Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third of coronaviruses causes an epidemic in human history after SARS_COV and Middle East respiratory syndrome (MERS). Coronavirus disease 2019 (COVID-19) can cause severe respiratory disease. It is highly infectious and can spread from one person to another . SARS-CoV-2 belongs to the family ‘Coronaviridae’, characterized by having crown-like spikes on their outer surface (Latin: corona = crown) . Currently, seven types of coronaviruses infect humans, causing diseases . Among them there are three Coronaviruses affecting lower respiratory tract causing severe pneumonia, comprising SARS-CoV, MERS-CoV and SARS-CoV-2 .
Regarding the third coronavirus pandemic, it started in early December 2019 in Mainland China. The China CDC reported that SARS-CoV-2 infection is the cause of the outbreak that started in Wuhan City (CDC, 2020) . On 23 September 2021, WHO declared that there have been 229 858 719 confirmed cases of COVID-19, including 4 713 543 deaths . COVID-19 as a pandemic needs a radical treatment. One of the most promising technologies for the treatment of COVID-19 is nanotechnology.
Nanotechnology is a combination of physics, chemistry, biology, and engineering sciences at the scale of atoms or molecules -sized 0.1–100 nm (1 nm = 1 × 109 m) . It has a critical role in virology because nanoparticles have been used to carry adjuvant to enhance virucidal effects . Virucidal nanoparticles have been used in fighting of human immunodeficiency virus (HIV), hepatitis (type A, B, C 50 and E) and herpes simplex virus (HSV-1 and HSV-2) .
As nanotechnology has been used to fight viruses and has accurate detection properties in low-volume samples , so that scientists resorted to using this technology in diagnosis, prevention and treatment of COVID-19. It is used in manufacture COVID-19 vaccines because it can induce a higher protective immunity response . Each technique has advantages and disadvantages. Challenges remain in the domain for its application due to lack of knowledge.
We wrote this review to summarize usages of nanotechnology in fighting of COVID-19 and to summarize the challenges, advantages, and disadvantages of the application of this technology.
- Etiology of coronaviruses
Hypothesis said that SARS-CoV-2 started in bats then transmitted to intermediate hosts then to humans [12,13]. The genomic comparison of sequences between SARS-CoV-2 and RaTG13 of bats (Rhinolophus affinis) shows high homology (96%) .
Coronaviruses (CoVs) family are positive-stranded RNA (+ssRNA) viruses that have spike glycoproteins on the envelope, giving it a crown appearance under an electron microscope. SARS-CoV-2 belongs to family orthocoronavirinae, which is divided into alphacoronavirus (alphaCoV), beta-coronavirus (betaCoV), delta-coronavirus (deltaCoV) and gamma-coronavirus (gammaCoV) . Sars-CoV-2 is a beta-coronavirus, found in bronchoalveolar lavage samples of patients with pneumonia in Wuhan City, China .
SARS-COV-2 is characterized by sensitivity to UV and Heat. It has a round diameter. Lipid solvents, including ether (75%), ethanol and chlorine-containing disinfectant can inactivate it. At an air temperature of 54.5°C (130°F) stainless steel surface can inactivate SARS-CoV-2 in 36 min and the virus half-life was 10.8 ± 3.0 min the coronavirus genome is encoded by four major structural proteins and spike protein is one of these proteins. To bind and mediates subsequent fusion between the envelope and host cell membranes, it uses angiotensin-converting enzyme 2 (ACE2) receptor to aid viral entry into the host cell [17,18]
α- and β-CoVs infect only mammals and animals while γ- and δ-CoVs, infect birds and mammals [19–21]. The HCoV-229E and HCoV-NL63 are α-CoVs; whereas HCoV-OC43, HCoV-HKU1, SARS-CoV, MERS-CoV and SARS-CoV are β-CoVs .
SARS-CoV-2 outbreak started in the Guangdong Province, China in November 2002, causing severe pneumonia within days of infection , it is highly contagious and spread to 29 countries, WHO reported that there were 8098 patients and 774 deaths during outbreak with a mortality rate of 9.56% . Regarding (MERS-CoV), the first case was identified in Jeddah, Saudi Arabia in 2012 . WHO reported that there were 2279 confirmed cases and 806 deaths (mortality rate: 35.37%) of which 1901 confirmed cases and 732 deaths (mortality rate: 38.51%) were from Saudi Arabia .
SARS-CoV and SARS-CoV-2 use the same mechanism in entering host cells which both use their S protein binding to ACE2 then exogenous proteases cleaved cells favors to enter the host cell . Although Dipeptide peptidase 4 (DPP4; also known as CD26) is well known host receptors for MERS.
SARS-CoV-2 ”S” protein has higher binding capacity to ACE-2 (around 10–20 times increased) than SARS-CoV-1 so that COVID-19 transmits in higher rate than SARS-CoV .
Because of both SARS-CoV and SARS-CoV-2 bind to ACE2 receptors, so they target epithelial cells where these receptors are expressed such as epithelial cells of trachea, alveolar monocyte and bronchial serous cells and macrophage , but MERS bind to DPP4 receptors, so it targets nonciliated bronchial epithelial cells, endothelial cells, and a little form of hematopoietic cell .
- Genomic Structure of SARS-CoV-2
The genes arrangement on the RNA strand of COVID-19 as follows: 5′-replicase (rep gene) ORF1ab, spike (S), envelope (E), membrane (M), nucleocapsid (N)-3′ with small untranslated sections at both terminals  as shown in Fig. 1. The rep genes account for around two-thirds of the viral genome and are coded for nonstructural proteins (NSPs). The first ORFs (ORF1a/b), which translate into two polyproteins called pp1a and pp1ab and encode 16 NSPs. They constitute two out of three parts of viral RNA while other ORFs are encoded for structural proteins. SARS-CoV-2 is similar to SARS-CoV and MERS-CoV and is composed of four main structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins, as well as other accessory proteins, enhances the host innate immune system's response [4,32]. The S protein consists of two subunits: S1 and S2. The S1 subunit with the receptor-binding domain (RBD) interacts with the ACE-2 receptor on host cells while The S2 component is responsible for the fusion of viral and hosts cell membrane [31,33]. Hypothesis said SARS-CoV spike can mediate cell–cell fusion with ACE2-expressing cells and this may be confirmed by the experiment announced that when ACE2 is expressed on the cell surface and cleaved by exogenous proteases favoring the entrance of the virus into the host cell . The E protein is required for virus endocytosis and assembly, the M protein is necessary for viral assembly and morphogenesis, and the N protein is required for RNA synthesis .
- SARS-CoV-2 variants of interest (VOIs)
VOls is defined as a variant that acquires specific mutations which make it has high infectivity, more virulence, and can also evade detection .
On June 22, 2021, WHO reported seven variants as follow: epsilon (B.1.427 and B.1.429); zeta (P.2); eta (B.1.525); theta (P.3); iota (B.1.526); kappa (B.1.617.1) and lambda (C.37).
Epsilon (B.1.427 and B.1.429): was first detected in US, it has specific mutations (B.1.427: L452R D614G; B.1.429: S13I, W152C, L452R, D614G), which make it transmits 18.6–24% higher than wild-type circulating strains .
Zeta (P.2): emerged in Brazil in April 2020. The mutations occur in spikes (L18F; T20N; P26S; F157L; E484K; D614G; S929I; and V1176F) which give it the ability to reduce in neutralization by antibody treatments and vaccine sera.
Eta (B.1.525) and Iota (B.1.526) variants were first found in New York in November 2020. They have key spike mutations (B.1.525: A67 V, Δ69/70, Δ144, E484K, D614G, Q677H, F888L; B.1.526: (L5F∗), T95I, D253G, (S477N∗), (E484K∗), D614G, (A701V∗))
Lambda (C.37) variant was first found in Peru and has been declared as a VOI by the WHO in June 2021 due to a heightened presence of this variant in the South American region.
Theta (P.3) variant, also called GR/1092K.V1: emerged in the Philippines and Japan in February 2021. The spike mutations that occur are: (141–143 deletion E484K; N501Y; and P681H).
Kappa (B.1.617.1) variant: emerged in India in December 2021, it has key mutations: ((T95I), G142D, E154K, L452R, E484Q, D614G, P681R, and Q1071H).
According to the WHO Weekly Epidemiological update on September 22, 2021, reported only two variants: lambda (C.37) variant and Mu B.1.621 variant. Mu B.1.621 variant was first detected in Colombia, January 2021 by WHO, and CDC declared that there are no variants of interest.
- SARS-CoV-2 clinical pathology
Regarding clinical pathology of SARS-CoV-2, it is classified to mild, severe and lethal . Regarding the mild stage, the patient may not complain of pneumonia and occasionally develop mild signs of URTI. But as for severe cases, there are dyspnea, shortness of breath, productive cough, and hypoxia, which lead to increase the rate of respiration >30/min. As for the lethal stage, it is characterized by severe pneumonia, respiratory failure, cardiac arrest and/or multiple organ failure leads to death .
- SARS-Cov-2 management
- Clinical diagnosis
As we mentioned before, there are three categories for the clinical presentation of COVID-19: the asymptomatic phase, the mild symptomatic stage, and the severe respiratory infection stage. Not necessary for all individuals to pass through all stages and asymptomatic or mild symptoms are most common stages among the previous stages . Because of most cases of COVID-19 are asymptomatic, herd immunity is spread among people .
In first category, individuals are known as “stealth carriers,” because they don’t have any symptoms and they are negative for RT-PCR and SARS-CoV-2 antigen testing, but in the 2nd stage there will be mild infection symptoms such as coughing and fever, they are positive in molecular assays .Regarding third stage, it is the most dangerous phase in which there is inflammation of respiratory tract with severe symptoms as we mentioned before . Gas exchange is altered, and respiratory failure maybe resulted from sequence of theses stages [42,43] and a higher production of neutralizing antibodies developed in the third stage of COVID-19 [34,44].
There are several laboratory tests used to diagnose COVID-19 as follows:
1. Molecular testing
- Real-time PCR assay is considered the standard diagnostic test. This test is very sensitive, and its sensitivity of PCR testing is dependent on multiple factor such as: time from exposure, specimen source, the adequacy of the specimen, and technical specimen collection .
- SARS-CoV-2 antigen tests are less sensitive but have a faster turnaround time compared to molecular PCR testing .
2. Serological testing
- Antibody-based test: rapid detection tests are used for surveillance activities.
- Viral antigen-based used for diagnosis of suspects of COVID-19 .
3. Imaging modalities
As mentioned above that, the critical stage comprised of severe pneumonia, respiratory failure, cardiac arrest and/or multiple organ failure, the type of imaging should be based on clinical evaluation
- Chest X-ray is a standard radiographic examination of the chest, but it has a low sensitivity in identifying early lung changes; that mean it can be completely normal in the early stage of the disease .
- Chest computed tomography (CT) use as an initial imaging study or screening, is the diagnostic method of choice in evaluating COVID-19 pneumonia, particularly when associated with disease progression .
- Lung ultrasound depending on the course of the disease, it may identify the first phase with focal areas of fixed B lines .
4- Other laboratory tests 
- Complete blood count (CBC)
- renal and liver function
- comprehensive metabolic panel (CMP)
- Coagulation panel should be performed in all hospitalized patients.
- tests for inflammatory markers such as ferritin, D-dimer, lactate dehydrogenase, c-reactive protein and ESR
- Antiviral drugs utilization of these antiviral drugs is specific and based on the severity of illness such as:
- Remdesivir is used for the treatment of Ebola virus disease and is effective in the treatment many viruses including SARS-CoV and MERS-CoV [48,49], and now experiments confirm that it probably successful in controlling SARS-CoV-2 infection .
- Hydroxychloroquine, cloroquine and lopinavir/ritonavir are antiviral drugs for COVID-19 used early during the pandemic, but clinical trials confirmed that the use of them didn’t improve the clinical status or decrease the mortality [50–52]. Lopinavir/Ritonavir isn’t used currently for the treatment of COVID-19 patients .
- Ivermectin is an antiparasitic drug used worldwide against COVID-19, due to an experiment showing inhibition of SARS-CoV-2 replication .
Immunomodulatory help combat the hyperinflammatory state more than any other drugs such as: Corticosteroids, Interferon-β-1a (IFN-β-1a), Interleukin (IL)-1 antagonists, anti-IL-6 receptor monoclonal antibodies, tocilizumab and Bruton's tyrosine kinase inhibitors [47,54–56] There is trial said that Interleukin (IL)-1 Antagonists reduced the need for invasive mechanical ventilation and mortality in patients with severe COVID-19 .
Prevention and control
1. Personal hygiene
WHO provides Different instructions to prevent viral infection, such as: wash their hands with soap and water regularly at intermittent intervals or cleaning with alcohol-based sanitizers in a number of times larger than normal, limit or avoid contact with diseased persons and stay at home, to avoid crowded places?
2. Isolation/quarantine to decrease the spread of infection people advised to stay at home, to avoid crowded places and advised for home-quarantine and if necessary, limit or avoid contact with diseased persons 
In addition to previous and other approaches which are taken to overcome viral spread and to control viral infection, vaccines are the best approach for prevention of infection so there are great efforts to develop an effective and safe vaccine to eradicate COVID-19 infection. Currently, four vaccines are approved for use against covid-19 in the European Union and these are manufactured by Pfizer-BioNTech (Comirnaty) , Moderna , Oxford-AstraZeneca (Vaxzevria) [59,60], and, most recently, Janssen . Interestingly, unrecognized nanotechnology reached clinical trials before the established approach (i.e., live attenuated and inactivated vaccines) reaching clinical trials and, if proven successful, could enable a faster response to emerging infectious diseases in the future.
Nanotechnology and nanomedicine
Nanotechnology represents manipulation or synthesis of systems or materials in which one dimension at least is in nanometer scale [62–66]. Studying interactions between nanostructured materials and biological systems is known as nanobiotechnology, it also merges between different fields with nanotechnology as proteomics, drug discovery and molecular engineering. Nanomedicine is the use of nanomaterials in different aspects of the medical field as diagnosis, prevention and treatment in application of nanobiotechnology , the nanomedical field utilizes nanomaterials, which are characterized by their small size- ranging from 10 to 100 nm- and their polarity . Biosynthesis of nanoparticles by microorganisms is considered as an alternative to conventional synthesis [69,70]. Synthesis of nanomaterials is in top-down approach or down top approach and material fabrication in nanoscale leads to magnetic, electronic, mechanical and chemical effects which don’t occur with bulk materials . What makes nanoparticles good tools for viral infection treatment is the unique properties as small size of the particles [71,72], massive surface area to volume ratios , and appropriate surface charge which permits cellular entry through negatively charged membranes [74,75]
Types of nanoparticles
There are different types of nanoparticles with different functions, shapes, sizes and shapes. Formations of smaller size NPs can occur by different techniques like lithography and nanoprecipitation. For example,
1. Liposomes were found for the first time in 1964 in the cell membrane . Since then, lysosomes have been used as one of the nanoparticles in gene and drug delivery . Unique advantages about liposomes are their different ranges of compositions, abilities to protect and carry many types of biomolecules, as well as their biodegradability and biocompatibility . All of these properties have led to the widespread use of liposomes as transfection agents from genetic material to cells in biological research . Liposomes can be functioning with targeting ligands to make more accumulation of therapeutic and diagnostic agents within targeted cells. Now, we have twelve approved liposome-based therapeutic drugs clinically .
2. Albumin-bound: albumin-bound NPs (nab) utilizes the endogenous albumin pathways to make hydrophobic molecules pass in the bloodstream . Albumin binds naturally to the hydrophobic molecules with reversible non covalent binding, preventing solvent-based toxicities of therapeutics , Abraxane, a 130-nm nab paclitaxel took the approval from FDA in 2005 for the treatment of breast metastatic cancer . Concentration of Abraxane in cells is through albumin receptor (gp60)-mediated transport in endothelial cells .
3. Polymeric: these NPs composed of biodegradable and biocompatible polymers have been investigated as therapeutic carriers . There are capsules formed of nanoparticles containing hydrophilic and/or hydrophobic small drug molecules in addition to proteins and nucleic acid macromolecules in their cores . Polymeric nanoparticles are used to improve the safety and efficacy of the drug, as they are functionalized to improve drug delivery because these molecules are unparalleled in their capability to be tailored prior to particle assembly. When nanoparticles are combined with target ligands to develop drug delivery, this increases the rate of drug uptake by cells, which improves therapeutic results.
4. Dendrimer: they are manufactured regularly from natural or synthetic parts including amino acids, sugars, and nucleotides . That is why it has been developed as a promising type of nanoparticles that are applied as sensors in addition to drug and gene delivery .
5. Iron oxide has a high magnetic property, so it can be used as a positive or negative agent in targeting imaging agents , this property depends on the size, which allows them to become magnetized in the presence of an external magnetic medium and lose this magnetization immediately after removing this field. SPIONS have been used as MRI contrast agents to track and monitor cells .
gold NPs have different optical and chemical properties, easy surface modification and biocompatibility that depend on its shape and size . Gold has different optical and chemical properties that depend on its shape and size. These particles can strongly enhance optical processes such as scattering, due to the interaction of free electrons in gold particles with light . These features made us use gold NPs in many fields.
Nanotechnology and viral detection (diagnosis)
nanotechnology is a reliable method for viral detection especially in HIV detection, these techniques have high degree of sensitivity, specificity, and work without enzymes as formation of bio-barcode assay in detecting protein and nucleic acid, two nanoparticles are used for this assay are gold and magnetic nanoparticles . no enzymatic amplification presents in these methods providing useful and powerful detection techniques, the aim of this method is detection of gag proteins and HIV-1 p24, this method has more sensitivity by 150 times than ELIZA method , another method uses gold NPs which undergo modification with ferrocene-pepstatin in detecting HIV-1 protease .
Nanoparticles based treatment of viral infection
One interesting characteristic about viral infection is establishment of reservoirs in privileged sites as blood test is barrier and BBB . Conventional therapeutics can’t reach these sites, but NPs can traverse these membranes , which make NPs unique in treatment of viral infection. Viruses are obligate intracellular organisms, complex life cycles, variations in stages of replications at various organelles or subcellular compartments and drug resistances , so all these characteristics make viruses in the needs of a specific system of treatment.
Nanoparticles based treatment of viral infection
Delivery system for reaching specific targets
Drug delivery by nanoparticles has been developed since the early 1980s especially in cancer treatment due to retention effect and enhanced permeability which provide away to increase targeting for tumors, with this in mind, we can use drug delivery system in delivering antiviral drugs to infected cells as in hepatic cell line there is more NPs uptake by trans infected cells more than nontrans infected cells leads to decrease side effects result from accumulation of drug outside liver representing promising future for usage of NPs in drug delivery . Nanoparticle-based delivery of drugs is preferred to protect drug particles and to target the drug to specific cellular and anatomical site, nanocarrier system has great value in delivering drugs to target sites and reservoir, nanocarrier systems in HIV can transport drugs to different compartment especially CNS, lymphatic system and macrophage. Lipid nanosystems have lipid bilayer or multilayer (the outer layer and core layer encapsulating the drug, lipid nano system makes hydrophobic drugs flexible, traverse mucosa and anatomical or physiological barriers .
Some antiviral nanotherapeutics include:
- 1. Inflexal which act as the virus, enter the cell and fuse with a membrane recommended for high immunogenicity as in influenza .
- 2. Epaxial which has a unique action and acts as a natural process for HAV .
- 3. Polytron acts by enhanced stability of proteins by PEGYlation for HCV 
- 4. Pegasys acts by enhanced stability of proteins by PEGYlation for HBV and HCV .
- 5. Influvac plus is composed of surface proteins of influenza, hemagglutinin, and neuraminidase for influenza .
- 6. Fluquit acts by gene silencing for H1N1 and H5N1 .
- 7. Cervisil acts by gene silencing for HPV .
Nanotechnology and Severe acute respiratory syndrome coronavirus 2
Nanoparticle-based antiviral drugs of coronavirus disease 2019
Drug delivery does not have target specificity due to poor cell uptake, nontarget effects, and excessive immunogenicity, which prompts us to use nanotechnology in drug synthesis . Therefore, new methods are used to manipulate these problems, such as the use of short interactive RNA molecules linked to nanoparticles, so these molecules interact with the biomarker that is located on the surface of the target cells, thus focusing the effect of the drug on these cells only, and preventing its effect on the rest of the cells so reducing its toxicity [104,105]. This technique is used to manufacture drugs used to treat COVID-19 by coating nanoparticles with specific antibodies against cellular receptors such as human angiotensin-converting enzyme-2 or against SARS-CoV-2 spike proteins. This is a very delicate delivery system that increases drug efficacy and reduces its toxicity . Nanoparticles can be used in the manufacture of nanobots as well, which are robots that cannot be seen with the naked eye can deliver the drug to its exact site precisely. It is expected that it will be used more widely in the coming days .
Nanocurcumin used as a therapeutic agent for treatment of SARS-CoV-2 patients
Curcumin, which is the medicinal part of turmeric, is extracted from a plant called “Curcuma longa” and is also called diferuloylmethane, the chemical formula of this substance is (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene -3.5-dione) . It was found that curcumin has been used for many years due to its anticancer, antioxidant and anti-inflammatory properties due to the methoxy group . Curcumin has the advantage that it inhibits ROS in macrophages, modulates T-cell proliferation and function, and upregulates CD80 and CD86 expression on dendritic cells (DCs), thus affecting the immune system , regulating the secretion of pro-inflammatory cytokines and adhesion molecules, and ultimately regulating the pattern of immune responses . Inflammation is the main mechanism in COVID-19, so curcumin can be used to treat inflammation associated with Covid-19 and relieve its associated symptoms. When it was applied in a randomized clinical trial to study its effect on inflammatory cytokines, it was found that nanocurcumin regulates the rate of curcumin that increases its secretion in inflammation, especially IL1β and IL-6 mRNA expression, which may improve symptoms associated with Covid-19 
Nanoparticle-based coronavirus disease 2019 preventive actions
Nanoparticles is designed to target SARSCoV-2 or to act as immune modulatory factors to prime and alarm the immune system and reduce the inflammatory response during COVID-19 . Some parts of SARS-CoV-2 – small-interfering RNAs – is put with lipid nanoparticle to suppress viral replication and improve survival of infected mice . Nanotechnology solves the problems which are associated with traditional vaccines and medications such as sensitivity to acidity, water insolubility, or absorption . There are nanoparticles can facilitate the transport of two or more drugs, so that can decrease each dose as well as the side effects, while augmenting the combined outcome .
Recently, there is another nanotechnology vaccine was found to enhance a persistent antibody production and long-lasting memory response for at least 7 months in mice 
The vaccine is a safe and smart method that stimulates the generation of the immune response within the body without causing disease . Recently, recommended COVID-19 vaccines are safe, effective and reduce your risk of severe illness. WHO recommend that there are 202 companies and universities worldwide working on a coronavirus vaccine 
Types of vaccines have been used against covid-19 (Fig. 2):
1. Live attenuated vaccines: They contain weekend SARS-CoV-2. The weekend virus is recognized by immune system to trigger response without causing illness. This response can build immune memory, so body can fight off SARS-CoV-2 in future. These vaccines required time and are extensive tests .
2. Inactivated vaccines: They contain killed SARS-CoV-2. This killed virus can be recognized by the immune system to trigger response without illness. But these vaccines may be administered with an adjuvant to boost immune response.
3. Subunit vaccines: In these vaccines, several injections are made to induce a systemic immune response against the virus because they have a short life .
4. mRNA vaccines: They are a new effective type of vaccine that was used recently. They depend on the cell to make a protein that triggers an immune response instead of using live virus to trigger an immune response. Instead of using a new virus to cause triggering. Once triggered, our body makes antibodies. These antibodies help you fight the infection if the real virus does enter your body in the future. The researchers use materials that are available to make and develop mRNA vaccines in labs. Once developed, large-scale clinical trials are carried out to show that the vaccine is safe and effective . It is known that mRNA vaccines have been studied for using in some diseases such as flu, rabies and cytomegalovirus (CMV). Researchers have also used mRNA to trigger the immune system to target certain cancer cells. It also has been used in COVID-19 by injection. (mRNA) is a molecule that provides cells with instructions for making proteins. mRNA vaccines contain the instructions for making the SARS-CoV-2 spike protein. This protein is found on the surface of the virus that causes COVID-19. The cell breaks instructions and gets rid of them after the protein piece is made. Then the cell displays the protein piece on its surface. Our immune system recognizes that the protein does not belong there and begins building an immune response and making antibodies [121,122] mRNA vaccines have many advantages such as: they have high efficiency and safety, low production cost and the potential for rapid large-scale production.
5. Viral vector vaccines: They similar to mRNA vaccines but differ in:
- I. The first difference is that the genetic material in this vaccine is DNA, not mRNA. But this does not affect your own DNA. This small piece of DNA harmless .
- II. The second difference is how this genetic material is packaged. Instead of an artificial lipid shell, the DNA of a viral vector vaccine is carried within a harmless adenovirus [123,124].
This adenovirus has been modified so that it's harmless. Its protein-based envelope is used as a DNA delivery mechanism that will help increase your immune response against the coronavirus. Adenovirus has been studied for its wide host range, robust infection, high protein expression, and high safety when saturated with a transcription defect . The most important advantages of these vaccines are:
(1) They are more stable because DNA itself is more stable than mRNA.
(2) The modified adenovirus that carries this DNA has a tough protein coat that is much stronger than the lipid envelope used to package the mRNA in mRNA vaccines.
(3) Viral vector vaccines can introduce genes encoding viral antigens into host cells. Infected cells produce and release immune antigens during a certain period after vaccination . The following are examples of COVID-19 vaccines in which nanotechnology are for their synthesis:
Results – mRNA vaccines: Moderna and Biontech/Pfizer
mRNA vaccines that encode for the S protein of SARS-CoV-2. The S protein is the viral protein that binds to ACE2 on cells to mediate infection and is a frequent vaccine target since it is expected that antibodies binding to the correct epitope on the S protein could be neutralizing and therefore block intracellular viral spread . Results from a multicenter, Phase 3 randomized trial declared that individuals who were randomized to receive two doses of mRNA-1273 (mRNA based, Moderna) vaccine showed 94.1% efficacy at preventing COVID-19 illness and no safety concerns were noted besides transient local and systemic reactions .
Results – non-replicating viral vector vaccines: Oxford/AstraZeneca and CanSino
One of the most explored viral vector options is the adenovirus (Ad), which is currently being used by both CanSino and Oxford/AstraZeneca. Ads are common cold causing viruses that have a double-stranded DNA genome. Specifically, CanSino is utilizing Ad type 5 (Ad5), giving the vaccine the name Ad5-nCoV . Oxford/AstraZeneca is employing a different viral vector, an Ad derived from the chimpanzee (the use of the chimpanzee vector minimizes possible interaction with prevalent antibodies against Ads), which was subsequently named AZD1222 . It is found that in case of taking two doses, efficacy, and safety against CoVs symptoms are 70,4% 
WHO recommended the wearing of face masks to prevent the spread of SARS-CoV-2  It is known that airborne transmission is one of the main pathways for the transmission of respiratory viruses, including the SARS-CoV-2. Cotton masks, N95 masks, and surgical masks provide some protection from the transmission of infective SARS-CoV-2 droplets that was declared by airborne simulation experiments, but these medical masks (surgical masks and even N95 masks) could not block the transmission of virus droplets completely .
Some studies showed that nanomaterials, such as nanofibers, have ability to reduce breathing resistance and reduce pressure to achieve comfort against small particles with size <50 nm while face masks N95 can only guard against 100–300 nm in size. Face masks have been nanoengineered to include new characters such as antimicrobial activity and hydrophobic without compromising their structure. Nanomasks, having extra layers of nanofibers and nanoscale pores, can prevent pathogens from entering the respiratory system. So, the efficiency of Nano-masks in defending against virus transmission is much higher than ordinary masks . This shows much greater protection than conventional surgical facial masks.
Silver particles used in coronavirus disease 2019 prevention
Several studies have been successfully conducted to test the ability of AgNPs against viruses. There are two methods for making AgNPs:
- 1. Physical methods: This method mainly depends on processes such as gamma irradiation, evaporation, condensation, laser ablation, gamma irradiation, lithography, redox reagents, and polymerases. Matrix isolation, cold gas flow trap, acoustic pulsation (PA) technique is among the primary methods that are used to study the synthesis of silver nanoparticles (AgNPs) .
- 2. Chemical methods: This method is according to the method of preparation and four different types of AgNPs were synthesized against Coronavirus (Preparation of GSH-Ag2S NC, PVP-AgNMs, GO-AgNPs and PDDA-PVP-GO-AgNPs).
- Preventive effect of AgNPs against CoVs
Silver nanoparticles are known to have a strong antimicrobial effect. It is also found that they have an antiviral effect. The efficacy of AgNPs, as antiviral agents, has been confirmed in humans against many different types of viruses [132,133] Therefore, AgNPs can be used effectively against coronaviruses (CoVs), as a cause of many diseases such as fatal human respiratory infections.
In general, NPs have some basic properties such as the generation of reactive oxygen species (ROS) and photodynamic and thermodynamic capabilities that make them used as an effective disinfectant against CoVs. So, these AgNPs act effectively against CoVs due to antiviral core structure of NPs such as ROS, photodynamic and thermodynamic leading to apoptosis mediated cell death and inhibiting viral infection . It is known that antiviral nano-materials also can suppress viral infection by blocking the interaction between the SARS-CoV-2 spike protein with the ACE2 receptor . So, AgNPs can bind to viral surface proteins rich in sulfhydryl groups and cleave disulfide bonds to disrupt the protein resulting in poor viral binding to the target cell receptor. The main steps are action of AgNPs against SARS-CoV-2 effectively to prevent the virus entry step by:
(i) Blocking viral binding. (ii) Interfering with virus entry. (iii) Damaging surface proteins to disrupt the structural integrity of virus .
Smaller molecules have a higher toxicity potential due to the larger surface area for interaction with the bound protein. The level of toxicity of these nanomaterials varies with dose [132,133].
Although the use of nanomaterials is still debated due to their toxicity or side effects on normal human cells, silver nanomaterials offer a promising way to carry antiviral or other drugs throughout the body. To reduce toxicity:
- I. Modifications must be made to the surface of the nanoparticles so that metallic surfaces do not adhere to cells directly.
- II. Their concentration inside the cell should not be high.
- NP-based diagnosis of COVID-19
Key point for decreasing the spread of COVID-19 spread is rapid diagnosis of cases to decrease primary reproductive number of affected patients. Nanoparticles are used as sensors to the detect biomarkers, including specific antigens (proteins, enzymes), antibodies or nucleic acids (DNA, RNA) to detect SARS-CoV-2 rapidly and accurately [68,134–136]. Recently, Graphene with an antispike antibody help in detection of SARS-CoV-2. This novel kit is very effective in diagnosis of COVID-19 and doesn’t need to be label . There are other many methods used in diagnosis of SARS-CoV-2 such as RT-PCRs. But they have many disadvantages: (a) lack of specificity due to similarity with other viral diseases, (b) low sensitivity, (c) high false negativity, and (d) time consumption. It is found that nanoparticles can solve these defects especially in the current situation in the diagnosis of the situation arising from production in the treatment of diseases.
Nanoparticles can be:
1. Selected as biosensor: a biosensor” that can be used, with the help of transducer and bio-recognition element, to diagnose analyses within solutions and body fluids
2. Used as transductions: whose nature is very stable in many media. Nanoparticles can achieve surface chemistry, which can be used for molecules bio-conjugation, high surface energy and a strong amplification effect on signals.
Metal and magnetic nanoparticles in diagnosis of coronavirus disease 2019
To detect COVID-19 rapidly, we can use quantum dots, metal, and magnetic nanoparticles to increase the efficiency of diagnostic tests , due to their characteristics which are: electrochemical, fluorescence, colorimetric, and optical detection techniques .
Because of localized surface Plasmon resonance (LSPR), a specific characteristic of metal NPs, the SPR can be tuned from 300 to 1200 nm . Regarding to COVID-19 diagnosis, N gene is targeted by using AuNPs with antisense oligonucleotides that resulting in the accumulation of AuNPs induced by the viral N gene . One of the most widely used nanoparticles nowadays is Iron oxide NPS, due to its high magnetic efficiency . The same method which uses the silica coated superparamagnetic NPs (SMNPs) in PCR-based assays is used to detect SARS-CoV-2 . A combination of magneto plasmatic NPs (MPNPs) and magnet plasmonic-fluorescent biosensors based on zirconium QDs (ZrQDs) and Fe can also be used to detect the virus by the photoluminescence (PL) properties of the ZrQD nanohybrids [144,145]
Some of methods of nanotechnology can be used in coronavirus disease 2019 detection
1. Point-of-care testing (PoC) is one of the tests used to detect COVID-19, it depends on using a kit which is put at where the patient can be treated. It has the ability to detect pathogens as it contains the biosensor, the most important component of it. The PoC test enables diagnosis without sending samples to specialized laboratories.
The advantages of using point-of-care testing are
(a) Flexible. (b) Not need much space as other tests. (c) Large-scale storage. (d) Not restricted to a specific place .
2. Microfluidic PCR devices: They can study the behavior of fluids through micro-channels, and the technology of manufacturing micro devices that contain chambers through which fluids flow or are restricted. Most current coronavirus tests are based on PCR and RT-PCR (real-time polymerase chain reaction). The PCR product has a specific volume that can be detected by fluorescence signals (RT-PCR) or by classical electrophoresis. In case of combination of PCR and microfluidic, this leads to acceleration of PCR, diagnostic test results could be faster and with higher accuracy. Microfluidic devices have been used successfully to develop cell-based virus assays. The development of micro-tissue engineering could help understand the coronavirus's entry strategy, how infection persists in human cells, and could accelerate the discovery of new antiviral drugs .
Advantage of nanomedicine
Nanotechnology could bring major development in medicine. Multifunctional NP complexes used for targeting, simultaneous therapy, and imaging. This feature is one of the most interesting features of nanotechnology now .
- 1. The use of nanoparticles has the capacity of transporting therapeutics to particular sites of a disease, thus decreasing the toxicity of many drugs. It provides an accurate intracellular uptake of the drug in the required cellular targets and at perfect bio-distribution. Also, it can improve the field of medical imaging by the ability for the specific targeting of diseased tissues providing resolutions not achieved by present technologies .
- 2. Nanoparticles are characterized by a better reaction rate and a large surface area, which results in a reduction in the dose of the drug, and its toxicity and increases patient adherence .
- 3. Nanotechnology improves the efficacy and safety of drugs with low bioavailability by delivering the drug to the target cells which limits its effect on other cells thus reduces its toxicity .
- 4. Nanotechnology is used to target cancer cells and concentrated the drugs on these cells only, which preserves other body cells from the damaging effect of these drugs .
- 5. Vaccines including nanoparticles can replace standard adjuvants and enable vaccines to reach a specific target and increase the inhibitory effect against microbes and increase safety .
- 6. Nano0drugs have a group of advantages in fighting against COVID-19 like a better virus inhibition, an improved drug safety and solubility, and organ targeting , in addition to:
- 1. Can decrease the analysis and detection limit time and also increase the sensitivity of diagnostic tests [139,155].
- 2. Can be used for colorimetric detection of coronavirus, which is simple, low-cost, and rapid [139,155].
- 3. Decrease toxicity because it decreases the concentration of the drugs in the nanotarget organs as we mentioned before [139,155].
- 4. Evade immune responses which complicate the treatment [139,155].
Challenges of nanomedicine
The most important challenges of using nanomedicine are the biological challenges, large scale manufacturing, biocompatibility and safety, government regulations, intellectual property, and the cost-effectiveness in comparison to the used therapies  In addition to that,
- 1. we need to learn further about materials and their properties at the nanoscale .
- 2. Nanoparticles may damage the lungs and can be picked up into the body through the skin, lungs, and digestive system .
- 3. the human body may develop a tolerance to nanoparticles .
- 4. Decrease in the acceptance of nanotechnology by community members due to claims concerning data confidentiality, ownership, and privacy are challenging to address in a short duration of time. In addition to, the acceptability of reliability of nanotechnology remains low .
- 1. Search for antiviral drugs with more bioavailability, sensitivity, efficacy, and low adverse effects.
- 2. Use of nanoparticles in the production of nanobased-vaccine which provide long-term immunization.
- 3. Use of gold nanoparticles in future studies on detection of coronaviruses.
- 4. Detection of new kinds of coronaviruses in future by electrochemical devices because of their good ability for coupling with nanomaterial.
Conflicts of interest
The authors whose names are listed immediately above certify that they have affiliations with two organization or entity with nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Authors do not have anything to be disclosed.
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