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The Silver nanoparticle (AgNPs) have received attention for their antiviral potential against SARS-CoV-2. The objective is to conduct a scope review and map the scientific evidence on the use of AgNPs in mouthwashes as an adjunct in decreasing the viral load in the oral cavity of patients with SARS-CoV-2. A search was performed in the PubMed, Medline, Scielo databases, and a manual search in the reference lists, following the standards of the Joanna Briggs Institute for Scoping Review without restriction of year, language or sample size. Thus, 14 articles were included, where they researched the use of AgNPs with antiviral effect against SARS-CoV-2, mouthwashes for SARS-CoV-2 and AgNPs as mouthwashes. We can suggest that AgNPs are likely antiviral therapies for SARS-CoV-2 and its use in mouthwashes associated with other therapies are promising strands for decreasing viral load and infection by the virus.


INTRODUCTION
At the end of 2019, a virus emerged in Wuhan, China, which would later be called severe acute respiratory syndrome coronavirus 2, and spread rapidly around the world causing a global health emergency [1]. According to the Centers for Disease Control and Prevention (CDC) in the United States [2], the transmission of the virus is carried out mainly through direct contact or respiratory droplets [3] in a close and time-dependent manner, in addition to air transmission in certain circumstances, as most recently demonstrated [4,5], including prolonged exposure in an enclosed space without proper air handling [6,7,8]. Despite advances, the complexity of transmission and presentation of the disease has increased this, added to new variants brings the need to develop new preventive approaches [9].
The oral cavity is an important reservoir of SARS-CoV-2 [10,11,12], the use of an antiviral mouthwash is an interesting strategy, especially in the initial stage of the disease [13], where its viral load is extremely high in saliva [7,14]. In addition, saliva is an important source of transmission during the COVID-19 pandemic [10]. When a person coughs, sneezes, breathes or talks, drops of saliva are produced and can dissipate the virus [10,15]. Considering mouthwash as agents that can reduce the viral load of SARS-CoV-2 in the fight against the COVID-19 [10,16] pandemic is an extremely important concept to be taken into account [10,17].
In this way, nanomaterials can be described as single structures [18], free or in a compound, with a size within the nanometer range, generally less than 100 nm in at least one of its three dimensions [18,19]. There is a growing interest in nanomaterials, precisely because of their new or improved physico-chemical properties, such as durability, chemical reactivity, biocompatibility, conductivity or reduced toxicity [18,20]. Thus, they can be used in disinfectants, diagnostics, imaging tools, dressings, clothing, anti-cancer therapies, pharmaceuticals, drug administration, vaccines, diagnostic techniques and implants, among others [21,22,23]. Also, development of antiviral and antimicrobial drugs [24,25]. Antiviral nanomaterials are typically smaller than most viral particles, such as the SARS-CoV-2 viral particle, which has an average size of 120 nm [19,26], so they can interact with the entire viral particle or with surface proteins and other components structural, leading to virus inactivation [10].
Silver is an elemental metal and has a broad spectrum antimicrobial action against bacteria, fungi and viruses [27]. Silver nanoparticles (AgNPs) are highly versatile and are already present in microbicides for biological surfaces in various forms, such as medical devices, wound dressings, sprays and tissues [28]. In dentistry, AgNPs have drawn special attention because of their broad spectrum of antimicrobial activity, where their efficacy has already been demonstrated, however, the toxicity of AgNPs for use in oral infections is still being discussed [29]. AgNPs also attract the attention of dental researchers due to their potential for anticarious use [30], as they can inhibit the growth and adhesion of cariogenic bacteria especially Streptococcus mutans [30,31,32]. Studies investigate the addition of AgNPs in adhesives, toothpaste and restorative materials, studying the association between AgNPs and fluoride to stop caries, potentiating an antibacterial and remineralizing agent [33,34]. In addition, studies have demonstrated the potent antiviral action of AgNPs against various human pathogenic viruses, such as respiratory syncytial virus (RSV), influenza virus, norovirus, hepatitis B virus (HBV), human immunodeficiency virus (HIV) [26,35,36], and more currently, as a possibility for SARS-CoV-2 [28,35,36].
Recent studies have demonstrated the effectiveness of different mouthwashes to reduce salivary load and consequently to help reduce the transmission of SARS-CoV-2 [37,38]. However, there are still no studies in the literature evaluating the effectiveness of mouthwashes with AgNPs in reducing salivary viral load in patients with COVID-19 [39]. Therefore, the objective of this scope review is to map the scientific evidence and any gaps in knowledge about the use of mouthrinses with AgNPs as a potent antiviral agent or adjunct in decreasing the viral load in the oral cavity of patients infected with SARS-CoV-2.

MATERIAL AND METHODS
The methodology was defined following the Joanna Briggs Institute for Scoping reviews [40] and the PRISMA-ScR guidelines (Preferred Report on Systematic Reviews and Meta-Analysis for Scoping Reviews - Figure 1) [41]. The bibliographic research was conducted in 3 databases and in the gray literature, whose question was to map evidence on the use of AgNPs as an antiviral agent against SARS-CoV-2, and its use in mouthwashes with the potential to reduce viral load in the oral cavity, from patients affected by SARS-CoV-2, and with the guiding question: Mouthwashes with AgNPs, can be effective in reducing the viral load in oral cavity, of patients affected by SARS-CoV-2?

Scope of the search
A search was performed in the PubMed, Medline, Scielo databases, as well as a manual search in the reference lists of the studies that were included [42], without restriction of year, language or sample size. The first phase established an investigation to define the terms MeSH (Medical Subject Headings) to ensure high sensitivity and accuracy, and the researchers tracked titles and publications of abstracts. The MeSH terms used in searches in all databases were "COVID-19" or "SARS-CoV-2" or "Coronavirus Infections" or "Coronavirus" and "Mouthwashes" or "Mouth-rinses" and "Silver nanoparticles" and "Antiviral", and crossed elements ("silver nanoparticle" and "oral rinses"), ("silver nanoparticles"and "COVID-19"), ("silver nanoparticle"and COVID-19 and mouthwashe) and ("oral rinse" and " COVID-19").

Inclusion and exclusion criteria
This review included studies reporting the use of AgNPs in mouthwashes, as a therapeutic approach to reduce viral load in patients infected with SARS-CoV-2, to solve the hypothesis that it would be possible to use mouthwashes with AgNPs to reduce viral load in patients infected with SARS-CoV-2. At first, the original articles, without language or year restriction, with an abstract available in the database, were evaluated and validated within the inclusion criteria, by reading the title and abstract, by two authors [43]. Inclusion criteria were defined  Table I) and consisted of primary research studies in full, "in vivo", "in vitro" or animal research, and excluded opinion articles, letters to editor and literature reviews.

Selection and quality assessment of relevant studies
The articles selected according to the election criteria were retrieved in PDF format, numbered and randomly distributed among two researchers [43]. To increase the sensitivity and quality of review, the references list was manually checked. To discuss divergences, a consensus meeting was held [43] and an third experienced researcher was consulted

Extraction and processing
The articles included in the study were randomly distributed among the researchers for the collection of relevant data [43]. The articles were then organized into 03 tables, namely: studies that portray the use of AgNPs against SARS-CoV-2 with antiviral potential (Table II); studies that portray the use of mouthwashes for patients with COVID-19 (Table III) and studies that bring AgNPs in mouthwashes (Table IV).

RESULTS
After the process of evaluation and selection of articles, 14 articles were included in the scoping review, 03 of which portray AgNPs as antiviral Table I -PCC estrategy and the criteria included in the search for articles

Population
People infected by SARS-CoV-2

Concept
Administration of mouthwashes with AgNPs to control / reduce the viral load of SARS-CoV-2

Context
Global health, in view of the current SARS-CoV-2 pandemic, and its high infectivity, mainly via the oral cavity through the formation of aerosol in the dental office, as well as droplets produced in speaking, coughing, and sneezing, for example. Particles in diameter around 10 nm were effective in extracellular inhibition of SARS-CoV-2 at concentrations ranging from 1 to 10 ppm, while the cytotoxic effect was observed at concentrations of 20 ppm and above. The luciferasebased pseudovirus entry assay revealed that AgNPs potently inhibited the viral entry step by disrupting viral integrity.
Valdez-Salas et al., 2021 [45] Promotion of Surgical Masks Antimicrobial Activity by Disinfection and Impregnation with Disinfectant Silver Nanoparticles.
Developed a new alcohol disinfectant formulation combining special surfactants and AgNPs The nano-disinfectant provides a valuable strategy for effective decontamination, reuse and even promotion of antimicrobials for surgical masks for frontline clinical personnel. Efficacy of commercial mouth-rinses on SARS-CoV-2 viral load in saliva: randomized control trial.
Iodine-povidone (PVPI) 0.5%, chlorhexidine 0.2%, cetylpyridine chloride (CPC) 0.075% The use of CPC and PI formulated that commercial mouthwashes can be useful as a pre-procedure rinse to help reduce the transmission of SARS-CoV-2.
Steinhauer et al., 2021 [43] Comparison of the in vitro efficacy of different mouthwash solutions targeting SARS-CoV-2 based on the European Standard EN 14476.
Chlorhexidine digluconate 0.2% and octenidine dihydrochloride (OCT) Based on these in vitro data, the OCT rinse is an interesting candidate for future clinical studies to prove its effectiveness in a potential prevention of the transmission of SARS-CoV-2 by aerosols.
Essential oils with ethanol (20-30% Ethanol Thymol 0.064% Methyl salicylate 0.06% Menthol (Racementol) 0.042% 0.092% Eucalyptol); 1% povidone-iodine; Hydrogen peroxide 1.5% and chlorhexidine gluconate 0.12% All mouthwashes tested against inactivated SARS-CoV-2 virus. Listerine and CHG were less cytotoxic than Colgate Peroxyl or povidone-iodine and were active against the virus. When mouthwash was present in the cell culture during infection, the potent antiviral effect of mouthwash was in part due to the cytotoxicity associated with mouthwash.
Pelletier et al., 2021 [47] Efficacy of Povidone-Iodine Nasal and Oral Antiseptic Preparations against SARS-CoV-2 PVPI 1% to 5% The nasal and oral antiseptic solutions of PVPI are effective in inactivating SARS-CoV-2 in a variety of concentrations (nasal, oral and surface decontamination) after exposure times of 60 seconds.
PVPI 0,5%, 1% and 1,5% PVPI preparations rapidly inactivated the SARS-CoV-2 in vitro. The virucidal activity was present at the lowest concentration of 0.5% PVPI and the lowest contact time of 15 seconds.
PVPI 0.5%, 1.25% and 1.5%, and hydrogen peroxide (H2O2) was tested at 3% and 1.5% SARS-CoV-2 was completely inactivated by the oral antiseptic rinse of PVPI in vitro, in the lowest concentration of 0.5% and in the shortest contact time of 15 seconds. H2O2 at the recommended oral rinse concentrations of 1.5% and 3.0% was minimally effective as a virucidal agent after contact times of up to 30 seconds. Therefore, the pre-procedure rinse with PVPI diluted in the range of 0.5% to 1.5% may be preferable to hydrogen peroxide during the COVID-19 pandemic.

Gottsauner et al., 2020 [50]
A prospective clinical pilot study on the effects of a hydrogen peroxide mouthrinse on the intraoral viral load of SARS-CoV-2.

Hydrogen peroxide 1%
A 1% hydrogen peroxide mouthwash does not reduce the intraoral viral load in individuals positive for SARS-CoV-2. However, the culture of the virus gave no indication of the effects of the mouthwash on the infectivity of the detected RNA copies.
ViruProX® with 0.05% cetilpiridinium (CPC) and 1.5% hydrogen peroxide (H2O2); BacterX® pro containing 0.1% chlorhexidine (CHX), 0.05% CPC and 0.005% sodium fluoride (F-); and some of their individual components as 0.05% CPC solution, 0.1% CHX solution, a combination of 0.05% CPC with 0.1% CHX solution, and 1.5% H2O2 solution While a combination of CPC and CHX, as well as CPC alone led to a significant reduction in infectious viral particles, H2O2 and CHX alone had no virucidal effect against SARS-CoV-2. It can be assumed that pre-procedure mouth rinsing with ViruProX ® or BacterX ® pro will reduce the viral load in the oral cavity and, thus, decrease the transmission of SARS-CoV-2 in dental practice.  (Table II), 08 articles bring the use of mouthwashes against SARS-CoV-2 (Table III) and finally, 03 articles expose AgNPs in mouthwashes (Table IV). These were articles in the English language, published between 2014 and 2021, covering experimental studies "in vitro" and "in vivo".

DISCUSSION
The SARS-CoV-2 has already caused millions of deaths worldwide and due to its rapid spread it is difficult to contain the transmission [9]. Personto-person contact through respiratory droplets generated by sneezing and coughing in infected individuals has been shown to be the main route of transmission of SARS-CoV-2 [10,43,44,46]. In addition to the efficient use of personal protective equipment, such as masks, and maintaining social distance, it is necessary to implement more active prevention strategies.
One of the main approaches to minimize the risk [37] of transmission of SARS-CoV-2 would be to reduce the viral load of SARS-CoV-2 in the saliva of infected patients [37], which is particularly important in high-risk procedures, such as dental treatment [37,47]. When a symptomatic or asymptomatic patient goes to the dental office, he can transmit the SARS-CoV-2 through contact with other people, direct transmission to the dentist or indirect transmission through contamination of surfaces, even more so today with the flexibility in use of masks [55].
The use of antiseptic mouthwash has been suggested as a pre-procedural infection control measure by health authorities since the early stage of the COVID-19 pandemic [37], when they recommended the use of mouthwashes with povidone-iodine (PVP-I) [47,48,49], hydrogen peroxide [49,50] or cetylpyridinium chloride (CPC) [43,46] as a pre-procedure preventive measure. However, it is important to emphasize that these recommendations were not based in robust scientific evidence. The first case report on the effectiveness of mouthwashes in reducing the viral load of SARS-CoV-2 in saliva was reported in Korea [13,37,56]. Other studies suggested that mouthwash with PVP-I could reduce the SARS-CoV-2 salivary viral load [47,48,49], and the efficacy of virucidal mouthwash activity against SARS-CoV-2 [46,51]. S i l v e r n a n o p a r t i c l e s a r e a n t i v i r a l a g e n t s a g a i n s t s e v e r a l t y p e s o f viruses [44,48,49,52,57,58,59,60,61,62,63], in addition to the antimicrobial activity against Gram-  Lu et al., 2018 [52] Redox/pH dual-controlled release of chlorhexidine and silver ions from biodegradable mesoporous silica nanoparticles against oral biofilms.
Ag-MSNs @ CHX exhibited dosedependent antibacterial activity against planktonic formation and Streptococcus mutans clones, and had an increased, long-term ability to restrict the growth of S. mutans biofilms compared to free CHX, and was less toxic to oral cells, even in vivo Ahrari et al., 2015 [53] The antimicrobial sensitivity of Streptococcus mutans and Streptococcus sanguis to colloidal solutions of different nanoparticles applied as mouthwashes.
Was evaluated the antibacterial effects of colloidal solutions containing zinc oxide, copper oxide, titanium dioxide and silver nanoparticles in Streptococcus mutans and Streptococcus sanguis and compared the results with those of chlorhexidine and sodium fluoride mouthwashes.
The antibacterial effect of silver nanoparticles was not desirable against Streptococcus mutans.

Besinis et al., 2014 [54]
The antibacterial effects of silver, titanium dioxide and silica dioxide nanoparticles compared to the dental disinfectant chlorhexidine on Streptococcus mutans using a suite of bioassays.
This study investigated the toxicity of silver (Ag), titanium dioxide and silica nanoparticles (NPs) against the oral pathogenic species of Streptococcus mutans, compared to the routine disinfectant, chlorhexidine AgNPs were the best disinfectants and performed better than chlorhexidine positive and Gram-negative bacteria [53,54]. A possible antimicrobial mechanism of AgNPs is attributable to suppression of respiratory enzymes and interference in DNA functions by released Ag + ions [44,52]. Elechiguerra et al. (2005) [57] in their study showed that silver nanoparticles undergo sizedependent interaction with HIV-1 and that they inhibit virus infectivity in vitro. El-Mohamady et al. (2018) [60] studied the inhibitory effect of silver nanoparticles on bovine herpesvirus-1 and showed that in non-toxic concentrations, AgNPs were able to inhibit BoHV-1 when administered before viral infection. Several other studies in the literature report the effectiveness of AgNPs as a potent antiviral against in humans and animals diseases, such as HIV [57,58,59], influenza [27,44], herpes type 1 and type 2 [60], respiratory syncytial virus, norovirus and hepatitis B [27,28].
Since the effectiveness of silver nanoparticles is known to be a potent antiviral agent, it is suggested that AgNPs may be effective in combating the transmission of SARS-CoV-2. In this sense, several studies are being developed and aim to test whether the AgNPs are also effective against SARS-CoV-2. In that way, AgNPs would have an antiviral effect on SARS-CoV-2 by disrupting disulfide bonds in spike protein and ACE2 receptors [28], inactivating the virus and preventing its replication or decreasing viral load in situ (Figure 2).
In their study, Jeremiah et al. (2020) [28] assessed numerous silver nanoparticles with varying sizes and concentrations. They found that silver nanoparticles with a diameter of approximately 10 nm were successful in inhibiting the extracellular growth of SARS-CoV-2 at concentrations ranging from 1 to 10 ppm, while concentrations of 20 ppm and above showed cytotoxic effects. Furthermore, the luciferase-based pseudo virus entry assay indicated that AgNPs effectively impeded the viral entry process by disrupting the virus's integrity.
The shortage of personal protective equipment and crucial medical supplies, such as surgical masks, is a major worry amid the COVID-19 outbreak [45]. The researchers aimed to create a cost-effective and straightforward study to enhance the antimicrobial capabilities of surgical   [64]. In addition, if we look at mouthwashes that are marketed as containing antiviral molecules, other compounds may be of interest in the fight against SARS-CoV-2, such as hydrogen peroxide, chlorhexidine, cyclodextrin, Citrox, essential oils, among others [10,65]. The effectiveness of mouthwashes against SARS-CoV-2 may support their use as additional hygiene measures in patients with COVID-19 [47], thereby reducing the viral load in ambulatory and clinical environments [47], and their use may be adjunctive to personal protective equipment for dentists and healthcare professionals during COVID-19 outbreaks [48,49,66]. A randomized trial conducted by Santos et al. (2021) [67] showed promising results where the use of a mouthwash with an antiviral derivative of phthalocyanine reduced symptoms, spread of infection, and hospital stay period in patients with COVID-19. This reinforces the importance of conducting further studies in this area.
Our work aimed to map the current evidence on the use of AgNPs in mouthwashes for patients with COVID-19, the limitation of this study was that we were unable to include in the review any study where an AgNPs mouthwash was used for SARS-CoV-2. But this hypothesis is supported by the fact that the nanoparticle has antiviral properties well described in the literature and allows for a call for controlled clinical studies on the topic of considerable importance. Given this information and considering the various studies on AgNPs and its antiviral potential, it is suggested, with this scoping review, new studies that associate AgNP with mouthwashes and in this way it is possible to use this nanotechnology appropriately as a way to help combat SARS-CoV-2.
In conclusion, this study mapped the evidence around the use of AgNPs as an antiviral agent and the use of mouthwashes with potential against SARS-CoV-2. With the findings presented in this study, we can suggest that mouthwashes with AgNPs have the potential to act against SARS-CoV-2, as a way of reducing viral load, preventing viral multiplication, but studies need to be done to prove the hypothesis.