Atherosclerosis (AS) is a chronic inflammatory condition of large arteries and a major contributor to cardiovascular disease (CVD) and stroke. The prevention of AS diseases involves numerous anti-atherosclerosis agents, including antihyperlipidemic and antihypertensive drugs. However, these drugs often exhibit poor aqueous solubility, which can affect their bioavailability and therapeutic efficacy. Mesoporous silica nanoparticles (MSNs) have emerged as effective drug delivery systems due to their high surface area, tunable pore sizes, surface functionalization potential, and physicochemical stability. These characteristics enable enhanced drug loading, regulated release, and stabilization of amorphous drug forms, thereby improving solubility, permeability, pharmacokinetics, and therapeutic efficacy. This review offers an in-depth look at MSN-based strategies for optimizing the delivery of anti-atherosclerosis drugs, particularly those targeting cholesterol levels and blood pressure control. Relevant data were sourced from PubMed, Scopus, and Google Scholar using the keywords "mesoporous silica nanoparticle", "atherosclerosis", "antihyperlipidemic", and "antihypertensive." Numerous studies have demonstrated the ability of MSN formulations to significantly enhance drug performance, with reported enhancements in solubility and bioavailability ranging from 1.4-fold to 88-fold, depending on the drug and formulation. For example, nifedipine-loaded MSNs showed an 88-fold increase in solubility compared to the pure drug and a 10-fold improvement over marketed tablets. Simvastatin-loaded MSNs achieved a 6.1-fold enhancement in oral bioavailability, while efonidipine-loaded MSNs exhibited up to a 3.5-fold increase in dissolution and permeability. These advancements may result in decreased dosing frequencies, reduced drug dosages, and fewer adverse effects, ultimately improving patient compliance. However, clinical translation remains limited due to the lack of early-phase cli In the United States, AS was a major contributor to cardiovascular diseases, including myocardial infarction (MI), heart failure, and stroke, with more than 50% related deaths each year. 1 AS underlies various arterial diseases, including ischemic stroke, heart attack, and peripheral arterial disease. 2 , 3 AS is closely associated with both aging and premature biological aging, as atherosclerotic plaques exhibit features of cellular senescence marked by reduced proliferation, cell cycle arrest, increased apoptosis, and elevated DNA destruction. These instances of cellular senescence play a significant role in the progression of AS. 4 , 5 Currently, pharmacological treatments focus on managing major risk factors, particularly hypercholesterolemia/hyperlipidemia and elevated blood pressure, using lipid-lowering and antihypertensive agents. Various pharmacological agents used to inhibit the progression of AS, including antihyperlipidemic and antihypertensive drugs, often encounter challenges such as poor aqueous solubility and adverse effects like myopathy and hepatotoxicity. These limitations compromise systemic bioavailability and reduce therapeutic efficacy. 6 , 7 To address these challenges, several strategies have been explored, including the use of nanocarriers. 34 Niemann–Pick C1-Like 1 Protein (NPC1L1) Inhibitor Ezetimibe is an established inhibitor of the NPC1L1. Ezetimibe diminishes the hepatic cholesterol reservoir and enhances the expression of LDL receptors on hepatocytes, resulting in increased elimination of LDL cholesterol from the circulation. 42 Bempedoic acid works by directly and competitively inhibiting an enzyme called ATP citrate lyase (ACL), reducing acetyl-CoA production and cholesterol synthesis in the liver. 34 Presenting profiles of approved anti-hyperlipidemic drugs currently available can be seen in Table 1 . A 2021 in vitro study by Pham et al demonstrated that rosuvastatin encapsulated in MSN resulted in significantly (p < 0.01) lower LDL oxidation (2.8%), in contrast to free rosuvastatin (10%), indicating a potential role in mitigating plaque development. 3 In addition to antidyslipidemic agents, researchers While these in vitro results suggest promising physicochemical and pharmacological enhancements, direct correlations with clinical outcomes—such as plaque regression or blood pressure normalization—remain limited. Future research should prioritize the integration of pharmacodynamic data to substantiate the translational relevance of these findings. In vivo Studies An in vivo study by Bharati et al 142 in 2024 using Wistar rats with acute renal hypertension demonstrated the enhanced antihypertensive efficacy of mesoporous silica-based amorphous formulations of the BCS class II drug EFE. Only a few MSN-based formulations have advanced to early-phase clinical trials, and comprehensive data on their long-term safety, biodistribution, metabolism, and pharmacodynamic behavior in humans are lacking. These gaps reduce regulatory confidence and hinder the approval of MSNs as viable drug delivery systems. Additionally, the large-scale industrial production of MSNs faces considerable challenges. Conventional batch-based sol-gel synthesis methods are difficult to scale due to their multistep procedures, high material and energy demands, and inconsistencies in particle size uniformity and surface characteristics. Mesoporous silica nanoparticles (MSNs) have been acknowledged as a promising strategy for next-generation pharmaceutical carriers due to their remarkable capacity to enhance the therapeutic efficacy of antihyperlipidemics and antihypertensives. Compared to conventional physical and chemical methods currently employed to address low solubility issues in antihyperlipidemic and antihypertensive drugs, these existing approaches primarily improve solubility, dissolution rate, and physicochemical properties without significantly reducing the required dose, potentially leading to drug toxicity.

Current treatment for atherosclerotic cardiovascular diseases (ASCVD) mainly focuses on the modification of systemic risk factors, such as hyperglycemia and hyperlipidemia. Despite significant efforts and expanse, achieving early and proper diagnosis of ASCVD to improve clinical outcomes remains challenging, and vascular-targeted therapies or genetic editing, while ideal, are still limited. The development of nanomedicine-based mRNA vaccines for SARS-CoV-2 has demonstrated the potential of nanotechnology to target previously inaccessible molecules. Precision therapies by nanomedicine targeting specific tissues/molecules hold potential for new treatment paradigms by precisely modulating disease-causing molecular pathways within diseased tissues, including dysfunctional vasculature. By leveraging insights into the pathogenic contributors of atherogenesis, researchers have optimized nanoplatforms' composition, synthesis strategies, and surface design to enhance therapeutic efficacy and enable early diagnosis. Herein, we present an updated overview of therapeutic and diagnostic strategies using nanomedicine for ASCVD, and explore future research directions and innovative approaches for nanomedicine-driven theranostics in cardiovascular care. Preventive lifestyle interventions, including adherence to a heart-healthy diet, regular physical activity, smoking cessation, and weight management, are fundamental in mitigating systemic risk factors. In parallel, pharmacological and interventional approaches play a critical role, encompassing lipid-lowering therapy, antithrombotic agents, plaque stabilization strategies, and coronary revascularization via percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) [ 6 ]. These nanomaterials have emerged as pivotal tools in managing ASCVD by providing precise targeting to inflammatory macrophages and foam cells that drive plaque progression. Nonmetallic NPs enable stimuli-responsive drug release triggered by the unique microenvironment of atherosclerotic plaques. By integration of advanced imaging with therapy, these NPs facilitate a theranostic approach that allows for real-time monitoring of treatment efficacy and plaque vulnerability, ultimately improving clinical outcomes in vascular disorders. In in vivo experiments in which ApoE ⁻/⁻ mice were subjected to PTT, the CS-CNC@Ce6/DS group exhibited a substantial reduction in the plaque area via ablation of the activated macrophages [ 44 ]. In summary, carbon-based NPs can reduce drug side effects by enabling lower drug dosages through their high drug-loading capacity. Organic nanomaterials , organic NPs, such as liposomes, high-density lipoprotein (HDL)-like NPs, LDL-like NPs, polymeric NPs, and PEG-NPs, offer several advantages. Passive targeting in atherosclerosis is primarily driven by the ELVIS effect (Extravasation through Leaky Vasculature and Inflammatory cell-mediated Sequestration), a phenomenon analogous to the EPR effect in oncology [ 101 ]. However, its clinical utility is often limited by the high heterogeneity of human plaque biology and vascular permeability compared to highly controlled animal models [ 102 ]. Contrary to passive targeting, the active targeting strategy provides more precise drug delivery to atherosclerotic sites. It is designed to create nanocarriers with surface-modified ligands, enabling NPs to selectively recognize and bind to plaque [ 103 ]. Oxidation-sensitive PEG-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr) micelles switch from hydrophobic to hydrophilic when their tyrosine-oxalate cores react with ROS, simultaneously scavenging peroxides and releasing simvastatin via CD44-targeted uptake [ 133 ]. Collectively, none of these platforms have yet entered first-in-human studies, but their capacity to convert an endogenous stress signal into site-restricted therapy positions ROS-responsive nanomedicine as a logical next step toward clinically Lipid-directed therapies Several groups now exploit the biochemical hallmarks of lipid-rich plaques—oxLDL, crystalline cholesterol, and lipase activity—to trigger site-restricted drug release. Sugar–cholesterol amphiphiles sterically cloak scavenger-receptor A1, preventing oxLDL uptake and foam-cell formation in ApoE −/− mice [ 138 ], and phosphatidyl­serine vesicles adsorb directly to cholesterol crystals, dissolve them, and dampen NLRP3 signaling in Ldlr −/− models [ 139 ]. Metallic/ nonmetallic) Passive (ELVIS effect); Active (ligand functionalization) pH (IONP-HP); ROS (nanozymes) To target vulnerable and macrophage-rich plaques due to acidic condition (IONP-HP) Metallic NPs require coating to avoid cytotoxicity; Low toxicity for non-metallic NPs High (easier to synthesize consistently at scale) • First-in-human NANOM-FIM clinical trial (silica-gold) Organic NPs (e.g. Ultrasmall superparamagnetic iron oxide (USPIO) NPs were employed in the first MRI study of human atherosclerotic plaques [ 168 ]. Although nanomedicine offers promising treatment strategies for ASCVD in terms of precision medicine, there are currently only a few ongoing clinical trials. These NPs can be categorized on the basis of their biological targets or nanoplatforms. At present, lipid metabolism and macrophages within atherosclerotic plaques are among the most widely targeted mechanisms, whereas polymeric, lipid-based and liposomal NPs represent the most commonly used platforms in clinical trials (Table 6 ). To achieve improved targeting efficiency and reduce adverse events, lipid-based NPs encapsulating anti-inflammatory drugs were further studied. A lipid-nanoemulsion coating (LDE) that mimics the lipid composition of LDL has been developed, enabling uptake by LDL receptor-expressing cells such as inflammatory plaque macrophages. Recent phase II/III clinical trials have evaluated paclitaxel-loaded and methotrexate-loaded LDE formulations for their safety and efficacy in patients with stable coronary artery disease (CAD).