs, and summa

rized their biomedical applications in scavenger and drug delivery. Furthermore, we highlighted the 

 recent advances, challenges and future perspectives of ROS-based NPs for treating AS. 

  • atherosclerosis
  • nanoparticles
  • scavenger
  • ROS-responsive therapy

1. Introduction

Atherosclerosis (AS) is the leading cause of death in western developed countries [1,2,3,4][1][2][3][4]. Currently, clinical treatment strategies focus on controlling risk factors, relieving symptoms and preventing future cardiac events. To date, the most common strategy is drug therapy. For example, the widely used statins could contribute to the inhibition of the formation and progression of AS [5]. In addition to drugs, further stent-assisted therapies or coronary artery bypass surgery have been used for advanced AS to prevent adverse cardiac events [6]. In order to prevent and treat AS and reduce the occurrence of cardiovascular and cerebrovascular events more efficiently, some new strategies, including anti-inflammatory therapy and immunotherapy for AS, are also being extensively studied [7,8][7][8]. The typical features of atherosclerotic lesions are the abnormal accumulation of lipids and progressive inflammation in vascular endothelial cells. Moreover, various stimuli, including low-density lipoprotein (LDL), oxidative active substances, infection, mechanical stress and chemical damage, could speed up the process of AS [9]. At present, oxidative stress is considered the main mechanism of AS, and it is widely believed that oxidative stress is an imbalance between the antioxidant capacity and activity species [10,11][10][11]. Activity species include reactive oxygen species (ROS), nitrogen and halogen species. Increasing evidence has demonstrated that ROS play a crucial role in the occurrence and progression of AS [12].
ROS, which participate in a series of physiological and pathological processes in the body, are the byproducts of aerobic metabolism. The ROS family is composed of free radicals and non-free radicals. Free radicals mainly include hydrogen peroxide (H2O2), singlet oxygen (1O2), superoxide ion (O2•−) and hydroxyl radical (OH•−). Non-free radicals include peroxynitrite (ONOO-) and hypochlorous acid (HOCl) [13,14][13][14]. ROS-dependent modification is the basis for the transduction of intracellular signals that control pleiotropic functions. Nevertheless, excessive ROS may induce a battery of inflammatory responses and exacerbate oxidative stress in cells and tissues. More importantly, the accumulation of ROS inducts lipid peroxidation and glycoxidation reactions, leading to protein cross-linking and aggregation, which causes cell damage and death.
Elevating ROS has been proven in the literature to be an effective strategy for treating tumors [15]. In recent years, some researchers have increasingly focused on ROS scavenging strategies, which could effectively inhibit the formation of foam cells and significantly improve the stability of atherosclerotic plaque.

2. Mechanism of Atherosclerosis

AS is a chronic inflammatory disease of the arterial intima, in which the infiltration and accumulation of lipids and inflammatory cells are the internal driving forces for the progression of the lesions. These inflammatory cells, especially macrophages, mast cells and T lymphocytes and release many cytokines, which promote ROS generation to stimulate the migration of smooth muscle cells and the deposition of collagen, leading to the development of an atheromatous plaque [16]. In addition, inflammation is triggered by an immune response in which T helper type 1 (Th 1) cells are involved in the formation of atherosclerotic plaques [17]. For many years, it has been believed that hypertension, diabetes, hyperlipidemia, obesity, and smoking are risk factors for AS [18]. In general, atherosclerotic lesions are the final result of multiple pathogenic factors [19]. Although current lipid-lowering strategies could effectively slow the progression of AS, the risk of cardiovascular events remains high. In the past few decades, researchers have identified that an excess of ROS could promote the progression of AS [20]. This opens up a new approach for the treatment of atherosclerotic lesions.

3. Generation of ROS

ROS are necessary mechanisms for organism growth, health and aging, and are important in adjusting various physiological activities. However, excessive production of ROS will cause mitochondrial deoxyribonucleic acid (DNA) and nuclear DNA damage and activate various signaling pathways, such as mitogen-activated protein kinase (MAPK), nuclear factor kB (NF-κB) and janus kinase/signal transducers and activators of transcription (JAK/STAT), which induces a cascade reaction to cell apoptosis [21,22][21][22]. Therefore, it is critical to understand excess ROS damage and the source of ROS. ROS come from various cells (such as foam cells, vascular smooth muscle cells, endothelial cells), organelles (such as mitochondria, peroxisomes and endoplasmic reticulum) and cytoplasm. Among them, the ROS produced by mitochondria have the highest content [23,24,25][23][24][25]. In addition, ROS can be produced by enzymatic and non-enzymatic pathways. The enzyme sources of ROS include NADPH oxidase (NOX), lipoxygenase (LOX), cyclooxygenase (COX), xanthine oxidase (XO), uncoupled nitric oxide synthase (NOS), myeloperoxidase and many other amine oxidases [26,27,28,29,30][26][27][28][29][30]. Additionally, some risk factors in daily life and work, such as bad living habits and exposure to harmful radiation, can increase the expression of ROS, which leads to more serious inflammatory damage. However, some researchers have indicated that the generation of a large amount of ROS can promote the autophagy of macrophages to slow down the process of AS [31,32][31][32].

4. Strategies to Reduce ROS for Atherosclerosis Treating

The dynamic balancing of ROS production and clearance is essential for oxidation-reduction equilibrium and cardiovascular fitness. Generally, the elimination of ROS depends on enzymatic and non-enzymatic pathways [13,19][13][19]. Nicotinamide adenine dinucleotide (NADH) transforms ROS into water via mitochondrial intima. Certain enzymes in the body, including superoxide dismutase (SOD), catalase (CAT) and peptide peroxidase (GPx), have the ability to clear ROS [19,22,33][19][22][33]. O2•− is catalyzed into hydrogen peroxide (H2O2) by SOD [34]. Next, CAT, GPx and glutathione (GSH) can efficiently convert H2O2 into nontoxic products, avoiding the accumulation of ROS [35,36][35][36]. Due to their poor stability and mass production difficulties, the application of natural enzymes is limited. Therefore, it is very important to develop nanomaterials with enzyme simulation properties to achieve ROS regulation. These nanomaterials have significant advantages in ROS scavenging. Compared with natural enzymes, they have a broad spectrum of ROS scavenging abilities, strong stability in physiological environments, and satisfying biocompatibility and biosafety.
In addition, various type of antioxidants, such as polyphenols, vitamin E and C, flavonoids, ferulic, tempol, statins, probucol and its derivatives, immunosuppressants and glucocorticoid play a crucial role in the prevention and treatment of AS through different mechanisms [37,38,39,40,41,42,43,44,45,46][37][38][39][40][41][42][43][44][45][46]. However, systemic exposure, off-target effects and poor bioavailability remain concerns for drug therapy [47,48][47][48]. Meanwhile, excessive antioxidants may also promote the occurrence and development of AS [49]. It is worth considering that the dosage and delivery of antioxidants used to treat AS are important factors.

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