Gold nanoparticle-based strategies against SARS-CoV-2: A review

Yousef Rasmi; Kevser K. Kırboğa; Johra Khan; Ena Gupta; Fadia Mostafa; Murali M. Yallapu; Fernanda Pilaquinga

doi:10.1515/rams-2023-0105

Artikel Open Access

Gold nanoparticle-based strategies against SARS-CoV-2: A review

Yousef Rasmi , Kevser K. Kırboğa , Johra Khan , Ena Gupta , Fadia Mostafa , Murali M. Yallapu und Fernanda Pilaquinga

Veröffentlicht/Copyright: 31. August 2023

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Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 has been an immense threat to global public health and has also had a negative socioeconomic impact worldwide. However, although the pandemic is now under control, it has demonstrated that society is unprepared to use analysis methods that are applicable to various types of viruses nor apply new therapies to prevent infections, considering the extensive time needed for vaccine development. The use of nanomaterial-based diagnostics and therapeutics can provide essential strategies for both virus detection and treatment. Gold nanoparticles (AuNPs) are the nanomaterials most commonly used to enhance virus detection because of their bioconjugation, high plasmon resonance, and excellent electrical, optical, and catalytic properties. The present review outlines the recent advances reported in the literature regarding using AuNPs for their antiviral activities with respiratory viruses, analysis techniques such as AuNP-assisted polymerase chain reaction, biosensors (electrochemical, piezoelectric, and optical), lateral flow analysis, nucleic acid assays, and gene and vaccine therapy. Finally, as a potential antiviral treatment, this review provides in vitro and in vivo toxicity results of AuNPs for respiratory viruses, as well as those related to their toxicity in humans, to evaluate their use as a future antiviral treatment.

Keywords: gold nanoparticles; detection techniques; coronavirus SARS-CoV-2; COVID-19; toxicity; in vivo ; in vitro

Abbreviations

ALP: alkaline phosphatase
ALT: alanine transaminase
AST: aspartate transaminase
AuNPs: gold nanoparticle
AuNRs: gold nanorods
AuNSs: gold nanospheres
CALNN: pentapeptide: cysteine–alanine–leucine–asparagine–asparagine
CREA: creatinine
CTAB: cetyltrimethylammonium bromide
HCT: hematocrit
MEEE: 2-(2-(2-mercaptoethoxy)ethoxy)ethanol
MES: 2-mercaptoethanesulfonic acid
N/R: not reported
PAH: polyallylamine hydrochloride
PEG: polyethylene glycol
PEI2: polyethyleneimine
PSS: polystyrene sulphate
RBC: red blood cells
TMAT: N,N,N-trimethylammonium ethanethiol
WBC: white blood cells

1 Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19 was first detected in December 2019 in Wuhan, China [1]. SARS-CoV-2 belongs to the Coronaviridae family, Betacoronavirus genus, and Sarbecovirus subgenus. According to the World Health Organization, from the start of the pandemic till June 2023, the virus has spread globally, causing 6.9 million deaths and 689 million infections (57% in men and 43% in women) [2]. Its spread has steadily normalized despite having a massive impact on health systems and economies [3]. Although vaccines have been developed to lessen symptoms, the virus has not been eradicated. The persistence of the coronavirus teaches us an important lesson: society is unprepared to stop a virus’s rapid and vast spread [4,5]. In addition, a number of side effects and diseases have been reported by people with COVID-19. Although most infected individuals recover completely within a short period of time, some may experience lingering symptoms. COVID-19 can cause inflammation, damage to organs such as the heart and lungs, and neurological, cutaneous, or psychological problems that can have major long-term consequences [6].

SARS-CoV-2 has a spherical polyhedral shape measuring between 80 and 120 nm, and its genome consists of a single strand of ribonucleic acid (RNA). Regarding its protein structure, one of its essential proteins is the spike (S) glycoprotein, which binds to the specific receptor of its host with its characteristic crown-like shape. In humans, this receptor is angiotensin-converting enzyme 2 (ACE2), which is found in the respiratory, circulatory, and digestive systems [7,8]. The viral infection process begins when the S1 subunit of the S protein recognizes the ACE2 receptor. The S2 subunit then cleaves deep inside the cell, activating the transmembrane protease serine 2 and initiating the fusion mechanism. All of the virus’s genetic material is deposited inside the cell, where it is quickly trapped, leading to the viral transcription process, and the new polyproteins and proteases move from the endoplasmic reticulum to the Golgi apparatus. New copies are then assembled and executed, which reinitiates the viral replication process [9].

Omicron, the fifth variant of SARS-CoV-2, is characterized by more than 30 mutations in the S protein, unlike its predecessor delta, which had approximately 10. Recent studies in murine models found that omicron efficiently replicates in upper airway mucosal cells, unlike its predecessor variants, which showed greater affinity for lung cells, specifically type II pneumocytes. This variant is far more contagious; however, its fatality rate is lower, especially in patients who have received at least two doses of the vaccine [10], although the vaccine’s effectiveness on omicron is still being assessed. Thus, there is still no effective treatment available to prevent its spread. Once an organism is infected, drugs capable of limiting viral replication can be administered, facilitating a much faster recovery [11].

As the need to prevent virus spread and treat those infected has grown with the COVID-19 pandemic, nanotechnology has emerged as an alternative strategy [12]. Nanoparticles (NPs), which range in size from 1 to 100 nm, have been developed as innovative tools with diverse applications. In the biomedical field, NPs have been used as antiviral and antimicrobial agents and in biosensing, drug delivery, and imaging, among others [13,14,15]. NPs’ unique properties, such as small size, adjustable surface load, and large surface-to-volume ratio, facilitate bioavailability and control of release time, encapsulation of various types of drugs, and increased solubility. Different NPs’ potential use as antiviral candidates for respiratory diseases has already been demonstrated [16], and NP-based materials have been recognized as promising tools for stimulating or suppressing immune responses. In addition, NPs can be loaded with a variety of specific antigens, rendering them a highly promising alternative when compared to conventional vaccinology methods [17,18,19]. In addition to preserving the native antigen structure, NPs also improve antigen delivery and presentation to antigen-presenting cells. The main advantage of nanocarriers of vaccines is their nano-size: NPs can be administered via oral or nasal routes and subcutaneous or intramuscular injections, targeting central locations such as lymph nodes and penetrating mucosal and epithelial barriers [20,21,22].

Different NPs have already been used to improve the immunization efficacy of coronavirus vaccines; among them, polymeric, inorganic, self-assembled protein, and lipid NPs have intrinsic antigenic properties and can be loaded with coronavirus antigens [23]. NPs have also been used to stimulate cellular immunity through the targeting of dendritic cells [24,25]. In addition, as coronaviruses need to access cells during the infection process to replicate, some studies have examined NPs’ ability to avoid transduction by impeding virus binding to cell surface receptors. Thus, designing NPs with the proper size and surface charge to interact with viruses or virus receptors on host cells is essential to stopping infections [26,27]. In addition, metallic NPs have been shown to limit viral replication via a cell–virus blocking mechanism. A number of Ag-, Zn-, carbon-, silica-, and Au-based NPs have shown considerable antiviral activity against the herpes simplex virus (HSV), influenza A, human immunodeficiency virus (HIV), human parainfluenza 3, and zika virus, among others. Further, a nanomaterial made of graphene has been able to detect coronavirus; mimicking a biosensor, its graphene coating with a monoclonal antibody makes it sensitive enough to detect 1 fg·mL⁻¹ of SARS-CoV-2 with no previous treatment. Likewise, magnetite NPs coated with carboxyl polymers (pcMNPs) act as ORF1ab and R gene sensors in reverse transcription-polymerase chain reaction (RT-PCR)-linked sensing, meaning pcMNPs may be a better option for quick diagnosis [28].

One of the most widely researched nanomaterials is gold nanoparticles (AuNPs). In fact, the evidence of colloidal gold usage in China dates back to 2500 BC, and more recently, Koch discovered gold cyanide’s bacteriostatic antibiotic activity against the tubercle bacillus, which was first used in tuberculosis therapy in 1920 [29]. AuNPs, like the other noble metals, possess unique electrical, catalytic, and optical properties. AuNPs demonstrate an optical phenomenon known as surface plasmon resonance (SPR), an oscillation of electrons, at the specific wavelength of 510 nm; accordingly, AuNPs are recognized for their phototherapeutic capabilities. Because AuNPs are activated and produce vibrations in the presence of laser light, they are extremely beneficial in the targeted therapy of tumor cells. As a result, considerable efforts have been made in recent years regarding the development and application of AuNPs for the early detection, diagnosis, and treatment of cancer [30].

Due to their redox and electrical properties, AuNPs can act as sensors in electrochemical analysis or catalytic activity. Further, AuNPs have been used to improve the detection sensitivity of some bioanalytical techniques in viral detection [31], and they can conjugate with biomolecules such as peptides, proteins, nucleic acids, and antibodies [32].

AuNPs can also be used in the preparation of nanostructured particles for the transport and selective vectoring of drugs and therapeutic macromolecules, as well as in gene therapy (vehicleization of plasmids, DNA, RNA, and so on). Also interesting is the application of AuNPs in the construction of intelligent transporter systems that allow the release of the associated medicinal drug to be controlled in terms of location and time through the activation of either an internal or external biological stimulus [33].

Because of their antiviral and antibacterial properties and selective toxicity toward microbes, AuNPs have a wide range of biological uses. They have shown significant antiviral activity when functionalized with 1-decanesulfonic acid or 1-octanethiol against HSV, human papillomavirus (HPV), and respiratory syncytial virus (RSV) [34]. Further, several studies have shown that AuNPs have an antiviral effect specifically against respiratory virus types such as influenza A (H1N1 and H3N2), RSV, and rift valley fever (RVF) [35].

Considering the challenge that SARS-CoV-2 has represented for global public health and the importance of investigating it thoroughly, this review aims to provide an overview of the recent advances in the use of AuNPs as practical diagnostic and treatment tools for SARS-CoV-2 that can be used to mitigate the spread of COVID-19 and similar viral pandemics in the future. Antiviral activity against respiratory viruses; different methods of detection including PCR, biosensors (electrochemical, piezoelectric, and optical), lateral flow analysis (LFA), and nucleic acid assays; vaccine development; gene therapy; and toxicity of AuNPs are discussed (Figure 1).

Figure 1

AuNPs against SARS-CoV-2: in vitro and in vivo studies, AuNP-assisted PCR, biosensors, lateral flow analysis, and gene therapy.

2 Antiviral activity of AuNPs on respiratory viruses

AuNPs’ antiviral activity against viruses that cause respiratory diseases like SARS-CoV-2 is well known, and previous studies have particularly focused on certain viruses. Table 1 presents a summary of types of viruses for which AuNPs have been used. Regarding the selected in vitro studies that tested AuNPs’ efficacy against SARS-CoV-2, some focused on the S protein and measured signal change via the SPR of the NPs (Figure 2). According to the crystalline structure analysis, the coronavirus has several key disulfide bonds, namely, Cys336–Cys361, Cys379–Cys432, and Cys391–Cys525. In particular, Cys480–Cys488 is a key in the junction between the virus crest and the N-terminal helix of ACE2 [36]. AuNPs, because of their chemical affinity with sulfur, could be coupled to the virus and thus stop viral replication [37].

Table 1

In vitro and in vivo studies of AuNPs analyzed against the respiratory virus

Virus	NPs	Size (nm)	Concentration (time), administration route	Cell type/model	Results	Ref.
SARS-CoV-2	AuNPs coated with SARS-CoV-2 S protein	10–100	—	—	The S-Au protein bind was demonstrated using the change of SPR band based on an external pH change	[145]
SARS-CoV-2	AuNPs-thiol-modified antisense oligonucleotides	55.4 ± 4.5	0.18 ng·µL⁻¹	Vero	AuNPs agglomerate selectively in the presence of the target RNA sequence of SARS-CoV-2. It was demonstrated in their SPR	[146]
SARS-CoV-2	NPs mixed with AuNPs: AgNPs, ZnONPs, and ClO₂	<40	0.01–0.425 ppm	Vero	NPs block viral entry by inhibiting the binding of SARS-CoV-2 S proteins to the ACE2 receptor	[147]
SARS-CoV-2	AuNPs-thiols and a new peptide	—	—	In silico	Notable effects on the SARS-CoV-2 receptor binding domain. Strong interaction with S protein. AuNPs-new peptide form was more stable	[34]
Influenza A	AuNPs FluPep	10	—	MDCK	FluPep-functionalized NPs have enhanced antiviral activity	[39]
Influenza A	AuNPs- sialic acid	2–14	—	MDCK	The high binding affinity of AuNPs to hemagglutinin is located on the virus surface	[40]
Influenza A	AuNPs	17 ± 2	0.5 µg·mL⁻¹	MDCK	Hemagglutination and virus infectivity was significantly inhibited	[148]
Influenza A	Porous AuNPs	154.24 ± 37.05	0.2 mg·mL⁻¹	MDCK	Notable decrease in viral replication. Strong affinity for disulfide bonds, which blocked the entry of the virus	[149]
Influenza H3N2	AuNPs-antibody specificity to influenza A	10	—	MDCK	Was observed a selective recognition of influenza H3N2 through a sensor	[150]
Respiratory syncytial virus RSV	Carboxylated AuNP-anti-RSV peptide	13	0.125–4 nM	HEp-2	The percentage of viral inhibition was 80–90%	[32]
RSV	Carboxylated AuNPs-dendrimer peptides	15	30 µg·mL⁻¹	HEp-2	The percentage of viral inhibition was 60 and 50% in already-infected cells	[42,43]
Rift Valley fever (RVF)	Spherical and rod-shaped AuNPs	20	40 µM	In vitro, vivo: Vero, rats	AuNPs can induce an autoimmune response after one dose	[43]

Figure 2

AuNPs mechanism against coronavirus SARS-CoV-2.

Further, various studies have shown that COVID-19 can be treated using peptide inhibitors like heptad repeat 1 (HR1), which has been shown to inhibit HR1/HR2-mediated sheath merging between host cells and the Middle East respiratory syndrome coronavirus [38]. In one study, the peptide FluPep demonstrated excellent antiviral activity and efficiently inhibited influenza A viruses when functionalized with AuNPs [39]. In another study on the viral proliferation of influenza A using Madin-Darby canine kidney cells, the virus was effectively inhibited when viral hemagglutinin protein was targeted with AuNPs functionalized with sialic-acid-terminated glycerol dendrons, which was visually observed under electron microscopy imaging [40]. Many studies have also reported that AuNPs can significantly inhibit the proliferation of viruses by targeting the viral outer envelope [41]. In other studies with RSV [32] and RVF [42], viral inhibition of over 60% was observed [42], and in in vivo studies, an adequate immune response has been induced [43].

3 AuNP-assisted polymerase chain reaction

The RT-PCR technique amplifies a segment of the genetic material of interest and produces multiple copies. Thus, the PCR allows for the generation of millions of copies, or sometimes a single copy, of a particular nucleic sequence from an initial small sample. The PCR technique can be used as a molecular test to determine whether a virus’s genetic material is present in the samples taken. In the case of severe and critical COVID-19 cases, the PCR test is highly accurate, sensitive, and specific [44]. However, more effective PCR results can be achieved by shortening the reaction time, increasing amplification efficiencies, and varying heating/cooling rates. For the latter, NPs can be used, as they have an essential role in heat transfer. Further, despite its many advantages, the PCR method may cause false-positive results owing to the long diagnostic time required and limited specificity; however, advancements in traditional methods, some of which have involved NPs, have reduced these false positives, and significantly decreased diagnostic time [45,46,47].

AuNPs are the most common NPs used in diagnosing viruses [31,48,49,50]. For example, AuNPs have been used to detect COVID-19 in a colorimetric PCR. In this hybrid method, AuNPs amplify the PCR to increase sensitivity, provide good visuals, and allow for in situ detection at a low cost thanks to properties including ionic force, pH, protein conformation, size, and shape [51]. Table 2 presents a summary of studies on AuNP-based PCR virus detection. Some of the studies that compared different PCR systems and found positive results for AuNPs showed that NPs did indeed significantly improve PCR results by at least 104%. Other studies also showed that AuNPs potentiated PCR products and could improve the test’s specificity [52,53]. It was further found that AuNPs did not increase PCR specificity but instead suppressed the amplification of longer products while promoting the amplification of shorter products regardless of specificity [54]. After observing the surface interaction of AuNPs with PCR components, Lou and Zhang [55] found that interactions modulated the enzyme’s binding with the template and primers during the reaction and thus lowered the melting temperature of the matching primers. Hamdy et al. [56] used an AuNP-assisted PCR test to detect foot and mouth disease virus (FMDV); they noted that NPs functionalized with FMDV-specific oligonucleotides increased the sensitivity and specificity of the typical PCR assay 10-fold. In terms of SARS-CoV-2, RT-PCRs were utilized to extract and partially purify RNA from saliva using the Boom (from Qiagen) approach and the sugar chain-immobilized AuNPs method. When compared to the standard Qiagen approach, the AuNPs method had a direct relationship with symptoms of mild or moderate COVID-19 in patients [57].

Table 2

Gold nanoparticle-based PCR detections of viruses

Group/Virus	Target	AuNPs shape	AuNPs size (nm)	Biomolecule	Assay	Detection limit	Detection range	Detection platform	Time (min)	Ref.
Bunyaviridae hantaan virus (HTNV)	NC Protein	Spherical	30	DNA	IPCR	10 fg·mL⁻¹	105–1 fg·mL⁻¹	Microtitre plate	125	[151]
Retroviridae HIV	p24 antigen	Spherical	30	Antibody/DNA	IPCR	1 pg·mL⁻¹	10,000–1 pg·mL⁻¹	Microtiter plate	>125	[152]
Herpes virus-1 (EHV-1)	ND	Spherical	15	DNA	PCR	10²	10²–10⁴	Microtiter plate	ND	[153]
Japanese encephalitis virus (JEV)	JEV genome	ND	13.2	DNA	PCR	ND	ND	Blood-Based PCR	ND	[154]
Respiratory syncytial virus	F-protein	ND	15	DNA/antibody	NPA-IPCR	4.1 PFU·mL⁻¹	ND	Microtitre plate	ND	[155]

Some colorimetric methods in which AuNPs and globular nucleic acids act as binders have also been explored. In cases where the PCR technique cannot be applied on a large scale owing to insufficient resources and infrastructure, AuNPs can be used to visualize PCR products. This method prevents the single-component formation of spherical nucleic acids during the amplification process. Thus, positive and negative viral samples produce red and purple colors in the post-PCR colorimetric test [45,58,59]. It has also been found that larger-sized AuNPs can cause complete PCR inhibition at a lower particle concentration than smaller-sized AuNPs [45,60]. However, because the extent of AuNPs’ effect on PCR efficiency is not clear, it is key that AuNPs studies be reviewed in detail and carried out using the correct dimensions.

Hence, AuNPs show promise for obtaining a more accurate DNA synthesis curve and improved reaction efficiency during real-time PCR analysis. The studies reviewed herein suggest that AuNPs will be very useful for future studies’ advancement of PCR techniques.

4 AuNP-based biosensors

Given their simple production pathway, high plasmon resonance, excellent electrical/optical/catalytic properties, biocompatibility, and ability to simply detect antibodies, antigens, DNA, and RNA with 89–100% sensitivity, AuNPs are the most widely used metal NPs in biosensing applications for virus infections [61]. In general, AuNPs have mainly been used in second-generation biosensors because of their high surface-to-volume ratios, which improves the interaction between analyte and sensor. AuNP-based biosensors are classified into three main categories – electrochemical, piezoelectric, and optical biosensors (Table 3) – which are discussed in the following sections.

Table 3

Studies of Gold nanoparticle (AuNPs) base biosensors analyzed against respiratory viruses

Biosensors	Virus	NPs	Core-shell size	Objetive	Results	Ref.
Electro-chemical biosensor	SARS-CoV-2	Particular antisense oligonucleotides (ssDNA) capped with AuNPs	44.7 nm	The quantitative paper-based and rapid electrochemical biosensor chip were used to detect SARS-CoV-2 viral RNA in less than 5 min	In the presence of its target - SARS-CoV-2 RNA, a significant improvement in output signal was provided within less than 5 min of incubation time, with a detection limit of 6.9 copies per μL and a sensitivity of 231 copies per μL, with no further amplification	[156]
Electro-chemical biosensor	SARS-CoV-2	Fluorine doped tin oxide electrode (FTO) with AuNPs	—	eCovSens-Novel ultra-sensitive in-house built biosensor device (eCovSens) was used to compare with a commercial potentiostat to detect nCovid-19 spike antigen (nCovid-19Ag) in spiked saliva samples	eCovSens and FTO based immunosensor show high sensitivity for detecting nCovid-19Ag, varying from 1 fM to 1 μM. In standard buffer, nCovid-19Ag at 10 fM concentration can be successfully seen through an in-house developed device which is in close agreement with AuNPs/FTO sensor	[157]
Electro-chemical biosensor	MERS-CoV	Carbon electrodes (DEP) modified with AuNPs	50 nm	Development of a novel electrochemical immunosensor for the detection of coronavirus (MERS-CoV) using an array of AuNPs-modified carbon electrodes (DEP)	For MERS-CoV and HCoV, an excellent linear response was observed between the sensor response at the concentrations from 0.001 to 100 ng·mL⁻¹ and 0.01 to 10,000 ng·mL⁻¹	[158]
Piezoelectric biosensors (QCM)	Dengue virus	Oligonucleotide functionalized with AuNPs	2 PFU·mL⁻¹	AuNPs layer-by-layer hybridization in a surface of quartz crystal microbalance (QCM) DNA sensing for the detection of dengue virus	The dengue viral RNA was detected in virus-contaminated serum through DNA-QCM biosensing when plaque titers were 2 PFU·mL⁻¹ and a linear correlation range between 2 and 2 × 10⁶ PFU·mL⁻¹	[63]
Optical biosensors	Porcine Reproductive and Respiratory Syndrome Virus	Quantum dots and AuNPs	—	Development and Utilization of optical biosensor and nanophotonic technology to detect Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)	The developed sensors can efficiently detect PRRSV in solution with a detection limit of 3 particles per μL	[70]
Optical biosensors	SARS-CoV-2	AuNPs-citrate	15–38 nm	AuNPs to detect the sequences coding for the RdRp, E, and S proteins of SARS-CoV-2	Detection limit ≥10³–10⁴ viral RNA copies per μL
Opto-microfluidic sensing	SARS-CoV-2	Au spikes	1 μg·mL⁻¹	An Opto-microfluidic sensing platform was developed with electrodeposition of gold nanospike to detect antibodies against SARS-CoV-2 spike protein	A detection limit of 0.5 pM in 30 min. was achieved by the developed sensing platform that falls under the clinically relevant concentration range. The Opto-microfluidic platform offers excellent potential for serological assays and promotes faster, cheap and easy SARS-CoV-2 diagnosis	[71]

4.1 AuNP-based electrochemical biosensors

Electrochemical biosensors are frequently created using AuNPs, as they possess excellent catalytic properties, conductivity, and biocompatibility; they thus enhance electron transfer between redox centers of proteins, amplify electrode surfaces, and act as catalysts to increase electrochemical reactions. AuNPs also support electrochemical biosensing as they are highly biocompatible with easy protein functionality, and they improve transfer efficiency and surface-to-volume ratio [62]. The electrodes formed by AuNPs possess intrinsic metallic characteristics, resulting in excellent electrochemical behavior where free electrons migrate from the valence band to the conduction band. Nevertheless, it is essential to both biologically and chemically adjust NP surfaces when used with human specimens because of their high salt concentration. In the case of COVID-19, electrochemical biosensors, some of which have used AuNPs, have been successfully utilized to detect SARS-CoV-2.

4.2 AuNP-based piezoelectric biosensors

Research has found that analytical sensitivity can be improved by coupling the quartz crystal microbalance sensing process with AuNPs, as a high surface-to-volume ratio can amplify a mass charge on the crystals. Further, in many piezoelectric biosensors, AuNPs can enhance sensitivity and amplify signals; AuNPs facilitate rapid, sensitive detection by serving as an antibody carrier and mass enhancer in many sandwich-type immunosensors. In addition, piezoelectric biosensors possess a high potential to detect viruses from mechanical vibration or frequency changes by directly using output voltage. Piezoelectric biosensors have detected coronaviruses, HIV, and the viruses that cause hepatitis B, HPV, Ebola, vaccinia, influenza A, and dengue [63]. Interactions between DNA and the NP’s surface (through electrons from bases, phosphate groups, or electrostatic forces) can influence both DNA’s conformation and its electrical properties. Nanosensor materials containing AuNPs may aid in the creation of photonic equipment or biosensors for DNA detection in viruses such as SARS-CoV-2 [64].

4.3 AuNP-based optical biosensors

Colorimetric biosensors detect the presence of target biomarkers by causing the solution’s color to change [65]. The AuNP-based colorimetric method for detecting nucleic acid was introduced by Mirkin using a DNA probe [66]. In this method, 30-nm nonaggregated AuNPs, in addition to functionalized magnet beads, are used for 60 min with a detection limit of 50 fmol·mL⁻¹ to identify oligonucleotide sequences [67], which are detectable by color change via UV spectroscopy (Figure 3).

Figure 3

Schematic representation of a colorimetric assay based on antisense oligonucleotide-capped with AuNPs.

AuNPs are frequently used in optical bioassays because of their enhanced detection characteristics, including controlled fabrication, excellent visual performance, good biocompatibility, and particular catalytic activity. The central part of optical biosensors measures changes in photon or light output, and there are two types of detection methods: (1) indirect optical biosensors, in which a label (e.g., chromophore or fluorophore) detects a binding event and amplifies the associated signal, and (2) direct optical biosensors, which function the same as SPR biosensors by detecting the change in the refractive index at the analyte–sensor interface [68].

AuNPs can be used in multiple optical sensing methods; one example is with the SPR that results from the interaction between conduction electrons in a metal and the electromagnetic wave. The primary function of SPR is to study and characterize the physicochemical changes of thin films on the metal surface [69]. Optical transducers have also been focused on by studies of Au nanostructures because of their plasmonic properties that produce interparticle distance and plasmonic coupling. In addition, optical biosensors have been developed for accurate and rapid identification and detection of target biomolecules.

Further, numerous limitations of laborious conventional methods can be overcome by employing NPs. For example, practical and sensitive detection assays have been developed using advanced NP‐based detection strategies to quickly confirm respiratory virus infection [70,71].

Functionalized AuNPs with single-stranded DNA have also been used to detect the human p53 gene, including its 12 point mutation. AuNPs also possess distinctive SPR properties with high molar coefficients that show color change and size dependency. The aggregation of AuNPs with an SPR of 20 nm results in a color shift from red to blue in a colorimetric assay at 520 nm [72]. In the labeled type of colorimetric method, DNA ligands attach directly to AuNPs via chemical linkages before detection. AuNPs with modified ligands have higher hydration-based interparticle repulsions and are more stable at high ionic strength than simple AuNPs [73]. The ideal AuNPs aggregation can be achieved using cross-linking and noncross-linking. AuNPs aggregation via the cross-linked method is performed by inducing the controlled assembly of ligand-functionalized AuNPs, which forms a hydrogen bond that overrides the interparticle repulsive force. Chandrawati and Stevens [74] showed that AuNPs with peptide conjugate can be used to observe the concentration of factor XIII during blood clotting. Further, a one-step method for the rapid detection of MDM2, p14, and p53 (oncoproteins) was developed by Retout et al. [75]; the peptide-modified AuNPs form a ternary complex with MDM2, resulting in a color change from red to blue. Some recent research has also reported DNA’s effect on the diffusion of Au particles, which helps control the morphology of AuNPs. For example, Soh et al. presented a combined diagnostic method using DNA aptamers and colorimetric techniques through physical adsorption [76], while Alafeef et al. developed an AuNP-based RNA extraction-free nano-amplified colorimetric test for point-of-care detection of COVID-19 [77]. This method uses a unique dual-prong strategy that integrates plasmonic sensing with nucleic acid amplification to detect SARS-CoV-2 with 98.4–100% sensitivity and specificity in a concentration of 10 copies per μL. This colorimetric test can be visualized as a quantitative response in a handheld point-of-care device.

A recent colorimetric study employing AuNPs to identify SARS-CoV-2 used molecular beacon oligonucleotides. The flanking nucleotides stabilized the oligonucleotide structure and enabled the selective identification of target sequences in the viral genome in 2.5 h with the naked eye, with an amplification of ≥10³–10⁴ viral RNA copies per μL [78].

5 AuNP-based lateral flow assays for COVID-19 detection

The NP-based LFA is an easy-to-use, rapid, sensitive, and robust method to detect COVID-19 (Table 4) [79]. In an LFA, an analyte first reacts with labeled antibodies and moves further through the membrane by capillary force to the test and control zones and binds to captured antibodies [80].

Table 4

Some Commercially available lateral flow kits for COVID-19 detection

Lateral flow test kit type	Sample and detection type	Detection method	Sensitivity (%)	Testing time (min)	Ref.
BinaxNOW COVID-19 Ag Card, Abbott Diagnostics Scarborough, Inc	Nasal swab/N protein detection	Visual	100	15	[159]
CareStart COVID-19 Anti-gen test, Access Bio, Inc	Nasal swab/N protein detection	Visual detection	100	10	[160]
Lumira Dx SARS-CoV-2 Ag Test, Lumira Dx UK Ltd	Nasal swab/N protein detection	Fluorescence	96	12	[161]
Sofia 2 Flu + SARS Antigen Flow Immunoassay, Quidel Corporation	Nasal swab/N protein detection	Fluorescence	99	15	[162]
Biohit SARS-CoV-2 IgM/IgG Antibody Test Kit, Biohit Healthcare (Hefei) Co., Ltd	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	96.7	10–20	[163]
COVID-19 IgG/IgM Rapid Test Cassette, Healgen Scientific LLC	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	100	10	[164]
Diagnostic Kit for IgM/IgG Antibody to Coronavirus (SARS-CoV-2), Zhuhai Livzon Diagnostics Inc	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	90.6	15	[165]
qSARS-CoV-2 IgG/IgM Rapid Test, Cellex Inc	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	93.8	15	[166]
Sienna-Clarity COVIBLOCK COVID-19 IgG/IgM Rapid Test Cassette, Salofa Oy	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	93.3	15–20	[165]
SARS-CoV-2 IgG IgM Antibody Rapid Test Kit, Lumigenex Co., Ltd	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	100	15	[167]
SARS-CoV-2 Antibody Test, Guangzhou Wondfo Bio-tech Co., Ltd	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	86.4	15	[168]
RapCov Rapid COVID-19 Test, ADVAITE, Inc	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	90	10–20	[169]
Rapid COVID-19 IgM/IgG Combo Test Kit, Megna Health, Inc	Serum, plasma, whole blood/Antibody detection (IgM and IgG)	Visual	100	10	[170]

AuNPs are extensively used in LFAs because of their bioconjugation, optically tunable, and plasmonic properties. AuNPs function as labels in LFAs and visualize results as red-colored lines. To increase LFA sensitivity, AuNPs have been decorated with silica nanorods [81]. To detect COVID-19, Khlebtsov and Khlebtsov [82] demonstrated an LFA incorporating visual color detection that used AuNPs in low concentrations (between 6.5 × 10⁷ and 1.4 × 10⁵ NPs·mm⁻²) in a nitrocellulose membrane with a pore size of 10 µM. Serebrennikova et al. [83] reported an LFA that was five times as sensitive using hierarchical AuNPs in place of spherical AuNPs, while Zhang et al. [84] reported a limit of detection that was 100 times lower than normal using tipped flower-shaped AuNPs. Huang et al. [85] found that AuNP-LFA strips were more sensitive, specific, and stable in testing for COVID-19 in both positive and negative samples; further, the entire testing process required only 15 min compared to the various hours needed for PCR results, and only a minimum concentration of 10–20 μL was required. However, AuNP-LFA performance in COVID-19 testing depended on AuNPs’ protein coating concentration and the block effects of the nitrocellulose membrane. Tests were performed with different concentrations (i.e., 0.3, 0.6, 1.0, 1.2 mg·mL⁻¹) of SARS-CoV-2 AuNPs coated on the test; for positive tests, the brightest intensity of the test line corresponded to 1.2 mg·mL⁻¹. In another study, Cavalera et al. [86] developed a multitarget LF strip that could detect complete antibodies (IgG, IgM, and IgA) and the nucleocapsid protein of SARS-CoV-2. LF strips with AuNPs achieved 94.6% sensitivity and 100% specificity regarding the identification of IgA, which is produced earlier and at more detectable levels than IgG after SARS-CoV-2 infection. Thus, AuNP-based LF strips are more sensitive and provide results within minutes, making detection of COVID-19 faster and easier at point-of-care testing.

6 AuNP-based nucleic acid assays

The World Health Organization recommends the nucleic acid-based assay for COVID-19 testing as it is very specific and sensitive. This test depends on hybridization between probes and target, resulting in stable paring. This assay can also incorporate AuNPs: In the AuNPs-based nucleic acid assay, NPs are created using bifunctional ligands that bind as moieties on the particle’s surface [87]. Nucleic acid assays using AuNPs can be divided into different categories based on the approach used for detection, as follows: (1) the AuNP-based sol-particle immunoassay, (2) the cross-linking approach using functionalized AuNPs, and (3) the noncross-linking approach [88].

7 AuNP-based approaches in DNA hybridization

DNA hybridization-based biosensors have enormous potential for disease diagnostics and forensic applications because of their speed, low cost, sensitivity, and suitability for point-of-care testing. Metal NPs like AuNPs are characterized by optical and electrical properties that are excellent for use in biosensors to identify DNA hybridization. Further, the use of enzyme-linked DNA probes and luminance-measuring labels has been incorporated into recently developed diagnostic approaches using AuNPs, also known as chemiluminescence [89]. For example, Li et al. aggregated AuNPs with different concentrations of NaCl, which facilitates label-free DNA hybridization detection [21]. This method does not require DNA strand labeling or a strict stripping procedure for AuNPs, which reduces the use of poisonous substances, and the separate hybridization steps under optimal laboratory conditions can detect target DNA strands as low as 1.1 fM [90]. In another study, Li and Rothberg used unlabeled or modified AuNPs for DNA hybridization detection between single-strand DNA probes and target DNA, resulting in AuNPs aggregation visible to the naked eye or with UV spectroscopy; it was found to be more sensitive than the labeled DNA probe [91]. Li and Rothberg developed a new approach for detecting target DNA in a homogenous solution based on an AuNPs light-scattering assay; it can be considered a one-step detection technique for DNA hybridization [92]. The light-scattering technique is unique in that it can detect a base change in DNA without temperature control. It is a simple, sensitive tool for AuNPs aggregation detection in a homogenous solution and provides a path for simpler and more specific DNA hybridization detection using AuNPs [93]. Thus, the research demonstrates that many metal NPs have been developed for medical applications; while all have their benefits, AuNPs are found to be ideal for COVID-19 diagnosis.

8 AuNP-based approaches for gene therapy

Regarding the effects of AuNPs in gene therapy, methods utilizing antisense oligonucleotides (ASOs) and peptide nucleic acids (PNAs) as therapeutic agents have attracted scholarly attention. ASOs activate and modulate RNA function in cells via different mechanisms. As the coupling between ASOs and mRNA becomes a substrate, the mRNA cannot be transported to the cytoplasm, and protein production is inhibited [94]. ASO treatment can be applied to target viral RNA; it has been shown to be a successful method for many diseases such as neurodegenerative and cardiological diseases [95,96]. In addition, ASOs have been used in many human subject studies to determine their clinical suitability, and they have shown high efficacy against viral infections [45,97,98,99]. ASOs can easily be directed against the viral RNA of interest, impairing viral expansion, including SARS-CoV-2. Oligonucleotides bind to the targeted RNA and inhibit ASO translation [100].

Nevertheless, PNA’s slow cellular uptake into cells is a challenge that needs to be overcome. This slow uptake may be because negatively charged phosphate backbones tend to fold into complex structures due to affinity. The hydrophobicity state causes PNA aggregation and nonspecific adhesions, and this folding tendency poses several limitations to this technology [101]. However, nanotechnological structures can assist PNAs at this stage: PNAs combined with AuNPs create more biocompatible candidates with lower toxicity and greater biodistribution, and AuNPs’ tunable properties and accessible synthesis are further advantages. A study on antisense treatment for bovine viral diarrhea virus, which is a surrogate model of the human hepatitis C virus, showed that AuNPs are the most suitable method to provide PNAs to cells, which could lead to a potential tool for virus removal from infected cells [102].

Further, in 2020, Moitra et al. detailed a colorimetric test based on AuNPs coated with appropriately designed thiol-modified ASOs specific to the N-gene (nucleocapsid phosphoprotein) of SARS-CoV-2. The test could be used to diagnose positive COVID-19 cases from isolated RNA within 10 min. AuNPs, one of the ASO delivery systems, offer several advantages, including being able to bind to various types of molecules, low toxicity, and a broader absorption spectrum than other NPs [103]. No detailed studies have been conducted on using PNAs to disrupt the viral life cycle of SARS-COV-2 [104].

9 AuNP-based approaches in vaccine development

The application of nanotechnology in vaccines, known as nanovaccinology, is a growing field that focuses on enhancing the body’s immune responses. NPs have been used in various ways, for example, to transport antibody-triggering antigens or make them more potent. AuNPs are a popular building block for nanovaccines because they are inert in the body and easily absorbed by specific immune cells. They have previously been used as carriers or enhancers in nanovaccine research and have also attracted medical attention for their antimicrobial and anti-inflammatory properties [101]. Intense research efforts resulted in the first vaccine candidate for COVID-19, which was tested in a Phase I clinical trial on March 16, 2020 [105]. By May 22, 2020, 10 COVID-19 vaccines were in human clinical trials, while 114 were still in preclinical development [106]. Vaccine development relies on the direct administration of viral protein antigens (e.g., recombinant proteins, whole inactivated or attenuated virus, or vectored vaccines) or RNA or DNA that encodes viral antigens. The antigen candidate that induces immunization is the immunogenic spike protein (S1 subunit). As the S1 protein is essential for cellular uptake of the virus particle, many researchers concentrate on this protein as the primary target for a vaccine [107].

Conventional vaccines, such as inactivated, live attenuated viral, or subunit vaccines, possess certain limitations; for instance, there is a potential risk of viral virulence reversion (live attenuated viral vaccines) or weak immune response (inactivated viruses), as well as limited immunogenicity (subunit vaccines). However, recent advances in biological engineering have led to the design of nanotechnology-based vaccines that generate enhanced antigen presentation and strong immunogenicity [108]. NPs can assist in different ways to boost stimulation of the immune system and precisely direct the immune response against antigens [109].

There are different ways to deliver protein, drug, or RNA into a patient, but certain challenges, such as the vehicle often being degraded or swiftly cleared, impede successful delivery. NPs in the form of nanocarriers have the potential to overcome some of these limitations. For example, lipid-based, polymetric, or inorganic NPs could be manipulated to encapsulate cargo proteins with better protein delivery and pharmacokinetics than conventional methods [110]. In addition, intranasal application of encapsulated antigens has been found to induce a robust immune response; however, vaccine effectiveness depended on employing a suitable polymer compound with the antigen [111].

The target goal for most vaccines is to stimulate the production of the S protein [112]. For example, SARS vaccine research focused on S protein subunits, the receptor-binding domain of the S1 subunit, and the S protein/gene as the primary target sites [113,114]. Farfán-Castro et al. conducted one of the few studies on the use of AuNPs in vaccines, using a SARS-CoV-2 peptide with SH-PEG-NH2; the approach showed increased immunogenicity and cytokine production in mouse models, supporting the efficacy of nanovaccines in the battle against COVID-19 [115].

10 AuNP toxicity

Of all NPs, AuNPs have been most frequently used as vaccine platforms, as they are easily internalized by macrophages and dendritic cells, which induce their activation [116]. Their ease of conjugation to biopolymers has allowed them to be used in cosmetic products, biological markers, biosensors, and theranostics, such as thermal ablation of tumors, radiation sensitizers, and real-time imaging in vivo and in vitro [117]. The advantage of AuNPs is that in their colloidal form, they do not accumulate in the liver. According to reports, they also do not cause liver dysfunction in in vivo or in vitro models [118]. Polyethylene glycol (PEG)-coated AuNPs, on the other hand, are protected from absorption by phagocytes and can be gradually eliminated from the body or degraded within cells [118,119].

In in vivo models using rats, AuNPs ranging in size from 5 to 100 nm were added intraperitoneally in concentrations from 5 to 20 µg·kg⁻¹, orally from 20 to 1,300 µg·kg⁻¹·day⁻¹, and intravenously from 0.9 to 90 µg per rat. The reported effects ranged from low toxicity to oxidative damage in the lungs, renal tubule damage, increased pro-inflammatory cytokines, and lipid peroxidation in the liver [120,121,122,123]. In rabbit models, added AuNPs ranged in size from 5 to 25 nm and concentrations from 300 to 1,000 µg·kg⁻¹ and were applied intravenously. The models were exposed from a minimum of 12 h to a maximum of 7 days and showed excellent results associated with mild toxicity such as inflammatory reactions in liver, lung, and kidney tissues; morphological or histological changes were not evident [124,125,126]. In an in vitro study of pulmonary 3D models, AuNPs toxicity was found. Their size varied from 15 to 175 nm, and the dose ranged from 40 to 500 µg·mL⁻¹. The results demonstrated that size and material affected AuNPs’ toxicological potential [127].

Regarding the metabolization of Au and its potential application in humans, studies carried out in patients with rheumatoid arthritis examining the dose and course of treatment of Au salts and articular morphology showed low toxicity [128,129,130]. Freyberg et al. [131] analyzed the dose of total Au ingested and plasma and urinary volume according to different intake schedules. They found the salts were not stored in the synovial fluid; their excretion was mainly hepatobiliary, approximately >70%, with secondary pathways including renal, skin, and breast tissue during pregnancy, and plasma values remained high after intake. It has also been shown that Au is distributed in the liver, kidney, spleen, hematopoietic tissues, bone, skin, adipose tissue, and eyes but does not reach the brain or skeletal muscle [132]. Biochemical analyses have shown that Au ions induce and bind to low-molecular-weight metalloproteins, albumins, alpha globulins, and histones in distributed tissues, with albumins and metalloproteins being the most abundant; in both cases, Au binds to free thiol groups in cysteine residues [133]. Au has a low affinity for keratogenic tissues; high levels are deposited in the dermis and connective tissues. Rarely, skin pathology resulting from prolonged contact with Au has been reported. However, there are millions of cases of allergic dermatitis from Au rings. In addition, Au can easily be removed by natural flaking of superficial squamous cells or natural growth in hair follicles or nail beds. Au particles have also been deposited in the corneal stroma, lens, conjunctiva, Descemet’s and Bowman’s membranes, and retina.

In cases of inhalation of Au dust from mines by humans, effects on the respiratory tract, stomach, and liver have been reported; only 15 min of exposure was needed to trigger a respiratory condition [134]. Further, Kusiak et al. analyzed post-mortem samples from more than 54,000 miners in Ontario between 1955 and 1986 and found a correlation with the occurrence of lung carcinoma [135]. Another study conducted on gold miners in Australia, the Americas, and South Africa found an association between stomach, liver, and respiratory tract cancer in people with alcoholism, smoking, localized diseases, and HIV [136]. The evidence is unclear regarding whether Au exposure is related to the occurrence of some specific cancer types; nevertheless, it has been confirmed that it is not mutagenic or genotoxic [137].

AuNPs toxicity is generally associated with particle size, surface coating [138], and shape. These specific aspects lead to different chemical attributes, some of which cellular research has shown to be toxic and others nontoxic. In addition, research has shown that the organ distribution of AuNPs is size dependent. For example, small AuNPs (5–15 nm) were more widely distributed among organs than larger AuNPs (50–100 nm), with the liver and spleen being the major targeted organs [139]. AuNPs’ cytotoxicity in human cells has also been examined in detail, and studies have shown these NPs were nontoxic up to 250 mM, while ionic Au had a cytotoxicity at 25 mM [140].

The toxicity and biodistribution of PEG-coated AuNPs have also been studied. Results have indicated that AuNPs measuring 20 nm and coated with thioctic acid (TA)-terminated PEG5000 were the most stable and had the lowest toxicity among the 20-, 40-, and 80-nm AuNPs covered with TA-terminated PEG₅₀₀₀ [141]. While the toxicity of some AuNPs has been found to be size dependent due to their ligand surface coating [142], in others, their large surface-to-volume ratio provided an avenue for enhanced surface particle activity [143].

AuNPs’ interactions with biological systems are mostly associated with their physicochemical characteristics, which allow them to be internalized within cells, unlike larger particles. Greater doses of AuNPs may be more toxic than those of larger particles, which indicates the relevance of their size, considering their high surface-to-volume ratio, for their use in biomedical systems [144]. Most studies have focused on simple AuNPs (citrate or cetyltrimethylammonium bromide capped); thus, more research is needed on the toxicity and pharmacokinetics of functionalized AuNPs and should include accurate surface composition (e.g., recognition and nonfouling molecules) since surface modifications can change the overall effect of the AuNPs.

Finally, most in vivo studies focused on intravenous injection as the main administration route of AuNPs. More investigation is required to evaluate the toxicity of AuNPs that include alternative means of AuNPs exposure, such as inhalation, oral absorption, and dermal absorption. Table 5 presents some of the studies that evaluated AuNPs toxicity.

Table 5

Studies evaluating AuNPs toxicity

Animal model	Surface coating	Size	Shape	Exposure: dose/Concentration	Main results	Ref.
Mice	PEG	13 nm	Spherical	Intravenous; Single injection of 170, 850, or 4,260 μg·kg⁻¹	Acute inflammation and apoptosis by AuNPs were observed in the liver in a dose-dependent manner for 850 and 4,260 μg·kg⁻¹	[171]
Mice	PEG	4 and 100 nm	Spherical	Intravenous; A single injection of 4,260 μg·kg⁻¹	The PEG-AuNPs influenced apoptosis, cell cycle, inflammation, and metabolic processes in the liver. No histopathological changes in the liver	[141]
Mice	PEG	5, 10, 30 and 60 nm	Spherical	Intraperitoneal; a single dose of 4,000 μg·kg⁻¹	Damage to the liver with 10 and 60 nm, as revealed by significant increases in the activities of ALT and AST; damage to the kidney with 60 nm, as shown by the significant decrease in the level of CREA; increased WBC and RBC count in 10 and 60 nm indicates an inflammatory response and effect on the hematopoietic system, respectively	[138]
Mice	PEG	15 nm	Spherical	Intravenous; a single dose of 5,000 μg·kg⁻¹	Liver damage was observed	[172]
Mice	PEG	4.4, 22.5, 29.3 and 36.1 nm	Spherical	Intraperitoneal; 4,000 μg·kg⁻¹	More significant liver toxicity in male mice is revealed by substantial increases in ALT and AST levels; possibilities of infection in male mice, as indicated by significant increases in WBC and RBC counts; no important toxicological response in the reproductive system in both female and male mice	[173]
Mice	PEG	10, 30 and 50 nm	Spherical	Intravenous; 400 µg·kg⁻¹·day⁻¹ for 14 days	No effect on systolic cardiac function, and no cardiac fibrosis or infiltration of inflammatory cells by the three sizes; 10 nm AuNPs for two weeks resulted in reversible cardiac hypertrophy, 30 and 50 nm AuNPs did not affect cardiac size over 12 weeks; administration of 50 nm AuNPs for 12 weeks decreased the synthesis of collagen, while 10 and 30 nm AuNPs did not affect collagen synthesis	[174]
Mice	Citrate	3, 5, 8, 17, 12, 37, 50, and 100 nm	Spherical	Intraperitoneal; 8,000 µg·kg⁻¹·week⁻¹	The 3- and 5-nm size AuNPs and 50–100 nm did not produce toxicity, But 8–37 nm induced death, with abnormalities in the liver, spleen, and lung	[175]
Mice	Citrate	10 nm	Spherical	Intraperitoneal; 2.5 × 104, 5 × 104, and 1 × 105 μg·kg⁻¹·day⁻¹	Significant increase in the RBC count and AST levels in the 5 × 104 μg·kg⁻¹·day⁻¹, which is an indication of toxicity	[176]
Mice	Citrate	13.5 nm	Spherical	Oral, intraperitoneal and intravenous; 1,100 μg·kg⁻¹·day⁻¹	The highest toxicity was observed in oral and intraperitoneal administration routes, while the intravenous (tail vein) course showed the lowest toxicity	[177]
Mice	Citrate	13.5 nm	Spherical	Oral; 200 μL at 137.5, 275, 550, 1,100, and 2,200 μg·kg⁻¹·day⁻¹	Decreased body weight, RBC levels, and HCT were observed at high concentrations (550–1,100 μg·kg⁻¹). There was no apparent toxicity at low concentrations (137.5–275 μg·kg⁻¹)	[177]
Mice	Citrate	21 nm	Spherical	Intraperitoneal; a single dose of 7,850 μg·kg⁻¹	No detectable toxicity to vital organs; results correlated with significant fat loss and inhibition of inflammatory effects	[178]
Mice	Citrate	12.5 nm	Regular	Intraperitoneal; 40, 200, and 400 μg·kg⁻¹·day⁻¹	No evidence of toxicity was observed	[179]
Mice	Citrate	52.9 nm	Spherical	Oral; 0.2, 2 and 20 mg·kg⁻¹·day⁻¹	No toxicity was observed	[180]
Mice	Citrate	50 nm	Spherical	Acute: intravenous (single injection of 1,000, 2,000, and 10,000 μg·kg⁻¹; chronic: intraperitoneal (1,000 and 2,000 μg·kg⁻¹·day⁻¹)	The toxicity was dose-, time-, and exposure frequency-dependent. Toxicity was observed in both exposures, especially with higher doses (2,000 and 10,000 μg·kg⁻¹), while mortality was during the chronic study (2,000 μg·kg⁻¹)	[181]
Mice	Tween 20	20 nm	Spherical	Intravenous; acute (single injection of 100, 250, 500, 750, 1,000, 1,250, 1,500, 1,750, and 2,000 μg·kg⁻¹); subchronic (1,100 μg·kg⁻¹·day⁻¹)	There was no severe clinical or behavioral alteration in the acute toxicity test at all concentrations. In the subchronic test, it was found to be hepatotoxic	[182]
Rat	Porphyran	14 nm	Spherical	Oral; 375, 750 and 1,500 ppm·kg⁻¹·day⁻¹	Nontoxic and no abnormalities (in body weight, haematology or biochemical parameters) were recorded	[183]
Rat	N/R	10 and 50 nm	Spherical and hexagonal for 10 and 50 nm, respectively	Intraperitoneal; 5 µg/rat/day	10 nm AuNPs induced the highest toxicity in the liver and lung about time exposure. Size-dependent toxicity was noted	[184]
Rat	N/R	10 nm	N/R	Intraperitoneal; 5 µg/rat/day	Lipid peroxidation in the liver, but not in the heart and lungs	[120]
0	N/R	20 nm	N/R	Intraperitoneal; 20 μg·kg⁻¹	There were induction of oxidative stress, impairment of glutathione peroxidase in rat brain, and decreased dopamine and serotonin levels	[185]
Rat	N/R	5–10 nm	Spherical	Intraperitoneal; 5-mL solution containing 5, 10, and 100 µg/rat/day	Damage to the renal tubules	[186]
Rat	N/R	10 and 50 nm	Spherical for 10 nm, hexagonal for 50 nm	Intraperitoneal; 22 µg·kg⁻¹	Increased pro-inflammatory cytokines, which returned to normal after repeated exposure. The 50 nm AuNPs produced a more severe inflammatory response when compared to 10-nm AuNPs	[187]
Rat	N/R	10, 20, and 50 nm	Spherical for 10 and 20 nm, and hexagonal for 50 nm	Intraperitoneal; 50 and 100 µL·day⁻¹	Changes in the hepatocytes, portal triads and the sinusoids; Nuclear destruction	[184]
Rat	Citrate	14 nm	Spherical	Intravenous; 0.9, 9, and 90 µg per rat (500 μL each)	No experimental acute or subchronic toxicity	[188]
Rat	Citrate	10–25 nm	N/R	Oral; 20 µg·kg⁻¹·day⁻¹	Toxic to the lung, liver, and kidney	[189]
Rat	Citrate	20 nm	Spherical	Intraperitoneal; 2,500 µg·kg⁻¹·day⁻¹	No observed toxicity with every 48-h administration. But 24-h administration showed marked parenchymal changes, necrosis and leukocyte infiltration	[190]
Rat	Citrate	5–15 nm	Spherical	Oral; 325, 650 and 1,300 μg·kg⁻¹·day⁻¹	No detectable toxicity	[191]
Rat	Citrate, CALNN	citrate-AuNPs: 16.1 ± 2.8 nm, CALNN-AuNPs: 16.3 ± 2.8	Spherical	Intravenous; single injection of ∼0.7 mg·kg⁻¹	Significant decreases in HGB, HCT levels, and the number of RBCs, as well as spleen atrophy, were observed in rats injected with CALNN-AuNPs	[192]
Rat	Silica	100 nm	N/R	Intraperitoneal; single injection of 1,100 µg·kg⁻¹ and exposure to the static magnetic field (1 h·day⁻¹ for 14 day)	Oxidative damage was observed in rat lungs treated with AuNPs only, and more damage was observed when coexposed with a static magnetic field. This was due to the accumulation of AuNPs in the lung under a magnetic environment	[122]
Rabbit	Citrate	5 and 25 nm	Spherical	Intravenous; 1,000 µg·kg⁻¹ single dose	No apparent acute toxicity	[125]
Rabbit	PEG	7 nm	Spherical	Intravenous; 300 µg·kg⁻¹ single dose	There was no apparent acute toxicity, but inflammatory reactions in tissues, such as the liver, lungs, and kidneys, were observed	[124]
Rabbit	PEI2	N/R	N/R	Topical; 100 µL	No observed inflammation, redness, or edema in rabbit eyes, indicating a lack of toxicity of PEI2-AuNPs in corneal gene therapy	[126]
Zebrafish	Plain (spherical), CTAB, PSS, PAH (rods)	38.1 ± 2.8 nm (spherical), 12.7 ± 1.8 nm × 51.6 ± 8.2 nm (rods)	Spherical, rods	0.01, 0.025, 0.05, and 0.1 nM	No significant toxicity was observed with AuNSs at all doses tested. CTAB-AuNRs and PSS-AuNRs caused significant toxicity by high elevations in mortality and a decrease in hatching and heart rate. Additional coating with PAH further reduced the toxicity	[193]
Zebrafish	TMAT, MES and MEEE	1.5 nm	N/R	Waterborne; 100 μL, 0–250 μg·L⁻¹	Sublethal malformations were observed when exposed to MES-AuNPs, with no adverse responses on exposure to MEEE-AuNPs. Embryo mortality was induced by TMAT-AuNPs, with no mortality after exposure to MES- and MEEE-AuNPs. Pathways involved in inflammation and immune responses were affected	[194]
Zebrafish	TMAT	1.3 nm	Spherical	Waterborne; 100 μL 80–5 × 104 μg·L⁻¹	Disruption of the progression of eye development and pigmentation, and embryonic mortality	[195]
Zebrafish	Mannose	16.5 ± 2.0 nm (spherical), 47.6 ± 3.0 × 12.3 ± 1.5 nm (Rod), 42.3 ± 2.5 × 16.1 ± 1.0 (nanostar)	Spherical, nanorod, and nanostar	Intraperitoneal; 2 µL contain five µg·g⁻¹ single dose	No toxicity was observed up to 120 h	[196]
Zebrafish	Citrate	14 nm	Spherical	1.6 × 104 and 5.5 × 104 µg·kg⁻¹ dry weight; 0.25 and 0.8 µg·L⁻¹ released in water column	As well as increased activity of acetylcholinesterase, as well as modifications of genome composition, gene expressions, and DNA alterations, were observed	[197]
Broiler chicken	Gold(iii) chloride hydrate (99.995%) HAuCl4	37.31 nm	Spherical	Lowest (5 ppm) and medium (15 ppm)	It caused recognizable oxidative damage to blood, histopathological changes, up-regulation of IL-6, expression of Nrf2 gene, fragmentation of DNA, a significant decrease in antibody titer against avian influenza and newcastle disease	[198]
Drosophila melanogaster	Citrate	5, 15, 40 and 80 nm	N/R	Dispersed in the food; 5, 15, 40 and 80 nm	Substantial reduction of Drosophila lifespan and fertility performance	[199]

Allometric scaling should be used as an empirical method for estimating the pharmacokinetic properties of pharmacological products in humans based on preclinical animal datasets during drug discovery and development, particularly to determine a safe initial dose for preliminary clinical trials.

11 Conclusions

This study reviewed the recent advances concerning AuNPs as an effective antiviral model, different methods of SARS-CoV-2 analysis with AuNPs, and their toxicity when used as a therapeutic strategy. Regarding the specific antiviral activity of AuNPs on SARS-CoV, viral replication inhibition occurs through NPs’ binding with the SARS-CoV-2 S protein via its disulfide bridges owing to chemical affinity with Au. The same mechanism was reported for similar viruses such as influenza, RSV, and RVF, which support AuNPs’ antiviral activity on respiratory viruses. In terms of utilizing AuNPs to detect respiratory viruses, with PCRs, the suggested size is 15–30 nm, the quantification limit for different viruses is 1 fg·mL⁻¹, and for SARS-CoV-2, the amplification is ≥10³–10⁴ copies of viral RNA per μL. When using electrochemical, piezoelectric, and colorimetric biosensors, AuNPs should measure 30–50 nm; electrochemical biosensors have the lowest detection limit (6.9 copies per μL) and optical biosensors approximately 0.5 pg·mL⁻¹ in 30 min, while no studies have examined piezoelectric biosensors specifically for SARS-CoVo-2. For gene therapy approaches using isolated RNA ASOs, SARS-CoV-2 can be diagnosed in 10 min, which is the shortest analysis time compared to other techniques. The literature is scarce on the use of AuNPs in vaccines; however, using the SARS-CoV-2 peptide with SH-PEG-NH2 showed increased immunogenicity and cytokine production in mouse models, supporting the efficacy of a nanovaccine. Finally, the principal challenge associated with AuNPs application in illness diagnosis is their toxicity, namely, that it needs to be reduced and their bioavailability improved. Studies have shown that one advantage of using AuNPs is that they do not accumulate in the liver in humans in their colloidal form. In rats, AuNPs showed low toxicity, oxidative lung damage, renal tubule damage, increased pro-inflammatory cytokines, and lipid peroxidation in the liver. In in vivo models using rats, AuNPs (size: 5–100 nm) were added intraperitoneally in concentrations from 5 to 20 µg·kg⁻¹, orally from 20 to 1,300 µg·kg⁻¹·day⁻¹, and intravenously from 0.9 to 90 µg per rat. In rabbit models, added AuNPs ranged in size from 5 to 25 nm and concentrations from 300 to 1,000 µg·kg⁻¹ and were applied intravenously. In in vitro studies, size varied from 15 to 175 nm and dose from 40 to 500 µg·mL⁻¹. Studies on toxicity in humans show AuNPs are excipient. Despite many studies on AuNPs, more research is required that evaluates their toxicity in terms of the various exposure routes, dose, and genetic effect over the long term.

Funding information: This study was funded by Pontificia Universidad Católica del Ecuador.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Conflict of interest: The authors state no conflict of interest.
Data availability statement: All data generated or analysed during this study are included in this published article.

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Received: 2023-02-24

Revised: 2023-06-23

Accepted: 2023-07-21

Published Online: 2023-08-31

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/rams-2023-0105

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gold nanoparticles; detection techniques; coronavirus SARS-CoV-2; COVID-19; toxicity; in vivo; in vitro

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