Addressing the intersection of COVID-19 and metal nanoparticle use: Risks and control strategies

Abstract The outbreak of the novel coronavirus lasted from 2019 into 2023 and the number of patients infected with the virus is still on the rise, greatly impacting people’s daily lives and the environment. Research on metal nanoparticles has developed rapidly during virus outbreaks. There have been review articles summarizing the important role of nanomaterials in the prevention, diagnosis, and treatment of viruses, because they have antimicrobial properties or can be used as drug carriers. However, the widespread application of metal nanoparticles is not yet mature, and there are many cases of abuse, which inevitably produce health and environmental risks. The aim of this review is to highlight the potential health and environmental risks of metal nanoparticles under the COVID-19 pandemic, to propose corresponding strategies to address them, and to point out promising research directions in future. Some metal nanoparticles exposed to organisms and the environment may incur bioaccumulation effects and direct toxicity. Toxicity can be reduced by changing the surface properties of metal nanoparticles, and the accumulation of metal nanoparticles in plants can be used for recycling and regeneration. More importantly, those papers related to life cycle assessment of metal nanoparticles tend to ignore their synthesis and regeneration processes. This paper believes that the production process of metal nanoparticles has a large environmental risk while the end-of-life process is often neglected. We conclude that the synthetic method can be optimized from the green synthesis of metal nanoparticles. Furthermore, additional attention can be paid to the recovery and regeneration of metal nanoparticles to promote the green use of metal nanoparticles and finally reduce pressure on the environment. ABSTRACT


Status of the COVID-19 pandemic
The COVID-19 outbreak has been a very severe and long-lasting epidemic, with the virus having the potential to continue mutating (Zhu et al., 2020).To date, omicron and other mutants have mutated rapidly and with high transmission rates, posing a great threat to human health (Sindhwani & Chan, 2021).It is highly contagious, with a mortality rate of approximately 1.5%.In early 2022, the number of coronavirus cases spiked, with the possibility of another outbreak.As of June 1, 2023, there have been 689,710,552 coronavirus cases and 6,885,234 deaths (Worldometer, 2023).
COVID-19 also poses a challenge to the world's medical resources and capabilities.There have been major advances in the prevention, diagnosis, and treatment of the virus during this epidemic (Duan et al., 2021).In the early stages of an epidemic, many countries resorted to traditional medicine and hygiene measures, based on the experience of the Severe Acute Respiratory Syndrome (SARS atypical pneumonia) epidemic in 2003 (Sivasankarapillai et al., 2020).Now that technology has advanced rapidly, there are many new treatments against COVID-19.For example, nanoparticles, due to their unique properties and structure, offer many possibilities to improve the disadvantages of traditional medicine and provide better preparation and measures for the possibility of a renewed outbreak of the virus (Bellan et al., 2011;Mitchell et al., 2021;Ragelle et al., 2017;Riley et al., 2019;Sindhwani & Chan, 2021;Zhou et al., 2021).

Applications and hazards of metal nanoparticles
Due to their small size and large relative surface area, metal nanomaterials have unique antibacterial properties and chemical modification functions, which play a great role in health care.Studies have shown that metal nanoparticles have diagnostic and therapeutic effects on the influenza virus and human immunodeficiency virus (Kurdekar et al., 2019;Maduray & Parboosing, 2021;Mastro et al., 2010).Metal nanoparticles also have great potential in the fight against COVID-19 and represent a new and efficient treatment method.At the same time, they have a wide range of applications in epidemic prevention, diagnosis, and treatment, such as vaccine production, optimization of personal protective equipment (PPE), and efficient diagnosis and disinfection (Gharpure & Ankamwar, 2021).Metal nanoparticles have great potential in medicine because of their adjustable size and specific surface area.Drugs made from metal nanoparticles are more effective and popular in some ways than traditional drugs because they are targeted, have better penetration, and can increase drug delivery (Singh et al., 2017).Other metal nanoparticles themselves, such as silver (AgNPs) and gold nanoparticles, have antiviral properties which can be widely used in the disinfection and treatment of COVID-19.As a result, nanotechnology has advanced rapidly during the COVID-19 outbreak, not only increasing its precision and sophistication but also partially commercializing it (Barata-Silva et al., 2021).
The widespread use of metal nanoparticles during the COVID-19 pandemic may pose hazards to the environment and human health.Considerable waste is generated as a result of the heavy use of PPE during epidemics, which places a burden on the environment (Silva et al., 2021).In June 2020, China produced 200 million disposable masks a day, which is 20 times more than usual (Aragaw, 2020).If the global population uses one disposable mask per day as the minimum, then 129 billion disposable masks and 650 medical gloves were consumed per month during the COVID-19 pandemic (Adyel, 2020).The World Health Organization estimates that at least 89 million masks are needed each month to protect people from the virus (Anonymous, 2020).With the high consumption of PPE, there are concerns about the final disposal of this waste.Most of this PPE is disposed of in landfills, which can easily cause environmental risks if not properly disposed of.In addition, disposable masks and other plastic waste are littering, which may release microplastics into the water environment and soil, resulting in a series of environmental problems (Nzediegwu & Chang, 2020).

Research status of metal nanoparticles
Current research on metal nanoparticles has focused on the applications and possible usefulness for the COVID-19 and medicine, with few articles revealing the possible risks behind them (Kar et al., 2022).In the COVID-19 pandemic, most of the reviews only pay attention to the great potential of metal nanoparticles in the treatment of diseases and their application in viral infection.And metal nanoparticles can be used for disease prevention, diagnosis, and treatment (Gharpure & Ankamwar, 2021;Medhi et al., 2020;Rasmi et al., 2021).Although these articles have promoted the widespread use of metal nanoparticles, the hazards of metal nanoparticles have not been fully considered.In addition, there is no possible solution for the rational disposal of metal nanoparticles.
At present, there are limited articles that present the environmental risks from metal nanoparticles during the COVID-19 pandemic and suggest possible solutions.It has been shown that excessive use of silver nanoparticles in advanced sanitation products can cause environmental problems and may have an impact on transformation and degradation in terrestrial or aquatic environments (Anand et al., 2022).The risk of leaching of titanium dioxide nanoparticles from masks increases the pressure to dispose of metallic nanoparticles.(Sullivan et al., 2021;Verleysen et al., 2022).However, there is a lack of risk assessment and resolution strategies for metal nanoparticles during the COVID-19 pandemic.Based on available researches, we pointed out that it remained enormous risks behind the widespread use of metal nanoparticles during the COVID-19 pandemic, and that the lacking of good control of related nanoproducts may lead to increased contamination by metal nanoparticles.Meanwhile, life cycle assessment of metal nanoparticles is inadequate, frequently ignoring their environmental release and not emphasizing synthesis, making it difficult to accurately assess their entire life cycle (Nowack et al., 2016).Therefore, this review focuses on the green use of metal nanoparticles and the full use of their role in the prevention and treatment of COVID-19.The wide application of metal nanoparticles, which play an important role in virus prevention, diagnosis, and treatment due to their unique physical and chemical properties, during the COVID-19 pandemic is discussed.The environmental and health risks of metal nanoparticles are critically discussed.Corresponding solutions are proposed according to the health risks of metal nanoparticles.For environmental risks, possible research directions are provided for the difficulties of the whole life cycle assessment.In addition, the synthesis, recycling and reclamation of metal nanoparticles are emphasized and solutions are provided.This review aims to provide guidance and assistance for the green and safe use of metal nanomaterials during the COVID-19 pandemic.

Application of metal nanoparticles in epidemics
Nanotechnology has been widely used for epidemic prevention, diagnosis, and treatment in the fight against COVID-19 as it continues to ravage the world (Rasmi et al., 2021).In this paper, we searched from Web of Science by taking life cycle assessment, silver nanoparticles, gold nanoparticles, titanium dioxide nanoparticles, and metal nanoparticles as keywords and got 102 related literatures from January 2020 to February 2023, including 25 silver nanoparticles, 58 gold nanoparticles, 6 titanium dioxide nanoparticles and 13 other nanometals (Fig. S1).The current applications are mainly divided into three areas: prevention, diagnosis, and treatment (Fig. 1).Among them, gold and silver nanoparticles are the most researched related to them, which may be related to their excellent physical properties.For example, AgNPs have been shown to possess the potential to inhibit the spread of viruses (Teirumnieks et al., 2021), leading to clinical trials and commercial use of metal nanoparticles.Due to the high affinity for sulfur-containing groups, AgNPs could also strongly bind to cysteine, methionine, and glutathione which are commonly found in the active sites of several proteins.Therefore, the presence of AgNPs may interfere with viral genome replication and protein synthesis on account of the inactivation of related proteins, thus contributing to its antiviral ability.In addition, the binding of AgNPs to viruses leads to the production of reactive oxygen species (ROS) on the surface of nanoparticles, which then leads to the destruction of the virus surface (Gharpure & Ankamwar, 2021).Because of their disinfectant and antimicrobial properties, AgNPs are most used in the prevention of COVID-19.
Gold nanoparticles have antiviral and anticancer properties, and their antiviral ability can be enhanced by surface functionalization.The gold nanoparticles attached to the anti-spike antibody can bind to the SARS-CoV-2 spike protein, then inhibit the binding of the virus to cell receptors and destroy the lipid membrane of the virus, preventing the infection and transmission of the virus (Pramanik et al., 2021).Similar physicochemical properties are present in other metal nanoparticles.For example, copper nanoparticles can release copper ions, resulting in oxidative stress and producing reactive oxygen species, which can cause oxidative damage to virus genes and inhibit their replication to achieve antiviral effects (Gharpure & Ankamwar, 2021).At present, metal nanoparticles are widely recognized by the public and partly commercially available.On the premise of ensuring their safe use, the widespread application of metal nanoparticles in the containment of COVID-19 has a bright future.The application of metal nanomaterials in the prevention, diagnosis, and treatment of COVID-19 will be discussed below.And in Table S1, we summarize the related research on the application of metal nanoparticles.

Prevention
Currently, there are two main methods that metal nanoparticles prevent COVID-19: by adding them to PPE to sterilize, and by adding them to surfaces to disinfect.As the number of COVID-19 cases continues to rise, the quantity of protective equipment needed by both healthcare workers and individual citizens increases.Masks treated with functional nanomaterials have been available since the SARS outbreak in 2003.Compared with N95 masks, masks containing nanomaterials have no difference in availability but have better protection and have shown great potential (Li et al., 2006).Currently, the widespread application of metal nanoparticles in PPE is a novel and more effective method.The main purpose is to block and sterilize, to prevent taking off these PPE and becoming infected with unextinguished viruses.Metal nanoparticles are perfect for this.Masks can be sterilized by changing the fabric material and adding metal nanoparticles, which are also hydrophobic and can avoid the breeding of bacteria.At present, polyvinyl alcohol filter media containing AgNPs have been developed and applied in masks.Based on the sterilization effect of AgNPs, they have a very high filtering effect on viruses (Blosi et al., 2021).In addition, some studies have shown that impregnating the nylon fabric developed by him with chitosan and AgNPs silver can improve the antibacterial effect of masks.As the effect decreases after washing, it can be applied to disposable masks in a small amount, providing a new idea for the coating of mask materials; however, the health risk needs to be evaluated (Botelho et al., 2021).The additional sterilization effect of masks should not be ignored at the same time to avoid the impact on the breathing of the wearer and avoid rashes and other symptoms that may occur when medical personnel wear masks for a long time.Cloth masks treated with metal nanoparticles are compatible with both techniques without affecting the wearer's oxygen saturation and heart rate.With the current global increase in COVID-19 infections in early 2022, the need for masks remains.Respirators impregnated with copper oxide can be reused and have higher bactericidal properties (Chua et al., 2020).Another mask containing copper nanoparticles, using photocatalysis and photothermal effects, can be self-sterilized only by sunlight so that it can be reused (Kumar et al., 2021).The development of such reusable masks could ease the country's production pressure.
Another application of metal nanoparticles is in disinfection.It is widely used in disinfectants, as well as on surface coatings containing metal nanoparticles.Fungicides containing AgNPs, titanium dioxide, silicon dioxide, and carbon nanotubes are more efficient and less toxic than conventional fungicides, causing damage to infection, attachment, and reproduction of the virus, which could be used to prevent COVID-19 (Khoshnevisan et al., 2021).Photocatalytic inactivation of viruses is also an efficient and safe method compared with traditional ultraviolet disinfection, which can be applied and optimized by taking advantage of the unique optical properties of metal nanoparticles.TiO 2 photocatalytic nanomaterials can be used in disinfectants, and thus have strong disinfection ability, no threat to human health, and no pollution byproducts.Disinfectants containing metal nanoparticles have more potential than chemical disinfectants during the COVID-19 pandemic (De Pasquale et al., 2021;Matsuura et al., 2021).The transmission of viruses can also be transmitted through the surface of objects, which can be considered a more serious threat in crowded public places such as hospitals and subways.Therefore, metal nanoparticles can be attached to the surface of the object for sterilization, and can be used in PPE.Tiles with photoactive AgNPs and titanium dioxide are feasible to combat surface contamination and reduce the frequency of disinfectant use (Djellabi et al., 2021).

Diagnosis
Metal nanoparticles can be used as biosensors to diagnose COVID-19.Functionalized metal nanoparticles can be made by immobilizing virus-associated proteins on the surface, which can bind specifically to the virus, enabling precise diagnosis.During the early days of the SARS outbreak in 2003, virus-associated proteins were immobilized on gold nanoparticles to diagnose viral infection by changes in their absorbance and color.This system is advantageous in that that it allows for high-throughput bioassays of multiple samples and can efficiently fix proteins to gold surfaces.This method provides feasibility for the subsequent virus diagnosis of COVID-19 by gold nanoparticles, and provides ideas for the fabrication of biosensors (Park et al., 2006).Applications stemming from the development of metal nanoparticles have been relatively mature.Previous studies have shown that different functional groups of gold nanoparticles can produce specific individual effects.COVID-19 enters host cells by binding viral spike proteins to ACE2 receptors on host cells.Therefore, a similar peptide was designed to modify gold nanoparticles based on ACE2, which binds to the receptor-binding domain of the COVID-19 virus.The gold nanoparticles bind to the receptor domain of COVID-19 to form very stable complexes, which can be used in the diagnosis of epidemic diseases (Mehranfar & Izadyar, 2020).Furthermore, gold nanoparticles can also be made into nanoprobes, and functionalized gold nanoparticles can be made into nanoprobes suspended in colloids.Nanoprobes can quickly and efficiently detect COVID-19 and are a simple method that can be detected using an inexpensive spectrophotometer.The detection time required by the nanoprobe is relatively short, which is expected to take only 75 min (Aithal et al., 2022).The traditional process of taking virus samples from patients through throat swabs and nose swabs, and then testing them in the laboratory through a complex process (qPCR) can take hours.This method provides a new idea for rapid and inexpensive detection.
There also exist some very interesting and effective diagnostic methods.There is a practical and less procedural diagnostic method for colorimetry.The color change can intuitively judge the virus infection situation personal use and detection are very friendly.For the detection of COVID-19 viruses, magnetic γFe 2 O 3 nanoparticles were used as a simulated peroxidase-like active molecule that can undergo color reactions when interacting with enzymes associated with the COVID-19 viruses.This reaction can be detected by colorimetry, and thus this method is simple and practical and can be used in diagnostic kits for the COVID-19 virus, and has the advantages of high accuracy and high ability to detect variants.It can provide diagnostic system support for rapid detection kits (Buyuksunetci et al., 2021).Combining virus prevention and diagnosis is a novel and efficient method.Another detection method based on plasma gold nanoparticles is a visual biosensor where the COVID-19 virus induces the aggregation of gold nanoparticles.Once aggregation occurs, the color effect is produced, and the infection of the virus is determined by observing the color effect.This color response can be analyzed directly by smartphones, greatly improving convenience and operability.The accuracy of the sensor is high, and the result is consistent with the traditional qPCR.Combined with smartphones, this method simplifies virus detection and is a very novel diagnostic method (Ma et al., 2022).

Treatment
Metal nanoparticles can be used as drug carriers and vaccines to treat COVID-19.The outbreak of COVID-19 requires new drugs for treatment.The disadvantages of current treatments are that they are not specific to the current outbreak and may have toxic effects on host cells (Rasmi et al., 2021).Metal nanoparticles have unique properties that can overcome these shortcomings.For example, the small size of metal nanoparticles can enter many parts that drugs cannot enter, and their relative surface area is large enough to be used as drug delivery carriers.Moreover, some metal nanoparticles, such as AgNPs, can be sterilized (Abdellatif & Alsowinea, 2021;Gartner & Jayaraman, 2019;Ratan et al., 2021).Metal nanoparticles have been widely used in the preparation of new antibacterial drugs and vaccines and have shown great potential.It has been shown in the literature that iron oxide nanoparticles, AgNPs, gold nanoparticles, gold-AgNPs, and copper nanoparticles have more or less alleviated the symptoms of infected persons (Bahrami et al., 2022).Since the COVID-19 infection is a respiratory disease, it can be treated with medicines for the respiratory tract.A method of inhaling AgNPs has been developed for early treatment, which may inhibit the spread of the virus in the respiratory tract, giving the body's immune system more time to react.This treatment can be used in a wide range of settings, from when an individual feels early symptoms of infection to in a hospital intensive care unit (Zachar, 2020).In addition, iron oxide nanoparticles have great potential in the production of therapeutic drugs, as they have previously been approved by the US Food and Drug Administration (FDA) to treat anemia.It can be seen that the safety and practicality of nano-iron oxide are recognized.Abo-zeid et al. found that nano ferric oxide has an inhibitory effect on the COVID-19 virus and can inactivate the virus (Abo-Zeid et al., 2020).Based on previous experience, it is possible to use iron oxide nanoparticles as a treatment for COVID-19, promising clinical trials for COVID-19.
Vaccine development is an effective way to contain COVID-19.According to World Health Organization (WHO) data on June 1, 2023, the total global dose per 100 people vaccinated is 171.35, and persons vaccinated with at least one booster or additional dose per 100 population is 31.42(World Health Organization, 2023).Some vaccines are already available in many countries, but more are emerging that may be more effective and easier to use.Vaccine production is still not high, and many people around the world have not been vaccinated.While some people are afraid of vaccination, which is a barrier to the widespread use of vaccines, mass production and lower prices are also crucial in the expansion of vaccination rates.Metal nanoparticles can carry drugs nonspecifically or specifically to target cells, making them more effective and cost-efficient.At present, metal nanoparticles have made great progress in vaccine production.For example, improving the vaccine's targeting effect could reduce systemic toxicity and allow for sustained drug release.In addition, metal nanoparticles are stable and can improve the shelf life of vaccines (Abdellatif & Alsowinea, 2021).Functional gold nanoparticles can also help in the development of vaccines, with research providing a platform for innovative vaccines for COVID-19 (Farfan-Castro et al., 2021).

Risks after the application of metal nanoparticles
Only a small number of studies have considered the possible environmental risks of metal nanoparticles after their application while the risks of metal nanoparticles should not be neglected (Fig. S2).In this section, both the health risks and environmental risks of metal nanoparticles will be considered, and we also summarize a comprehensive assessment and corresponding solutions.

Health risks brought by the application of metal nanoparticles
The environmental and health concerns arising from the wide application of metal nanoparticles cannot be ignored.Metal nanoparticles can affect biological health in the process of use and obsolescence (Dhama et al., 2021).First, there is the inevitable risk of exposure when using consumer products containing metal nanoparticles (Subramaniam et al., 2019).Second, only by fully understanding the toxicity mechanism of metal nanoparticles can we better study the method of reducing toxicity.Finally, the bioaccumulation of metal nanoparticles can also be used as a method to reduce the concentration of metals in the environment.Therefore, this paper will review the health risks of metal nanoparticles in three parts: exposure, toxicity, and accumulation, and then propose corresponding solutions, hoping to provide information for reducing the health toxicity of metal nanoparticles and provide new ideas for the removal of metal nanoparticles.

Environmental and biological exposure of metal nanoparticles
Metal nanoparticles are inevitably exposed to the environment during their use in the prevention and treatment of COVID-19.Consumer products containing nanoparticles may be a source of nanoparticles in the environment, with many studies showing that nanoparticles are released from commercial products (Peters et al., 2018) exposed to water and soil by leaching or to air by other processes.In this case, the antibacterial properties of metal nanoparticles themselves are reduced, leading to environmental risks.For example, masks containing metal nanoparticles can be harmful to the environment.Antiviral masks containing Ag and AgNPs are currently being sold in Brazil to help local people fight COVID-19.However, the concentration of silver in this mask will decrease to a lower degree of efficiency after washing, which not only reduces the disinfection performance of the mask itself but also causes pollution by washing silver into the water environment.Four samples were evaluated in their study, and for each sample washed for six cycles, 72.7 micrograms per gram of Ag were released into the environment (Barata- Silva et al., 2021).At the same time, some studies have used masks treated with deionized water, detergent, and artificial saliva for ICP-MS analysis and found that one mask can leach 100% silver.Not only does the use of such masks have the potential to introduce metal nanoparticles directly into the body, but it also has a significant impact on the environment after washing.An analysis of masks made by several manufacturers revealed varying levels of quality, and although some had little metal loss, even low concentrations of metal nanoparticles could have toxic effects (Pollard et al., 2021).For protective equipment such as masks and disinfectants, once the metal nanoparticles leak, they can be inhaled into the body (Muzata et al., 2021).AgNPs can spread throughout the body if damaged skin is exposed to them (Johnston et al., 2010).With healthy, undamaged skin, it is highly unlikely that metal nanoparticles will pass directly through the skin to enter the organism (Subramaniam et al., 2019).Disinfectants with metal nanoparticles have been heavily used throughout the COVID-19 pandemic.However, their improper use can still produce biological toxicity and environmental toxicity.For example, aerosolized disinfectants can easily enter the lungs through breathing and penetrate the skin, causing irritation and even inflammation of the respiratory tract (Dhama et al., 2021).
We believe that nano-consumer products can be used safely, in which metal nanoparticles do not directly cause toxic effects on the human body.However, metal nanoparticles are difficult to recycle during or after the use of some nano-consumer products, which will enter the environment and cause new environmental risks.Exposure of metal nanoparticles into the environment can create a range of health problems for a variety of organisms.When designing products containing metal nanoparticles, it is important to consider not only the direct health risks to users but also the recycling and regeneration of metals.There is an urgent need for environmental impact assessments of emerging nano-consumer products and nanomedicine products.Guidelines for their use should also be clarified to reduce the exposure of metal nanoparticles to organisms and the environment.

Toxicity evaluation of metal nanoparticles
The involvement of metal nanoparticles in the control of COVID-19 has brought great benefits, however, it should not be ignored in the assessment of potential toxicity.It is important to clarify the mechanism by which metal nanoparticles produce toxicity.First, due to their small size and high permeability, nanoparticles can easily enter organisms.Furthermore, metal nanoparticles can impact the antioxidant damage system of organisms and induce a large amount of ROS production (Pujalté et al., 2015), resulting in oxidative damage.ROS can cause lipid peroxidation (Czyżowska & Barbasz, 2019), DNA damage, and Mitochondrial dysfunction (Klaunig et al., 2010).Finally, some metal nanoparticles will release free ions and further produce toxic effects and inflammation (Garcia-Torra et al., 2021).For example, silver acetate and PVP-stabilized silver nanoparticles are highly toxic to bacteria (Escherichia coli DH5α and Staphylococcus aureus) and human cells (human mesenchymal stem cells and human peripheral blood mononuclear cells) owing to a massive release of silver ions (Greulich et al., 2012) (Fig. 2).Meanwhile, whole-body migration is a characteristic of metal nanoparticles.They can enter the lungs when masks or aerosol disinfectants are used.Researchers found inflammation in the lungs of mice exposed to AgNPs (Kim et al., 2015).Metal nanoparticles can also be transferred to other organs through the lungs.The mouse heart region produces oxidative stress and DNA damage and has cardiovascular effects (Ferdous et al., 2019).
The toxicity of metal nanoparticles is mainly related to their physical and chemical properties.Therefore, the size and shape of metal nanoparticles can be modified from the physical aspects, and the synthesis of metal nanoparticles should be considered to reduce or even eliminate the toxicity of metal nanoparticles.Gold nanoparticles with a minimum size of 4.6 nm and a maximum size of 62 nm were synthesized using monosodium phosphate, and spherical, star, and flower-shaped gold nanoparticles were synthesized with Disodium phosphates (Liu et al., 2018).Gold nanoparticles of different sizes and shapes to evaluate three fungal species, Aspergillus niger, Mucor hiemalis, and Penicillium chrysogenum.Larger nonspherical gold nanoparticles were found to be more toxic to fungi.The reason may be that the non-spherical gold nanoparticles have a larger specific surface area and are more likely to attract free radicals.Therefore, in the synthesis of metal nanoparticles, a full understanding of the effects of size and shape on their toxicity can fundamentally reduce the health risks caused by metal nanoparticles.The control of the size and shape of metal nanoparticles also depends on advanced synthesis methods (Karabasz et al., 2019).
Improving the stability of metal nanoparticles is also a way to reduce toxicity.The absorption and biocompatibility of metal nanoparticles can be improved by functionalizing their surfaces.Functionalization of nanoparticles using polyethylene glycol (PEG) is the most commonly used method to improve stability.It can prolong circulation time and improve absorption, thus reducing the systemic toxicity of nanomaterials, and will participate in the metabolism of the liver and gallbladder.Metal nanoparticles are not biodegradable, so finding the most suitable surface functionalization of different metal nanoparticles can reduce the generation of toxic and harmful substances in biological circulation as much as possible.In short, we can continuously optimize the size and shape of metal nanoparticles and select the most suitable surface functionalization to achieve the minimum biological toxicity on the premise of ensuring the same disinfection performance of metal nanoparticles.

Cumulative assessment of metal nanoparticles
Biological exposure to metal nanoparticles not only produces toxic effects but also tends to accumulate.When metal nanoparticles enter the environment, plants first accumulate them (Haverkamp & Marshall, 2009).Hawthorne et al. found that metal nanoparticles such as Ag, Au, and Cu affect the transpiration, biomass, and element content of zucchini.Metal nanoparticles may have a unique accumulation pattern (Hawthorne et al., 2012).Algae in aquatic environments are the basis of aquatic food webs.They can absorb metal nanoparticles in the environment, but metal nanoparticles can produce toxic effects on algae.Through the continuous transfer of the food chain and food web, through biological control, aquatic organisms with high trophic levels will also enrich metal nanoparticles (Mahana et al., 2021).For example, bivalve mollusks, which mainly filter feed, can be used as biological indicators of aquatic ecosystems.Metal nanoparticles are accumulated in the gills and digestive glands of these creatures (Tangaa et al., 2016).
Metal nanoparticles can also accumulate in biological tissues, organs, and even cells.They mainly accumulate in various target organs in animals, and the target organs may be related to the corresponding metal nanoparticles (Johnston et al., 2010).Gold nanoparticles, for example, are concentrated in the liver.Intranasal exposure to AgNPs in rats shows that Ag accumulates in brain tissue and that the concentration increases with time (Liu et al., 2022).It has been found that accumulation also occurs in the organs of the reticuloendothelial system; for example, metal nanoparticles accumulate in the spleen (Malaczewska, 2014).Metal nanoparticles can also accumulate in cells, such as in various organelles.The accumulation of metal nanoparticles can lead to functional changes in organelles, such as disturbance of energy metabolism, affected protein synthesis, and interference with normal digestion.In addition, metal nanoparticles are also easily engulfed by macrophages but cannot be destroyed.Therefore, it will remain unchanged in the cell for a long time and affect the immunity of the organism (Huang et al., 2020).
The accumulation of metal nanoparticles in living organisms can be used to remove heavy metals using bioremediation technology.This technology uses natural biological processes to accumulate pollutants without causing environmental harm.Current bioremediation technologies include bioremediation, phytoremediation, bioleaching ventilation, bioleaching, land formation, bioreactors, composting, bioenhancement, and biostimulation, among which phytoremediation is considered to be the most effective, and least costly method (Ullah et al., 2015).The primary phytoremediation technologies can be divided into phytofiltration, phytostabilization, phytoextraction, phytovolatilization, and phytotransformation (Gerhardt et al., 2017) (Table S2).Plant extraction can significantly reduce metal contamination and has fewer side effects than other methods.The use of ultra-enriched plants for heavy metal enrichment is low cost, easy to recover, and safe to dispose of, so they can be used to extract economically efficient metals.In addition, to avoid contaminating the food chain, plants should not be selected for crops that animals and humans can consume.Plant stability can play an important role in metal nanoparticle leakage accidents, however, phytoremediation technology has some defects.First, environmental conditions are a very important factor that directly affects the efficiency of plant repair.Second, different plants are needed for different kinds of metals.Finally, phytoremediation techniques usually require more time than other types of remediation.As a green repair method, phytoremediation technology has great potential for metal nanoparticle repair in the future, although there are some difficulties at present.

Potential environmental risks and corresponding solutions during the COVID-19 pandemic
Metal nanoparticles are widely used in the fight against COVID-19.While they play an important role in the elimination of the virus and the diagnosis and treatment of cases, metal nanoparticles are a new type of pollutant that will produce a series of environmental pollution and toxic effects when entering the environment and living organisms (Adam et al., 2015).
Limited data on the production of metal nanoparticles can be collected.Existing studies manifested a large number of metal nanoparticles are manufactured worldwide every year.Approximately 10 tons of AgNPs are produced and used in Europe each year.The output of CeO 2 , FeOx, AlOx, ZnO, and other metal oxides is between 10-10000 tons (Piccinno et al., 2012).During the COVID-19 pandemic, metal nanoparticles were more widely used in medical applications (Domingues et al., 2022).Such large consumption of PPE places great pressure on waste management and may lead to inappropriate solutions.Direct incineration and landfill disposal of waste are prone to the improper treatment of metal nanoparticles.The best treatments for disposable masks, including masks containing metal nanoparticles, are incineration and landfills, where they enter the environment, making the metals difficult to recover (Prata et al., 2021).Many masks are discarded directly into the environment leaving out the waste disposal process.A study found that PPE accounted for 55.1% of man-made beach garbage on urban beaches in Kenya (Okuku et al., 2021), and more masks were found in Jakarta rivers from March to April 2020 (Cordova et al., 2021).Therefore, assessing the total amount of metal nanoparticles entering the environment provides a visual representation of their environmental risk.We developed models to briefly assess the total amount of metal nanoparticles that may enter the environment after application in masks.
Assuming the world consumes one mask per person per day after the end of the embargo, the new crown pneumonia will result in the global consumption of 129 billion masks and 65 billion gloves per month.Only 1% of masks are improperly disposed of 30,000-40,000 tons of waste will enter the environment (Adyel, 2020).89 million surgical masks are needed every month, leading to disposable masks being found mainly in landfills, waste incineration plants, freshwater, seawater, and public areas.Masks containing metal nanoparticles release metals into the water environment after washing.Pollard et al. chose nine commercially available masks for leaching experiments to quantify silver and copper exposure during washing and mask wearing.The silver content of the nine masks was 0.02-5.27mg/mask, and the copper content was 0.09-1.11mg/mask.Different masks had different metal nanoparticle contents, and the leaching rates were also quite different, with the maximum leaching rate reaching 100%.At present, the production of masks containing metal nanoparticles is unclear.Assuming 1 antibacterial mask per 1000 masks, antibacterial metal nanoparticle masks mainly end up in landfills, incineration plants, freshwater, seawater, and public places.Of these, 63-91% went to waste incineration sites and landfills, and other improper recycling assumed to account for 10%.Remarkably, waste will enter the environment, with 8-28% entering the soil, 0.4-7% in the water, and 0.1-1.5% in the atmosphere after incineration and landfill (Keller et al., 2013), which will exert a negative influence on the environment.Models (Fig. 3) were developed to estimate the amount of silver and copper nanoparticles that might enter the environment (Table 1).Among them, silver nanoparticles and copper nanoparticles in landfills were 2.71-773.31ug/ kg and 12.19-162.88ug/kg, respectively, significantly higher than the content of silver nanoparticles in landfills before the COVID-19 pandemic (170 and 340 ug/kg) (Mitrano et al., 2017).The application of metal nanoparticles in masks will increase the pressure of landfill recycling, thus inevitably increasing the total amount of metal nanoparticles entering the environment.In addition, the risks of metal nanoparticles applying in other applications such as disinfectants, gloves, and vaccines are difficult to assess due to the lack of data.Therefore, the possible risks associated with the application of metal nanoparticles during the COVID-19 pandemic cannot be ignored.
Therefore, the application of metal nanoparticles against COVID-19 inevitably generates environmental risks.However, there is a lack of research on its risk assessment at present, and the main difficulty may be the lack of specific quantitative data.Given the limited amount of research on the life cycle assessment of metal nanoparticles, it is crucial to address the significant and often overlooked environmental hazards associated with their synthesis and recycling (Fig. 4).To tackle these challenges, we propose a comprehensive approach that considers the life cycle assessment, synthesis, and recycling of metal nanoparticles as key areas for future study and solutions.

Life cycle assessment of metal nanoparticles
LCA is a method that uses materials and their emitted energy and emissions to assess the impact of a product on the environment during its life cycle.This method can evaluate the material consumption, energy consumption, and environmental pollution of metal nanoparticles.LCA has four main steps: (1) objective and scope definition, which requires system boundaries and functional units to be defined, (2) lifecycle inventory (LCI), (3) lifecycle impact assessment (LCIA), and (4) interpretation and strategy, which includes results analysis and recommended methodology (Rosenbaum et al., 2007(Rosenbaum et al., , 2008)).
Using the keywords "life cycle assessment," "silver nanoparticles," "gold nanoparticles," "titanium dioxide nanoparticles," and "metal nanoparticles," we searched on the Web of Science and screened to find 18 articles.Table S3 in the supporting information (SI) shows the 18 selected articles on LCA research of metal nanoparticles in the past 10 years.The majority of the research focuses on the process of metal nanoparticle synthesis and use, and the most important is the FIG. 3. schematic diagram of estimation model for silver and copper nanoparticles."1" referred to Keller et al. (2013), "2" referred to Pollard et al. (2021).% is the rate at which products and substances are transformed or flowed.
process of metal nanoparticle synthesis, including the mining, processing, and manufacture of raw materials, by assessing the behavior of environmental impact.This process consumes a large amount of energy and greatly impacts global warming, which is the focus of current environmental problems.At present, most studies do not pay attention to the scrap stage of metal nanoproducts, and there are few studies on the recovery and regeneration of metal nanoparticles.Therefore, research on the scrap stage of metal nanoparticles may have great potential.
Metal nanoparticles are in the early stages of commercialization, and much research is now focused on "cradle to gate", which is the process of bringing metal nanoparticles into the "gate" of the factory from the extraction, processing, and manufacturing of raw materials.This process can assess the environmental risks and uncertainties caused by the production of metal nanoparticles.For impact assessment, existing LCI data are typically used for modeling.LCI results are divided into different impact categories (e.g., human toxicity) and then impacts are calculated through established LCIA models.Impacts can also be normalized, grouped, and weighted.Because LCIA models do not yet exist for many metal nanoparticles or those that do exist do not properly assess the environmental impact, there has been little assessment of their life cycles ("cradle to grave") of production, use, and end-of-life.Figure S2 shows that 81.8% of the research methods of metal nanoparticles in the past 10 years are from cradle to gate, mainly studying the energy consumption and environmental pollution of products or materials from development and manufacturing to use.The cradle-to-grave method of the whole process accounted for only 18.2%, and insufficient attention was given to the final disposal of metal nanoparticles and their possible environmental problems.There are many challenges in the current LCA process for nanomaterials.First, the functional units used must fully consider all the additional functions of metal nanoparticles.Second, the production process of metal nanoparticles lacks life-cycle inventory data.Third, it is difficult to calculate the amount of metal nanoparticles lost during use and obsolescence, and they are used in many different applications.Finally, the characteristic factor (CF) is crucial to explain metal nanoparticles in life cycle impact assessment (LCIA).However, there is a lack of CF of metal nanoparticles released by related processes, so there are few studies on LCA of metal nanoparticles (Salieri et al., 2018).
There is a lack of cradle-to-grave studies of metal nanoparticles for two reasons: lack of LCI data and lack of specific characterization factors for potential effects associated with metal nanoparticle toxicity.It is challenging to evaluate comprehensive data on the life cycle of metal nanoparticles because the great majority of recent studies do not include the environmental release of nanoparticles in the LCI (Table S3).Only a few studies have quantified their eventual release throughout their life cycle, and their approach to assessing the environmental release of metal nanoparticles still assumes that metal nanoparticles do not undergo transformation (Mitrano & Nowack, 2017).However, metal nanoparticles may only remain in their original form during production, and their morphology may change after use and environmental release in real environments.Additionally, the environmental release of metal nanoparticles is complex, as they can be released from point sources such as landfills and incineration plants on the one hand, and from surface sources at any stage of the production and use of the product in question on the other hand (Nowack et al., 2016).The synthesis and recycling processes of metal nanoparticles are more challenging to evaluate than those of traditional materials.Therefore, a comprehensive life cycle assessment of metal nanoparticles should include two main points: 1) establish separate LCIs for each stage where releases are likely to occur, and 2) take into account any changes in metal nanoparticles that may occur during production, use, and release.

Green synthesis
Metal nanoparticles entering the marine environment will have a large impact on marine organisms (Roma et al., 2020).Due to the unique physical and chemical properties of metal nanoparticles, they are transformed when they enter the ocean and enter organisms through different types of pathways.Therefore, the treatment of this new pollutant is very difficult, and it has become an important way to prevent metal particles from entering the environment from the source.Therefore, the development of metal nanoparticle-related products should consider practicality and safety (Table 2).The development of green and sustainable metal nanoparticles can protect the ecological environment as much as possible.
At present, there are many green synthesis methods for metal nanoparticles, such as those for plants, bacteria, and fungi.Diatoms, mushrooms, algae, plants, fungi, bacteria, actinomycetes, lichens, cyanobacteria, and microalgae have been shown to successfully reduce metal precursors to their corresponding nanoparticles (Asmathunisha & Kathiresan, 2013).The synthesis of metal nanoparticles in living plants is a low-cost, low-toxicity, and energy-saving method.Park et al. cultured soybean, radish, and alfalfa seeds as materials in an aqueous solution containing metal salts to synthesize gold and AgNPs from living plants.20-25 nm nanoparticles were found on the vascular column and inner surface of the cortex.Although metal ion solution greatly inhibits plant root growth, which may directly affect the production of metal nanoparticles, it is still a green and effective method to synthesize metal nanoparticles from living plants (Park et al., 2016).
Cyanobacteria are not only producers in the food chain but are also capable of synthesizing large quantities of nanoparticles.Cyanobacteria can also be used to synthesize nano cadmium and nano metal oxides, including copper oxide and zinc oxide (Hamida et al., 2020).Different kinds of microalgae can also be used to synthesize green metal nanoparticles.The yield of metal nanoparticles can be improved by controlling the concentration of metal salts, pH value, type of microalgae, temperature, time, and other parameters.The green nanoparticles produced by this method can be widely used in the medical industry and have great practical value (Taghizadeh et al., 2021).Fungi are very promising as a kind of biological synthesis of metal nanoparticles.Due to the advantages of simple culture, strong binding ability, and easy biomass processing, the fungal system is an efficient nanoparticle synthesis system and has good prospects in the synthesis of metal nanoparticles (Yadav et al., 2015).However, compared with other synthetic methods, the synthesis method using plants and their extracts has the greatest potential (Iravani, 2011).Since plants have bioactive compounds (Chandra et al., 2020), such as related enzymes and proteins, and carbohydrates, they can be synthesized faster and more stably and efficiently than microbes.In addition, metal nanoparticles can also be enriched in different organs of plants (Soltys et al., 2021), making plant extracts green and sustainable synthetic materials.The synthesis of metal nanoparticles from plants has also been developed for many years.Plants and their extracts are a promising direction for metal nanoparticle research due to their low cost and easy availability (Mittal et al., 2013;Shiny & Sundararaj, 2021).Earlier, researchers found that gold and AgNPs could be formed from living plants (Gardea-Torresdey et al., 2002, 2003).Later, Roy et al. obtained AgNPs by reducing silver ions using extracts from apple (Malus domestica) (Roy et al., 2014).Similarly, Velmurugan et al. synthesized 10-50 nm AgNPs from peanut shell extract, and found that their antibacterial activity was comparable to that of commercial AgNPs (Velmurugan et al., 2015).The synthesis of metal nanoparticles from plants and their extracts can realize the reuse of wastes to a certain extent.Metal nanoparticles can be synthesized from the remains of plants produced in agriculture.This not only reduces the pollution caused by incineration but also enables the synthesis of metal nanoparticles more efficiently and inexpensively.In addition, most plants are easy to obtain and have economic value.Making full use of plants can better reduce energy consumption and produce less environmental pollution compared with traditional synthetic methods.

Recycle and regeneration
The recovery and regeneration of metal nanoparticles is also an important way to reduce environmental pollution.The recycling process can reduce the introduction of heavy metals into the environment and achieve a better circular economy.At present, the direct recovery of metal nanoparticles is still a difficult problem, but new techniques are constantly emerging.Wang et al. used a coagulation-combined ultrafiltration process (coagulation-ultrafiltration process) to recover AgNPs from sludge by combining modified sodium alginate (MSA) with TiCl 4 (Wang et al., 2018).This provides a possible method for the removal and recovery of AgNPs.Similarly, Deep et al. recovered ZnO nanoparticles from alkaline zinc-manganese electrodes through chemical reactions and precipitation (Deep et al., 2016).This also provides a simple and efficient method to recover metal nanoparticles.
For the regeneration of metal nanoparticles, other aspects focus on the synthesis stage of metal nanoparticles; that is, the design of renewable metal nanoparticles or metal nanoparticles that can be recycled with less loss can reduce the consumption of resources.Hu and Shipley et al. investigated the environmental risks of titanium dioxide nanoparticles as adsorbents in water treatment.When the TiO 2 nanoparticles were adsorbed at pH = 2 and EDTA, the regeneration ability was stronger.After regeneration four times, the adsorption and desorption rates of TiO 2 nanoparticles are above 94% (Hu & Shipley, 2013).Therefore, this is a method for the application of metal nanoparticles with strong regeneration ability.In addition, Singh et al. prepared copper oxide nanoparticles using jujube juice extract as adsorbents, with a slight decrease in adsorption capacity after each adsorption-desorption cycle (Singh et al., 2017).This process still has room for improvement, but it also provides a renewable synthesis method for metal nanoparticles.
The recovery and regeneration of special magnetic nanomaterials is different from that of ordinary nanomaterials.Magnetic nanomaterials are mainly used as adsorption materials to remove pollutants from the environment.In the process of material adsorption and desorption, the loss of magnetic nanomaterials can reduce regeneration.At present, studies on the factors affecting the adsorption of magnetic nanoparticles mainly focus on pH value, which can improve or reduce the adsorption rate of magnetic nanoparticles by adjusting pH value.Therefore, it is speculated that adjusting pH value can help the recovery of magnetic nanoparticles to a certain extent.For example, Chao et al. prepared chitosan modified peroxide magnetic nanoparticles for the adsorption of Mo(VI) in water.After three regenerations, the adsorption rate of magnetic nanoparticles is above 90%.The researchers found that adsorption was best at a pH of 4 (Chao et al., 2021).Badruddoza et al. synthesized silane phosphine-coated magnetic nanoparticles (PPHSi-MnPs) by a coprecipitation method to remove As(V) and Cr(VI).When pH = 3, the adsorption effect is the best.The cationic modified magnetic nanoparticles can be easily recovered and regenerated (Badruddoza et al., 2013).In addition, Su et al. inlaid the prepared magnetic Fe 3 O 4 nanoparticles into the composite crystal to prepare the magnetic composite crystal.The magnetic composite crystals are rigid and can be recovered and regenerated by magnetic fields (Su et al., 2018).Magnetic nanomaterials have the advantage of being magnetic and can be recycled by applying an external magnetic field.The separation of magnetic nanoparticles by a magnetic field usually uses permanent magnets to provide the magnetic field, which requires less energy, is highly selective, and is fast.Magnetic nanoparticles can be separated by intermittent magnetic filters (HGMSs).The main principle is to separate magnetic nanoparticles by applying an external magnetic field to create a magnetic gradient in the metal wire inside the separator, absorbing the magnetic nanoparticles to their surface (Gomez-Pastora et al., 2014).

Conclusions and prospective
Metal nanoparticles are widely used in medical treatment and daily life because of their unique physicochemical properties.During the COVID-19 outbreak, metal nanoparticles also played an important role in the prevention, diagnosis, and treatment of the virus, which promoted the development of nanotechnology and limited the infection and transmission of COVID-19 to a certain extent.However, there are some irregularities and irrationality in the application of metal nanoparticles.Some metal nanoparticles can enter the environment or living organisms through products, thus creating health and environmental risks.The main health risks are exposure, toxicity, and accumulation risks.We propose that the main strategies are 1) to avoid exposure risks in material synthesis and product manufacturing, 2) to significantly reduce toxicity by improving the stability of metal nanoparticles, and 3) to recycle and regenerate metals in the environment by accumulating plants.
To summarize the research on the LCA of metal nanoparticles, we found that most of the research focuses on the "cradle to gate", and the whole LCA of production, use, and scrap is very limited.The recovery and regeneration technologies of metal nanoparticles are constantly emerging, which may be an important research direction in the future.Therefore, we think that the primary issues that require attention are 1) the application of green synthesis in the synthesis phase of metal nanoparticles, and 2) the recycling and regeneration phase of metal nanoparticles depending on the nature of the metal nanoparticles.Although the synthesis and regeneration of metal nanoparticles is challenging, it is very critical.Through the above strategies, we hope to reduce the secondary damage of metal nanoparticles to the environment and human body during the COVID-19 pandemic.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Table 1 .
Predicted mass contents of silver and copper nanoparticles at different stages.
FIG. 4. synthesis, recycling, and regeneration of metal nanoparticles are important research directions to solve environmental and health risks.

Table 2 .
manufacturing processes and sterilization mechanisms of major metal nanoparticles during Covid-19.