Using nanotechnology for the diagnosis and treatment of coronary artery disease: a narrative review

Cardiovascular disease incidence is increasing worldwide, rendering it the most common cause of death worldwide. As such, nanomedicine has emerged in the context of overcoming these biological barriers. In this review, novel technologies are illustrated on two levels: molecular imaging and nanotechnology in atherosclerosis and therapeutic options in atherosclerosis. The former includes many diagnostic techniques, such as fluorescence imaging, computed tomography angiography (CTA), magnetic resonance imaging (MRI), photoacoustic imaging, contrast-enhanced ultrasound (CEUS), and multi-modality imaging. The latter is divided into two main subgroups: the first group includes inflammation-targeted therapies involving the endothelial cells and macrophages, and the second group includes nanoparticle transporters, like liposomes, micelles, dendrimers, polymeric nanoparticles (NPs), gel-like NPs, carbon nanotube, magnetic NPs, iron oxide NPs and gold NPs, and nanocoating (stent polymeric coatings to nanotextured ceramic coatings). In conclusion, nanoparticles show promise in enhancing the early diagnosis and targeted treatment of coronary artery disease. While several imaging and therapeutic techniques have demonstrated efficacy in preclinical models, only a few have progressed to human trials or clinical use.

Introduction

Cardiovascular diseases (CVDs) are responsible for the demise of 17.9 million people yearly, making it the main cause of death in the world.¹ According to the American Heart Association’s (AHA) 2022 report on heart disease and stroke statistics, the average yearly indirect and direct expenses of CVD in the US were an estimated $378.0 billion in 2017–2018.² Early detection of coronary artery disease (CAD) and proper treatment can reduce mortality, and the economic burden it brings along. Although progress has been made in the diagnosis of CAD, it has been limited by the low signal-to-noise ratio of conventional imaging modalities. Low drug bioavailability, due to poor absorption, drug metabolism and nonspecific distribution, is a great limitation in the management and prevention of CAD.³

To overcome these biological barriers, cardiovascular nanomedicine research has fabricated nanoparticles (NPs) for improved targeting and bioavailability. Different forms of nanostructured materials exist. There are nanoparticles, nanocapsules, nanotubes, nanogels, and nanofibrils. For years, researchers have been looking at using nanomedicine to diagnose, treat, and prevent CAD. Nanomedicine’s revolutionary outcome originates from its intrinsic tiny dimensions (1–1,000 nm). With their small size, NPs minimise their clearance rate, increase bioavailability, and improve solubility.⁴ Another desirable feature of NPs is their targeting moiety. Nanoscale carriers are made up of numerous functional components, including a targeting moiety, therapeutic payload, and nanoparticle core. NPs with targeted moieties to plaque and heart tissue can deliver the drug to desired therapeutic sites. Cardiovascular nanomedicine has evolved from employing NPs as targeted carriers to using them for actuators, biosensors, and devices that may be incorporated in the evaluation, therapy, early detection, and treatment of postoperative pain.⁵

This narrative review aims to discuss the application of nanomedicine in constantly evolving technology, diagnosis, and treatment methods for atherosclerosis and CAD. Despite impressive laboratory advances, the clinical adoption of nanotechnology in cardiology remains limited. Many approaches remain in preclinical or early investigational stages. This review distinguishes between technologies with established human use and those still confined to laboratory research, focusing on clinical relevance and translational hurdles.

Diagnosis of atherosclerosis using nanotechnology and molecular imaging

The traditional approaches of CAD diagnostic procedures do not detect ‘susceptible plaques’ as such. As diagnostic standards and technologies advance, molecular visualisation of CVDs using nanotechnology is evolving to identify particular targets, such as oxidised low-density lipoprotein (oxLDL), macrophages, microvessels, and so on.⁶ Early identification of CAD improves the chances of effective therapy and probable cure, giving patients a better prognosis and longer survival (tables 1 and 2).⁷

Fluorescence imaging

Because of its excellent qualities, such as non-invasiveness, high sensitivity, and ease of use, fluorescence technological advances in imaging have emerged as an important research tool in the fields of modern biomedicine and diagnostics. Synthetic fluorescent NPs can be used as probes to detect biological markers at the location of pathogenic changes, resulting in particular specificity. As a result, study on fluorescent nanoprobes used in preclinical studies to monitor the formation of arteries and inflammation has become a popular topic in recent years.³

Fluorophore-labelled nanomaterials have improved our comprehension of post-myocardial infarction (MI) reconstruction, including the role of inflammatory monocytes. Fluorescence detection needs light to absorb and emit, with the light wavelength employed influencing penetration.

Fluorescence molecular tomography (FMT) is another potential fluorescence-based imaging technique. Fluorescent nanoprobes, or photons, are carried three-dimensionally across the cells of interest before being collected to reconstruct an image. This image is made by combining the 3D data and calculating the arrangement of fluorescent particles. This method offers a spatial accuracy of about 1–3 mm. Increasing the number of source-detector pairs and nanoparticle contrast substances can improve resolution and quantification. The use of nanoparticle Bsmart probes to target macrophage-specific protease activity and active macrophages – both of which contribute to atherosclerosis – is one instance of FMT application in atherosclerosis.⁸

While fluorescence imaging excels in small animal models, it is limited in clinical translation due to poor tissue penetration and signal loss at greater depths.

Computed tomography

Computed tomography (CT) is the most reliable method of evaluating coronary artery narrowing and plaque calcification. Contrast compounds are frequently used in CT imaging. Unfortunately, most effective contrast agents contain hazardous atoms with high atomic weights. Nanomaterials outperform their molecular equivalents in terms of pharmacokinetics, biological distribution, and toxic effects, as well as contrasting capabilities and the ability to target specific organs or tissues.³

CT angiography (CTA) offers an image resolution of 25–250 µm, but it lacks the delicate connective tissue differentiation compared with magnetic resonance imaging (MRI), as well as the ability to characterise high-risk plaques, due to their heterogeneity. To solve these constraints, multi-colour spectral CT was developed, which employs hot-spot imaging to identify particular elements, such as calcium from iodine. CTA can identify several plaque features associated with acute ischaemia events, such as bigger vessel regions, positive remodelling, and a greater proportion of non-calcified and mixed plaques.

Monitoring macrophages is vital for early detection because they contribute significantly to acute plaque instability and thrombus development by secreting large quantities of tissue factor, which speeds up the growth of thrombus and rupture of plaque. An iodinated polymer nanoparticle for CT examination of macrophages in coronary atherosclerotic plaques was developed, and it resulted in significant amplification in differentiating atherosclerotic plaques from surrounding tissue, which was not possible with traditional contrast agents.

Similarly, a preclinical micro-CT method employing nanocapsules with high iodine concentrations (ExiTronTM MyoC 8000) was recently developed to continuously evaluate cardiac processes in vivo in healthy and MI-affected mice. ExiTron MyoC 8000 may detect MI at extremely low levels owing to its ability to be picked up by infarcted myocardium but not healthy tissue. The signal amplification following contrast agent injection was used to quantify infarct size. As a result, the established micro-CT approach enabled the monitoring of a wide range of processes, including heart remodelling.⁹

MRI

As a common non-invasive imaging tool, MRI is excellent for detecting abnormal blood vessel walls with plaques and thrombi. MRI, unlike positron-emission tomography (PET) or CT, does not employ ionising radiation, whereas ultrasonic and optical methods are unable to penetrate deep tissue. MRI has a major advantage over PET in terms of spatial resolution (submillimetre). Three-dimensional time of flight and rapid spin-echo angiography using MRI were recently employed to analyse carotid plaques with atherosclerosis, and the fatty core volume, fibrous cap thickness, and bleeding volume were precisely estimated. Stress projections and tissue strength assessments utilising multi-contrast MRI and MRI-inflammation imaging might also be used to assess the risk of plaque rupture. However, one disadvantage of MRI is that it detects contrast agents with far lower sensitivity than nuclear techniques. As a result, developing probes with sensitivity and specificity for excessive accumulation at vascular lesions is crucial to boost MRI use in CAD diagnosis.

MRI-specific contrast agents, notably gadolinium (Gd)-based and ferrous oxide NPs, have lately been studied for molecular visualisation of atherosclerosis and thrombosis. Because of their characteristics, NPs made of Gd or ferrous oxide provide obvious contrast effects in T1/T2-weighted MRI. Iron oxide NPs exhibit a variety of specific magnetic behaviours and properties, including superparamagnetism, surface-to-volume ratio, larger surface area, and ease of separation methodology, whereas Gd-based NPs exhibit high relaxivity, adapted biodistribution, and passive uptake in the tumour due to enhanced permeability and retention effect. Furthermore, ultrasmall nanoscale sizes combined with savvy surface modifications, such as biocompatible coverings (polymers or cell membranes) and targeting elements (antibodies, peptides, or ligands), significantly improve the specific build-up of MRI nanoprobes in shattered or rupture-prone lesions, resulting in a longer circulation time. As a result of these targeted Gd-based and iron oxide NPs, MRI may be performed with reasonable sensitivity for the identification of atherosclerotic plaque development, critical components, and associated illnesses, such as inflammation, laying the groundwork for future clinical applications.⁷

Inflammation following an acute MI has a negative impact on myocardial remodelling, reperfusion, and ventricular performance. Alam et al. were among the first to use MRI to detect inflammation in cells in human cardiac tissues via ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. Given the multi-functionality of USPIO-based nanoparticles and their enhanced safety characteristics, their findings provide new avenues for USPIO clinical application.⁹ Iron oxide NPs have been extensively studied due to their better biocompatibility, as a result of dextran coating. Preclinical investigations using nanoparticle-enhanced MRI have revealed information concerning neovascularisation, plaque macrophage inflammation, adhesion molecule expression, and inflammatory leukocytes throughout time.⁸ However, iron oxide NPs are not widely used due to safety and regulatory concerns.

Furthermore, the apolipoprotein monolayer facilitated the development of high-density lipoprotein (HDL)-like nanoparticles with an intrinsic affinity for atherosclerotic plaque macrophages, furthering the evolution of MRI contrast agents. These HDL-like particles have several benefits, including: a tiny size (7–12 nm diameter); endogenous, biodegradable protein components that do not cause immunoreactions; and the particles are not identified by the mononuclear phagocyte system (MPS). Furthermore, HDL-like particles are quickly reconstituted and may transport large amounts of a contrast agent, such as phospholipid-based gadolinium. Recent research has revealed that metal NPs, such as gold-coated iron oxide NPs for CD163 detection, can be utilised to image and treat atherosclerosis. The increased expression of the membrane receptor CD163 in macrophages from intraplaque haemorrhagic areas or asymptomatic plaques provides the foundation for this targeted method.⁹

Despite the preclinical effectiveness of MRI-based NPs, there are numerous challenges to scaling this technology for general use, including the need for baseline imaging with longer acquisition times than other techniques, complex synthesis schemes, and an improved comprehension of the interaction between synthetic polymers and biological systems.⁸

Photoacoustic imaging

Photoacoustic (PA) imaging is a novel biomedical imaging technique that employs broadband acoustic waves generated by the reaction of nanosecond pulsed light with photoabsorbers in tissues. PA imaging, which employs the same signal recognition methodology as ultrasound imaging, has the potential to combine high spatial resolution with conventional ultrasonic waves deep penetration by selective optical absorption.⁷ PA imaging creates spectroscopic ultrasound signals by absorption of light. Pulsed laser light raises the temperature near contrast substances by photothermal conversion, resulting in acoustically recorded pressure transients. Single-walled carbon nanotubes (SWNTs) were created for the specialised detection of early-stage high-risk atherosclerosis plaques by PA imaging, which relies on the selective phagocytosis of SWNTs by inflammatory monocytes and foam-like macrophages. Interestingly, PA signals from inflammatory atherosclerotic plaques were six times greater than in the control groups.³

Various nanostructures, including gold nanorods, gold nanocages, copper sulfide (CuS) nanoparticles, and graphene oxide, have been employed to identify CAD by PA imaging.⁷ The use of gold nanoparticles (GNP) can increase the contrast of a PA picture by causing free charges on the GNP surface to oscillate with the excitation wavelength, resulting in significant optical absorption and contrast. One research study established the feasibility of employing gold nanorods bonded to intercellular adhesion molecule-1 (ICAM-1) to detect early inflammation in endothelial cells, which might be associated with atherosclerotic plaque progression. Another research study employed accumulated NPs of gold to aim at atherosclerotic plaques in macrophages. When plasmon resonance coupling (approximately 700 nm wavelength) was used, the intravascular PA method was able to detect the presence of clumped NPs within macrophages in atherosclerotic plaques, providing greater resolution.⁹

Contrast-enhanced ultrasound (CEUS)

In healthcare settings, microbubble amplification mediums (albumin, lipid, and synthetic polymer) have been utilised to increase intravascular tracing reproducibility, used especially in echocardiography. Echogenic liposomal substances have been developed as novel ultrasonic wave contrast agents for studying the molecular aspects of atherogenesis and endothelial biology. Liposomes range in size from 20 nm to 10 µm and can form a variety of secondary forms dependent on dispersion. These aspects are critical in the development of cell-specific acoustic agents, since they all have an impact on the contrast agent’s biological properties. Acoustic liposomes conjugated with antibodies to vascular cellular adhesion molecule-1 (VCAM-1), ICAM-1, or fibrin, have been utilised in preclinical studies on atherosclerosis. Recent study has focused on VCAM-1, which allows for direct molecular visualisation of endothelium and vasa vasorum receptors, with reversible VCAM-1 expression discovered after starting statin medication. Many of these agents have been utilised therapeutically, therefore, there is a high likelihood of translating them, particularly for recognising high-risk plaques or intraplaque neovasculature.

PET

One of the most fundamental molecular imaging approaches is the use of the PET-tracer fluorodeoxyglucose (FDG) to capture metabolically active cells that are associated with underlying atherosclerosis. As a matter of fact, ¹⁸F-FDG is Food and Drug Administration (FDA)-approved for assessing inflammation in myocardium and arteries. PET has an enhanced resolution of 250 µm to 5 mm, which is acceptable for diagnostic purposes. FDG absorption has been associated to macrophage infiltration and circulating inflammatory markers in arteries with clinically significant CAD, according to studies. Despite these findings, numerous fundamental questions remain unsolved, such as uneven glucose absorption with pro-inflammatory mediators and non-specific glucose uptake due to tissue hypoxia.

A selective ligand of translocator protein (TSPO) is an alternative radiolabelled tracer that may be employed with PET and causes a multi-fold increase in monocyte activation during plaque formation. Carotid plaques with concomitant neurologic symptoms (stroke or transient ischaemic attack) were examined using PET/CT and the TSPO, which revealed a higher tissue-to-background ratio and decreased CT attenuation. TSPO uptake appears to be more focused and localised than FDG uptake, meaning that it may be more effective for interrogating intraplaque inflammation, while further study is needed for cardiovascular applications to become clinically approved. One important disadvantage to using this method is the necessity for an on-site cyclotron facility.⁸

Multi-modal imaging

Compared with the approaches outlined above, combining various imaging modalities produces complementary diagnostic data and provides complementary advantages over a single imaging modality, resulting in more sensitive and accurate CAD diagnosis. The objective is to improve detection by combining the characteristics of various NPs in hybrid nanosystems and use a variety of imaging modalities. PET-CT and PET-MRI, for example, combine PET’s sensitivity for metabolic imaging and tracking of labelled cells or cell receptors with MRI’s superior structural and functional tissue characterisation and CT’s anatomical precision.

One research study developed modified magneto-fluorescent nanomaterials that had a high affinity for endothelial cells expressing VCAM-1 and could be identified using MRI and fluorescence imaging. VCAM-1 expression begins early in human atheroma and is an important component of the inflammation that occurs during atherosclerosis, helping to attract monocytes and lymphocytes from adventitial arteries and the arterial lumen. Endothelial adhesion molecules are ideal targets for diagnostics due to their stringent temporal and spatial control and critical function in atherosclerosis.⁹

In addition to macrophages, myeloid cells contribute to the complicated immune response in ischaemic heart disease. Another study described an imaging technique that included myeloid cell-specific and multi-modal nanotracers. The nanotracers are composed of HDL with a perfluorocrown ether payload (¹⁹F-HDL) and are labelled with zirconium-89 and fluorophores, enabling simultaneous MRI, PET, and optical imaging. This multi-modal imaging technique will be a valuable addition to the immunology toolbox, enabling the dynamic analysis of complicated myeloid cell behaviour. Furthermore, integrating MRI and optical imaging for dual-modal imaging may effectively address their respective limitations: MRI’s limited sensitivity and optical imaging’s poor tissue penetration and spatial resolution.⁷

Targeted magneto-fluorescent nanomaterials, and other hybrid particles based on iron oxide and gold, have been utilised to detect several processes involved in MI, such as cardiomyocyte apoptosis and phagocyte recruitment, utilising multi-modal imaging. Furthermore, drug delivery strategies have been created employing liposomes, polymer nanosystems, extracellular vesicles, micelles, and lipid nanoparticles. The objective was to combat a range of ischaemia-related pathogenic processes, including ischaemia/reperfusion damage, cardiomyocyte apoptosis, inflammation, and oxidative stress, therefore, reducing post-MI pathological remodelling and preventing heart failure. To lower the risk of death, early identification of cardiac biomarkers, such as cardiac troponin I (cTnI), released into the circulation following myocardial injury has become critical.⁹

Despite great achievements, clinical implementation of nanoprobe-based molecular visualisation remains problematic. First, the biocompatibility, pharmacokinetics, and safety of nanoprobes in vivo should be extensively investigated. Second, large-scale manufacture of nanoprobes with regulated physicochemical qualities is essential for boosting their clinical use. Third, further research on the results of nanoprobes in complicated plaque microenvironments, as well as indicators of pathological alterations in susceptible plaques and thrombosis, will be prioritised in the diagnosis and treatment of CAD.⁷

Using nanotechnology in the treatment of atherosclerosis

Nanoparticles are promising agents in treating CAD, demonstrating potential for targeted drug delivery with improved efficacy and bioavailability. Their small size and biocompatibility make them ideal carriers for therapeutic drugs, allowing for precise intervention and addressing challenges associated with traditional treatment approaches (table 3).

Inflammation targeted therapy (table 4)

Endothelial cells

One therapy that may be very useful in cases of coronary heart disease is restoring oxygen and supplying nutrients to the site of ischaemia, and it can be done by promoting angiogenesis. Reis et al. mentioned that Wnt activation and neovascularisation result from a deficit in very-low-density lipoprotein (VLDL).¹⁰ At this level, plasmids with the extracellular domain of VLDL were created in encapsulated poly-nanoparticles (VLN-NPs) that have shown efficacy in suppressing cell migration, proliferation, and tube formation induced by Wnt3a, resulting in beneficial outcomes for plaque stabilisation and regression in atherosclerosis. Besides, Wnt activation plays a beneficial role in ischaemic heart injury by regulating the mobilisation of endothelial cells and their proliferation, in addition to its profibrotic effect: it raises the differentiation and proliferation of cardiac progenitors during ischaemic heart attacks.¹¹

Most appreciated therapeutic approaches focus on inflammation resolution: notably, annexin A1 (ANXA1) whose activity is mimicked by Ac2–26, its amino-terminal peptide containing amino acids. Note that ANXA1, with its mimetic peptides, are considered an endogenous anti-inflammatory agent and pro-resolving mediator, and as such, ANXA1 has a protective role in vascular injuries.¹² Collagen IV nanoparticles targeted with Ac2–26 have shown an augmentation of collagen and a diminishment in oxidative stress, and, thus, a reduction in plaque necrosis.¹³

Furthermore, on the level of molecular imaging and therapeutics, some NPs deliver therapeutic payloads to endothelial cells that overexpress the receptor for aortic plaque angiogenesis. In a study using integrin-targeted paramagnetic NPs incorporating fumagillin, molecular imaging demonstrated an effective non-invasive definition of atherosclerotic plaques and accurate delivery of targeted drugs. The NPs specifically targeted vascular alpha(v)beta3-integrin (αvβ3) expression, resulting in decreased MRI enhancement in fumagillin-treated rabbits (2.9%) compared with untreated ones (18.1%), showing the promise of molecular imaging and medication administration combined for assessing and treating atherosclerosis.¹⁴ These findings align with the concept of targeted NPs, such as arginine-glycine-aspartate (RGD) perfluorocarbon (PFC), which can efficiently deliver therapeutic payloads to cells that overexpress αvβ3, an integrin receptor, a critical marker in aortic plaque angiogenesis.¹⁴

Macrophages

Macrophages play a central role in the thinning of the atheromas’ fibrous cap, and subsequently their rupture, by phagocytosis, differentiation into foam cells, and secreting inflammatory cytokines. That is why one of the promising therapies is to diminish the recruitment of monocytes and their proliferation. As such, the differential activation of signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1-alpha (HIF1α) has been used to modulate macrophage responses in a hypoxic environment. Plus, this activation impacts other atherosclerotic phenomena like cholesterol biosynthesis.¹⁵

Moreover, docetaxel NPs have shown the ability to reduce the invasion of atherosclerotic plaques, macrophages and smooth muscles. In one study, a novel preparation of docetaxel carried in LDL-mimicking nanoparticles (LDE-DTX) demonstrated significant anti-atherosclerotic effects in cholesterol-fed rabbits. The intravenous administration of LDE-DTX resulted in an 80% reduction in atheroma area, pronouncedly lowered pro-inflammatory markers, and elicited a marked decrease in proliferation-promoting factors, suggesting the potential of LDE-DTX for future clinical trials without observable toxicity.¹⁶ On the level of direct action on monocytes, potent anti-inflammatory hormones, such as ANXA1 and anti-tumour necrosis factor (TNF), can be delivered through prolonged circulation of the liposomal glucocorticoid carrier.¹⁷

A study done by Wang et al. shows the effect of macrophages when coated with NPs, notably rapamycin, and rapamycin NPs may aggregate with activated endothelial cells, by which they suppress phagocytosis and consequently the progression of atherosclerosis is slowed down and delayed; as such macrophage-membrane NPs represent a biocompatible therapeutic target of the drug delivery system to treat atherosclerosis.¹⁸

In addition, the monocytic inflammatory cascade can be attenuated by administering lipid NPs that deliver small-interfering (si)RNA against C-C chemokine receptor 2 (CCR2), the pro-inflammatory chemokine receptor.¹⁹ This is a promising method to decrease macrophages in atherosclerotic plaques, as well as to reduce the infarction size after coronary occlusion.

Nanoparticle transporters (table 5)

Liposomes

Liposomes are nanometric vesicles composed of concentric lipid bilayers. Wang et al. have shown a possibility of using liposomes as nanocarriers due to their extensive plasma circulation, and the fact that some of them are heart-homing because of their CRPPR conjugation (ligand-conjugated) to cysteine-rich protein receptors. In atherosclerosis, the endothelial cells lining the atherosclerotic plaque become inflamed and express many chemokines and cell-adhesion molecules, notably VCAM-1, ICAM-1, ICAM-2, P-selectin and E-selectin.²⁰

Atherosclerotic lesions can be modified with antibodies to target vascular injuries using the expression of cell-adhesion molecules, integrins, selectins, and collagen. Moreover, liposomes may serve as nanocarriers for drugs. One study focused on enhancing thrombolysis efficacy using cyclic RGD (cRGD) functionalised liposomes encapsulating urokinase, a common thrombolytic drug. The results demonstrated that these cRGD liposomes, through specific binding to activated platelets and controlled release of urokinase, significantly improved thrombolysis efficacy by almost four-fold compared with free urokinase. This shows the potential of liposomes as effective nanocarriers for targeted drug delivery in thrombosis treatment.²¹

The advantage of using liposomes as carriers is their low immunogenicity. Moreover, they can cross the blood–brain barrier and can be used to carry drugs that treat strokes.²² Concerning the disadvantages, the greater costs and difficulty in fabrication may constitute some obstacles, in addition to their short-term stability, inducing premature drug release.²³

Dendrimers

Dendrimers are macromolecules that consist of a central core and numerous external functional groups. According to research by Katsuki et al., inflammatory monocyte recruitment plays a critical role in the pathophysiology of plaque instability and rupture in mice lacking apolipoprotein E.²⁴ By controlling monocyte recruitment and lowering gelatinase activity in the plaque, intravenous therapy with pitavastatin-included NPs, which were incorporated by monocytes from poly(lactic-co-glycolic) acid, indicated reduction of plaque instability and rupture. This implies that pitavastatin distribution via NPs, has potential as a treatment approach to prevent plaque instability and rupture by adjusting monocyte recruitment.²⁴

The application of dendrimers has been directed towards preventing thrombosis and providing cardioprotection through the delivery of protective factors, including poorly soluble hormones. Additionally, dendrimers have been utilised in conjunction with S-nitrosothiol, a recognised carrier of nitric oxide (NO), allowing them to store and release NO, offering potential benefits in inhibiting platelet aggregation.²⁵ Additionally, to improve siRNA internalisation in the cardiomyocytes and maintain their function after an infarction, dendrimers can be complexed with cell-penetration peptides.²⁶ Furthermore, polyamidoamine (PAMAM) dendrimers have been preferred for treating CVD. Additionally, photodynamic therapy using PAMAM dendrimers may show promise in the treatment of atherosclerosis.²⁷

The three main benefits of utilising dendrimers over other particles are their high solubility, low immunogenicity, and low leakage. They also have low poly-diversity. Nonetheless, they have high branch volume and surface charges, which can render them toxic.⁵

Micelles

Micelles are molecules consisting of amphiphilic substances, such as lipids and some polymers. They can incorporate hydrophobic therapeutic agents due to their self-assembling properties in an aqueous solution. As such, the hydrophobic core can be used to encapsulate or deliver bioactive therapeutic molecules. The active attachment to diseased cells and tissues can be increased by moiety attachment targeting the outer shell of the micelles.²⁸ In a study addressing restenosis after angioplasty, micelles and liposomes were investigated for local intra-arterial drug delivery.²⁹ Additionally, macrophages in atherosclerotic human aorta specimens can be targeted by micelles loaded with Gd and bearing anti-CD36 antibodies.³⁰

Polymeric nanoparticles

The primary class of materials used in the production of nanoparticles is polymers. A polymeric nanoparticle is a colloid that can have an active component on its surface or inside its core. Sizes range from 1 to 1,000 nm. Polymers are widely used because they are less toxic than metals, and can be accessed via chemically dynamic locations to functionalise an object. Polymers can be synthetic or natural.

One of the crucial steps in the development of atherosclerosis is the presence of arterial leukocytes, which are prompted by adhesion molecules. Polymeric endothelial-avid NPs encasing siRNAs were created to silence five crucial adhesion molecules to block recruitment more effectively. The aforementioned NPs could shield the siRNAs from degradation in serum and potentially stop serious consequences following acute MI.⁷

Apart from the beneficial effects of polymeric NPs, toxic effects have been reported. Amphiphilic polymeric micelles, namely poly(ethylene glycol)-polyglycerol-poly(ε-caprolactone) (PEG-PG-PCL), poly(ethyl ethylene phosphate)-co-poly(ε-caprolactone) (PEEP-PCL), poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL), and poly(ethyleneglycol)-distearoyl-sn-glycero-phosphoethanolamine (PEG-DSPE), caused alterations in cell size at high concentrations and increased pro-inflammatory molecules as a result of the elevated reactive oxygen species (ROS) level. However, no indication of a toxic effect on cellular membranes was reported.

Gel-like nanoparticles

Gel-like NPs are usually formed by suspension of pre-formed polymeric particles in a gel solution. A few sorts of injectable biomaterials were highlighted for the treatment of MI. A couple of them are made from nanofibres that can be connected for conveying restorative specialists. An example is injectable hydrogel RAD16-II (hydrogels of self-assembling peptides) for the delivery of vascular endothelial growth factor (VEGF), primarily utilised for intramyocardial carriage.³¹

Reddy et al. stacked gel NPs with an antiproliferative medication into a rodent carotid artery model of vascular injury to test the theory that intimal hyperplasia can be anticipated by confining the vascular smooth muscle cell (VSMC) from apoptosis.³² A great decrease was noticed in thrombosis while re-endothelialisation of the damaged artery increased.³³

Carbon nanotube

Carbon nanotubes are cylindrical structures built of sheets of carbon atoms and can range from 1 nm to more than 100 nm. Carbon NPs have been in use for in vivo imaging of CVD and acute MI.⁷

Carbon nanotubes (CNT) were utilised to provide conductive prompts to polymer frameworks utilised in cardiac recovery. Single-wall carbon nanotubes (SWNT) functionalised with Cy5.5 fluorescent dye (Cy5.5-SWNT) were utilised for photothermal ablation of macrophages in atherosclerotic plaques. Cy5.5-SWNT appeared to have a greater signal concentrated in ligated carotids by near-infrared fluorescence imaging.⁹

SWNTs were created to recognise early-stage high-risk atherosclerotic plaques by photoacoustic imaging based on the phagocytosis of SWNTs by the incendiary Ly-6 Chi monocytes and foam-like macrophages. Essentially, the PA signals from the affected wall plaques were six-fold more prominent than control.³

Magnetic nanoparticles

As MRI contrast agents, superparamagnetic iron oxide NPs are greatly used and are formed of two basic components, a magnetic material and a functional chemical component. Iron oxide NPs are T2-weighted contrast agents that generate a negative signal, in contrast to Gd, which is a T1 contrast agent.³⁴

Using magnetic nanoparticle-coated microbubbles (MMB-PLGA-PTX), Wang and colleagues demonstrated how to magnetically target poly (lactide-co-glycolide) nanoparticles (PLGA-PTX) loaded with paclitaxel (PTX) into the stents. Effective carriers for CVD work-up, treatment and focused targeting are provided by magnetic NPs. Bio-engineered proteins for therapeutics, gene trajectories, and magnetic nanoparticles are also said to be useful.³³

Chorny et al. (2010) created a magnetic nanoparticle that is biocompatible and loaded with paclitaxel, which is pulled to the stent struts and adjacent arterial tissues when a magnetic field exists.³⁵ This makes it easier for NPs to be localised and effectively inhibits in-stent restenosis.³⁶

Even though percutaneous coronary intervention (PCI) is now the most common method of revascularisation, in-stent restenosis still has negative side effects. Nanotechnology has been extensively used to prevent scaffold proliferation and inflammation in a variety of anti-restenosis studies. The localisation rates of stent-targeted magnetic NPs presented were, as a result, four to 10 times more than those of no-magnetisation groups.³⁷

Iron oxide NPs and gold NPs

Iron oxide particles share a fundamental composition of Fe, O, and OH, but vary in iron valency and crystal structure. Gold NPs, ranging from 1 nm to 100 nm, can form colloids when dispersed in water. Numerous studies have shown that iron oxide NPs are safe for human tissues and the environment.³⁴ Nevertheless, the passive delivery of iron oxide NPs primarily results in an enhancement effect at the plaque site, via increased vascular permeability, due to factors like injured endothelium and leaky microvessels.³⁸

Platelet membrane has been used to coat urokinase-loaded gold nanorods for the treatment of pulmonary thrombus, endothelium-protective epigenetic inhibitor-loaded dendritic nanoclusters for the treatment of restenosis, and rapamycin-loaded PLGA nanoparticles for stopping the progression of atherosclerotic plaque.³⁴ Briley-Saebo et al. designed lipid ultra-small iron oxide particles (LUSPIO NPs, 20 nm) conjugated with malondialdehyde-lysine or oxidised phospholipid epitopes to target and detect high-risk plaques.³⁹

Nanocoating: stent polymeric coatings – nanotextured ceramic coatings

Nanocoatings are ultra-thin layered structures that are built upon surfaces of a variety of materials. They are under testing for use with embolic spheres, stents, and synthetic heart valves. For uniform and controlled drug delivery into the vessel wall, co-polymer coating of a balloon-expandable EXPRESS2 stent with paclitaxel is one example.⁵

As a molecular-based therapy for atherosclerosis, a recent study developed HDL-like magnetic nanostructures (HDL-MNS). A research project carried out by Kheirolomoom et al. developed a novel strategy for specific binding of atherosclerotic plaques using cationic lipoparticles (CCL) with an anti-miR-712 core and a neutral coating adorned with a peptide to target VCAM-1 (VHPKQHRGGSKGC).⁹

Incomplete endothelialisation, extensive vessel remodelling, neo-atherosclerosis, and delayed arterial healing due to chronic inflammation have all been linked to the persistence of durable polymer coatings. In one study, among 32 patients, a polymer-free, dual-drug-eluting stent demonstrated favourable outcomes at 30 days, exhibiting no target lesion failure. Notably, at four months, the stent maintained promising angiographic results, with an in-stent late loss of 0.14 ± 0.19 mm and a low in-stent binary restenosis rate of 3.1%. The persistent durability of the stent’s polymer-free design was evident through extensive strut coverage (98.2%) and minimal malapposition (0.2%), further supporting its preliminary feasibility and safety for future comparisons with bio-permanent polymer drug-eluting stents.⁴⁰

In order to treat CVDs, cardiovascular stents coated with appropriate endothelial cells (ECs) have led to the creation of stents with active surfaces, particularly antibodies made to seize circulating ECs and endothelial progenitor cells (EPCs) in vivo. A novel method known as ‘cation electrodeposition coating’ was used to coat a stent with NPs that were captured by a fluorescein isothiocyanate (FITC) fluorescent marker.³³

Yi Wang et al. hypothesised that coating NPs with red blood cell (RBC) membranes may allow them to fool the phagocytosis process and stay in the circulation for a longer period. Adding an anti-atherosclerotic coating on RBC membrane-coated NPs may prove to be more beneficial, rather than uncoating them, for treatment.⁴¹

Conclusion and future perspective

The interest in nanomedicine for CAD has been on the rise, as it continues to show promising results in both the diagnosis and treatment of CAD.

Cutting-edge techniques on the horizon could redefine the future of CAD management. Nanoparticles, intricately coated with contrast agents, reveal a novel realm in diagnostic imaging, offering unparalleled visualisation of atherosclerotic plaques. Beyond the current capabilities of traditional imaging, nanomedicine’s unique advantage lies in its early detection of atherosclerotic changes, which can dramatically improve the prognosis.

The evolving future perspective embraces innovative techniques that delve deeper into the molecular pathogenesis of CAD. Using NPs in imaging, not only enhances our current understanding, but drives the development of highly targeted therapies. Future methodologies may optimise drug efficacy and bioavailability, using the small size and inherent biocompatibility of NPs. This multi-faceted application makes them the ideal vehicles for targeted drug delivery, promising to reshape the landscape of CAD treatment. Clinical translation remains an aspirational goal for most nanotechnologies. Only a few, such as PET and CEUS, have been partially integrated into cardiology practice. Bridging preclinical success with real-world application requires targeted trials and regulatory support.

While nanotechnology’s promise in CAD diagnosis and treatment is undeniable, the road ahead is extensive. Most studies remain confined to in vitro or animal models, necessitating crucial advancements in clinical trials to validate safety and efficacy in human subjects. Additionally, the unstable nature of nanoparticles remains a major challenge for manufacturing companies, and overcoming these challenges stands as a pivotal milestone, emphasising the ongoing commitment to refining and advancing nanomedicine for CAD.

Key messages

• Comprehensive nanotechnology integration: exploration of the diverse nanotechnology techniques for both diagnosis and treatment of CAD
• Precision imaging techniques: nanoparticles can enhance the accuracy of non-invasive imaging methods like fluorescence imaging, magnetic resonance imaging (MRI), computed tomography (CT), and positron-emission tomography (PET) in detecting atherosclerosis and inflammation markers
• Innovative approaches: nanotechnology provides groundbreaking approaches for detecting atherosclerotic plaques and treating them using nanoparticles and their transporters, targeted inflammation therapies, nanocoating technique, nanotubes, etc.

Conflicts of interest

None declared.

Funding

None.

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