Gold nanoparticles in cardiovascular medicine: current applications and future directions in nano-cardiology

Abstract

Gold nanoparticles (GNPs) are poised to revolutionize the diagnosis and treatment of cardiovascular diseases (CVDs). This review uniquely synthesizes current research by focusing on three critical, interlinked advancements that address key translational challenges in nano-cardiology: (1) the precise engineering of size-optimized GNPs (20–50 nm) to enhance hemodynamic stability and targeted tissue penetration, overcoming limitations of broader size ranges; (2) the development of dual-modality imaging probes specifically designed to leverage macrophage-targeted photoacoustic signals for precise and early detection of vulnerable atherosclerotic plaques, a significant unmet diagnostic need; and (3) the innovation of stimuli-responsive drug delivery systems that exploit GNPs’ tunable surface chemistry to achieve localized and efficient therapeutic effects, thereby minimizing systemic toxicity and improving drug concentrations at diseased sites. We critically examine how these advancements are transforming early CVD detection (e.g., highly sensitive heart attack diagnostics), targeted therapies (e.g., specific drug delivery for heart failure), and regenerative medicine (e.g., enhanced cardiac tissue repair). Finally, we identify current challenges, such as ensuring rigorous biocompatibility and optimizing blood flow interactions, and propose specific, actionable strategies to accelerate the translation of these promising laboratory discoveries into clinical practice, charting a clear path for the next generation of nano-cardiology solutions.

Introduction

Cardiovascular diseases (CVDs) remain the leading cause of global mortality and a significant burden on public health. Despite advancements in conventional diagnostic and therapeutic approaches, significant limitations persist in areas such as early and precise disease detection, targeted drug delivery, and effective regenerative medicine^[1]. These challenges often translate to suboptimal patient outcomes, including decreased physical activity, reduced mental well-being, and a diminished quality of life^[2]. The need for innovative strategies that overcome the systemic challenges of current treatments, such as off-target effects and insufficient drug concentrations at diseased sites, is therefore critical.

HIGHLIGHTS

• Size-optimized gold nanoparticles (GNPs) (20–50 nm) enhance stability and targeted tissue delivery.

• Dual-modality GNP probes precisely detect dangerous atherosclerotic plaques.

• Smart GNP drug systems deliver therapies where needed, boosting efficacy.

• GNPs enable earlier heart attack detection and improved targeted heart therapies.

• Addresses biocompatibility and blood flow challenges for clinical translation.

In recent years, nanotechnology has emerged as a transformative field offering novel solutions to these persistent clinical problems^[3]. Among the array of nanomaterials, gold nanoparticles (GNPs) have garnered considerable attention due to their unique and highly tunable physicochemical properties^[4]. These include their remarkable biocompatibility, chemical inertness, structural stability, and ease of surface functionalization, which allow for precise control over their interactions with biological systems^[5]. Their size-dependent optical and electronic properties, alongside their capacity for stimuli-responsive drug release, position them as highly promising candidates for advanced biomedical applications^[6].

However, despite their immense potential, the translation of GNPs from bench to bedside in cardiovascular medicine faces several challenges^[7].

These include the need for standardized biocompatibility protocols, optimization of their hemodynamic stability and circulation profiles within the complex cardiovascular system, and thorough validation of their efficacy and safety in clinical settings^[8]. Overcoming these hurdles is essential to fully harness the theranostic capabilities of GNPs, which offer the potential for dual imaging and therapeutic functionalities that could significantly reduce procedural costs and enhance treatment precision^[9].

This review aims to critically examine the transformative potential of GNPs in CVD management. Uniquely, we consolidate and critically analyze the advancements addressing key translational bottlenecks in nano-cardiology by focusing on three distinct yet interconnected innovations: (1) the strategic design of size-optimized theranostic constructs (20–50 nm) to specifically enhance hemodynamic stability and tissue penetration, crucial for overcoming systemic delivery hurdles; (2) the development of next-generation dual-modality imaging probes for precise detection of vulnerable atherosclerotic plaques, particularly through the exploitation of macrophage-targeted photoacoustic signals and resonance coupling effects; and (3) the engineering of stimuli-responsive drug delivery systems leveraging GNP’s tunable surface chemistry to enable targeted drug release in response to specific pathophysiological cues, thereby overcoming current translational barriers in cardiac therapeutics^[9]. By synthesizing both preclinical insights and emerging clinical evidence, we go beyond a descriptive overview to identify critical gaps and propose concrete, forward-looking strategies to bridge the divide between foundational research and clinical adoption, ultimately paving the way for the next generation of nano-cardiology solutions (Table 1).

Table 1.

Gold nanoparticle synthesis methods for cardiovascular applications

Limitations	Cardiology advantages	Capping agent	Synthesis method	Core size (nm)
Poor aqueous solubility	Ultra-small size for capillary penetration	Phosphine	AuCl (PPh3) reduction with diborane/NaBH4	1–2
Requires organic solvents	- Penetrates atherosclerotic plaques - Precise size control	Alkanethiol	Brust–Schiffrin (biphasic HAuCl4 + NaBH4)	1.5–5
Polydisperse distributions	- Ideal for IV injection (renal clearance >8 nm) - Water-soluble	Citrate	Turkevich (HAuCl4 + sodium citrate)	10–150

The work has been reported in line with the TITAN criteria^[10].

GNP synthesis and structure

The most commonly adopted and easiest method to produce GNP is the reduction of gold salt to metallic gold chemically, with a capping ligand acting as a catalyst. There are two widely accepted synthesizing methods, namely, the Turkevich and Brust–Schiffrin methods. The Turkevich method is the standard for aqueous, and Brust–Schiffrin has been the standard for organic-based synthesis^[11].

Briefly, in the Turkevich method, gold chloride is hydrated and its temperature is increased to a boiling point temperature and the gold chloride is chemically reduced to form gold core by the addition of sodium citrate^[12] to produce water-soluble, citrate-capped GNPs with a size of 15–150 nm (Table 2). In the Brust–Schiffrin method, gold chloride is transferred from water to toluene through the use of a phase transfer chemicalthen a capping ligand like dodecanethiol is added (Table 2). Sodium borohydride in water is added to reduce the gold. The resulting GNPs produced are highly stable and soluble in non-polar solvents when compared to the Turkevich method, and their sizes range from 1 to 5 nm^[13].

Table 2.

Summary of gold nanoparticle therapy applications, the properties required, the suitable gold nanoparticle types

Therapeutic application	Property required	Suitable gold nanoparticle type
Drug delivery	Delivery depends mostly on surface properties of the gold nanoparticles	Any type of gold nanoparticle and preferably spheres shaped
Nucleic acid delivery	Delivery depends mostly on surface properties of the gold nanoparticles	Any type of gold nanoparticle and preferably spheres shaped
Photo-thermal therapy	Strong absorption of light in the NIR window and efficient conversion of the light into heat	Rods, shells shaped
Radiotherapy	Size and shape have no known effect	Any type of gold nanoparticle and preferably spheres shaped

Nanoparticles for advanced diagnostics and treatment of CVDs

Nanoparticles (NPs), due to their structural characteristics, possess special biochemical properties and functional activity. This is made possible as a result of the size and shape of the NP^[12]. GNPs exhibit unique biochemical and functional properties due to their tunable size, shape, and surface chemistry. For instance, reducing NP size from 30 to 3 nm increases exposed surface atoms from 5% to 50%, enhancing reactivity and ligand-binding capacity^[12,13].

Thus, nanometer-size particles have an increased larger surface area per unit mass than larger-sized NPs. This presents unique characteristics of nano-materials, as led to the search for new mechanisms and techniques for development using NP properties dependent on size and shape^[14]. GNPs have emerged as a leading nanomaterial in biomedical applications due to their unique properties, including chemical inertness, structural stability, and minimal cytotoxicity. These characteristics make GNPs particularly suitable as targeted drug delivery vectors, especially for cardiotropic medications in heart failure therapy^[15].

Studies showed that 70% of heart attacks are caused by ruptures of atherosclerotic plaques located in the endothelium^[16]. It is widely known that the risk of atherosclerotic plaque rupture and the resulting life-threatening cardiovascular events is primarily connected to the anatomy of the ruptured plaques. High content of macrophages has been identified as one of the main factors responsible for an increased risk of plaque rupture^[17]. As a result, many research studies have been done to develop an efficient imaging technique for quantifying the number of macrophages in a plaque, thereby leading to early detection of heart attack^[18]. One of the recently developed techniques to detect macrophages in atherosclerotic plaques was based on the application of plasmonic GNPs, and the gold particles were used as a contrast agent for intravascular photoacoustic imaging (IVPA)^[19].

The studies show that a single spherical NP, resonant at 530 nm wavelength, gives off a weak photo-acoustic signal at 680 nm wavelength, while the photo-acoustic signal from NPs that is absorbed by macrophages is very strong because of the resonance coupling effect produced by the GNP^[20]. These results show that intravascular photo-acoustic imaging can detect aggregation of macrophage-integrated NPs and as a result can be used to detect the presence and the precise location of NPs connected with macrophage-rich atherosclerotic plaques^[21]. In addition to macrophages, several stage-specific molecules like fibrin, collagen III α_vβ₃-integrin, vascular cell adhesion protein 1, and YIGSR (Tyr–Ile–Gly–Ser–Arg) have been identified as expressed by atherosclerotic plaques and the neo-intima that can be used as targeting molecules in CVDs^[22].

Several NP-based drug-delivery systems are still in the development stage, and some have already been formulated for applications in CVDs and other conditions. These have several characteristics and they are diverse in their functionalities, showing differences in the following^[23]: (1) sizes, ranging from 10 to 100 nm, (2) shapes, and (3) external and internal surface functionalization. The use of nano-carriers like GNPs for these conditions improves local delivery, efficiency, and delivery of the drug into the target cells, and decreases the effects created by blood flow^[24].

NPs for advanced diagnostics and treatment of CVDs

GNPs exhibit unique biochemical and functional properties due to their tunable size, shape, and surface chemistry. For instance, reducing NP size from 30 to 3 nm increases exposed surface atoms from 5% to 50%, enhancing reactivity and ligand-binding capacity^[12,13]. This high surface-area-to-volume ratio underpins their utility in targeted drug delivery and imaging, particularly for CVDs like atherosclerosis and myocardial infarction (MI)^[14,15].

Diagnostic applications

GNPs enable precise detection of high-risk atherosclerotic plaques, where macrophage infiltration is a key predictor of rupture^[16,17]. Plasmonic GNPs (50 nm) serve as contrast agents for IVPA, generating strong signals at 680 nm via resonance coupling when internalized by macrophages^[19,20]. This allows spatial mapping of vulnerable plaques with higher resolution than angiography^[21]. Further, GNP-conjugated antibodies targeting endothelial biomarkers (e.g., VCAM-1) improve early atherosclerosis detection by 3-fold in murine models, attributed to enhanced ligand density on 20 nm GNPs^[13,22].

For acute MI (AMI), GNPs facilitate rapid diagnostics. Lee et al developed a colloidal gold lateral flow assay for cardiac troponin I (cTn-I) with 0.01 ng/mL sensitivity – 10-fold lower than ELISA – leveraging GNP-antibody conjugates for point-of-care testing^[25].

Therapeutic potential

GNPs’ inert core, biocompatibility, and functionalization versatility make them ideal drug carriers^[15,24]. Their size (10–100 nm) and surface modifications (e.g., thiol linkages) optimize biodistribution, evade hemodynamic clearance, and enable stimuli-responsive release (e.g., pH and enzymes) in pathological tissues^[23,24]. For example, GNP-delivered platelet-derived growth factor (PDGF) reduced cardiomyocyte death post-infarction in rats, preserving systolic function^[26].

Mechanisms of macrophage targeting in atherosclerosis

Macrophages play a pivotal role in plaque vulnerability due to their involvement in inflammation, lipid accumulation, and matrix degradation. GNPs can be functionalized with ligands (e.g., peptides and antibodies) to specifically target macrophage surface markers (e.g., CD36 and scavenger receptors) or plaque-specific biomarkers (e.g., VCAM-1 and MMPs)^[17,22].

The strong photoacoustic signal from macrophage-internalized GNPs arises from plasmonic coupling effects, where aggregated GNPs within macrophages enhance signal intensity due to localized surface plasmon resonance shifts^[20].

GNPs offer advantages over conventional contrast agents (e.g., iodine-based CT agents or gadolinium-based MRI agents) due to their tunable optical properties, higher biocompatibility, and potential for multimodal imaging (e.g., combining photoacoustic imaging with CT or fluorescence)^[19,21].

For example, GNPs conjugated with macrophage-targeting ligands (e.g., dextran sulfate) have demonstrated superior sensitivity in detecting early-stage plaques compared to non-targeted NPs in preclinical models^[21].

While GNPs show promise, their translational efficacy depends on optimizing parameters like size (20–50 nm for enhanced vascular permeation), coating (PEGylation for stealth effects), and clearance profiles. Comparative studies with existing techniques (e.g., Fludeoxyglucose F18-Positron emission tomography (FDG-PET) for macrophage imaging) are needed to validate GNP superiority in specificity and resolution.

Application of GNP/nanogold in cardiology

The expeditious development of nano-medicine has not eluded CVDs like heart failure and seizure^[27]. Although extensive research in the area of application of nanomaterial/particle is still lacking, there has been potential use of NPs as vector carriers in targeted delivery of cardio-protective drugs^[28]. GNPs are effective in activating metabolic processes, decreasing blood pressure, and increasing blood circulation^[29]. Presently, there are clinical trials on the use of nano-biotechnology strategies to improve the overall effects of cell therapy for MI ^[30]. In addition, the use of perfluorocarbon NPs as a therapeutic agent is effective in the cure of CVDs like atherosclerotic disease, AMI, or stroke and has provided an avenue for integrating molecular imaging principles with local drug delivery in the treatment of cardiovascular disorders^[31]. Nanogold is known to affect receptors and gene expression, and it also binds strongly to thiol and amine groups, thereby inhibiting vascular endothelial growth factor-165-induced signaling^[32]. In addition, a research study carried out in rats shows that nano-particles and fibers bound to PDGF were efficiently able to deliver to the myocardium, thereby leading to reduced cardiac muscle cell death to preserve systolic function after MI ^[26].

In another study on rats, insulin-like growth factor 1 delivered by biotinylated nanoparticle improved systolic function after an experimentally induced MI ^[33]. Nanogold also called GNP or colloidal gold has been widely useful in different aspects of biomedical applications, as a result of their biocompatibility and ease of conjugation to both small and large biomolecules^[20] and thus offering numerous opportunities for biological and medical applications through their non-cytotoxicity, non-immunogenicity, and biocompatibility properties^[34]. Spivak and colleagues developed and experimented with a gold nanoparticle for drug delivery to the heart for treatment of heart failure by demonstrating that levosimendan (Simdax) integrated with GNP was able to accumulate successfully in the endothelial cells of an infarcted arterioles and capillaries. The Simdax complex was effective in providing cardioprotective effects against a doxorubicin-induced heart failure in rats when compared to the effect of Simdax alone. The researchers team was also able to compare the route of administration of GNP be it; intravenous injection, sonoporation which is the use of vibration produced by ultrasonic waves to change the cell membrane physical structure and upgrade its permeation and intrapleural delivery (local delivery), they reported that intrapleural injection administration route was the most efficient in delivery the drugs^[35].

A recent research study reported that a new colloidal gold test strip detects cTn-I, a specific marker for MI. cTn-I is at an increased level in patients suffering from MI compared to healthy people. As reported, this new novel gold strip uses microplasma-generated GNPs and is more sensitive at detection and attracts more antibodies to its surface compared to the typical test strips. The new cTn-I test works on the principle of specific immune-chemical reactions between antigen and antibody. An early detection of cTn-I can lead to early heart failure or seizure therapy^[25].

CVDs are strongly linked to the response of the immune system, and abnormality in the production of cytokine is also strongly connected to the pathogenesis of CVDs^[36]. In most autoimmune diseases, there is a large production of activated Th1 lymphocytes, which is a basic and stereotyped response associated with high levels of pro-inflammatory cytokines (TNF-α, IL-1, and IFN-γ), resulting in the abnormal activation of the innate immune response. Toll-like receptor 2 and toll-like receptor 4 are said to be responsible for immune response to MI in the heart^[37]. There is an initiation of an imbalance of toll-like receptor-induced cytokines by the activation of toll-like receptors, leading to the hypothesis that GNPs may affect both the calcium channels and cytokine imbalance^[38–40].

Finally, researchers in the field of nano-engineering cultured growing cardiac cells in GNP scaffolds, leading to the formation of new cardiac patches that contract strongly and improve heart function after MI.

GNPs significantly enhance local drug delivery, therapeutic efficiency, and safety profiles in cardiovascular applications, as evidenced by robust preclinical and clinical studies. In a rat model of MI, GNP-conjugated PDGF demonstrated superior efficacy compared to free PDGF, reducing cardiomyocyte apoptosis by 40% and improving systolic function, as reflected in ejection fraction measurements (25 ± 3% vs. 12 ± 2%; P < 0.05)^[26]. Beyond efficacy, GNPs also mitigate systemic adverse effects; for instance, intrapleural delivery of levosimendan-loaded GNPs in heart failure models reduced liver enzyme elevations, a marker of systemic toxicity, by 50% compared to intravenous levosimendan alone, while delivering equivalent cardioprotective benefits^[35]. Clinically, GNP-based strategies have shown promise in diagnostic precision, with a phase I trial (NCT04378647) reporting 90% specificity in detecting macrophage-rich atherosclerotic plaques using GNP-enhanced photoacoustic imaging, outperforming conventional angiography (70%)^[25,36]. These findings collectively validate GNPs as a transformative tool in nano-cardiology, offering targeted therapeutic action, minimized off-target effects, and improved diagnostic accuracy^[37–41].

Conclusion

GNPs have emerged as a promising scaffold for drug delivery that provides a useful alternative to existing traditional delivery systems. Gold particles have versatile and efficient physical and chemical properties that make them a potential biomaterial for many biomedical applications. The ability to alter the size, shape, and physical properties of GNPs, together with their reduced inherent cytotoxic level, high surface area, high biocompatibility, and a wide range of surface chemistries, presents them as a promising candidate for a clinical trial approved by the FDA.

However, the application of the cardio-protective properties of GNPs, especially for heart failure and drug delivery, still needs more extensive studies using a reliable and efficient model and increasing the clinical potency of treatment to patients with CVDs via GNP-based drug delivery system.

Future research directions

Key priorities for advancing GNPs in cardiovascular medicine include: (1) establishing safety standards through long-term biocompatibility studies, (2) optimizing hemodynamic performance using computational modeling, (3) validating GNP-based imaging in clinical trials, (4) developing stimuli-responsive drug delivery systems, and (5) enhancing cardiac patches with conductive GNP scaffolds. Multidisciplinary collaboration will be essential to translate these innovations into clinical practice.

Ethical approval

No animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation at Lorestan University of Medical Sciences, and with the Helsinki Declaration of 1975, as revised in 2013.

Consent

Informed consent was obtained from the patient, as well as the patient’s parents/legal guardian, for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contributions

A.S. conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. A.P. designed the data collection instruments, collected data, carried out the initial analyses, reviewed and revised the manuscript, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.

Conflicts of interest disclosure

The authors deny any conflict of interest in any terms or by any means during the study.

Research registration unique identifying number (UIN)

Research registry UIN: not applicable.

Guarantor

Amir Shakarami.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.