Ecotoxicology and Environmental Safety 253 (2023) 114636

Contents lists available at ScienceDirect

Ecotoxicology and Environmental Safety

journal homepage: www.elsevier.com/locate/ecoenv

Review

Synthesis, applications, toxicity and toxicity mechanisms of silver

nanoparticles: A review
Penghui Nie , Yu Zhao , Hengyi Xu *
State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China

A R T I C L E I N F O A B S T R A C T

Edited by Professor Bing Yan Silver nanoparticles (AgNPs) have become one of the most popular objects of study for the past few decades. The
ability to design AgNPs through different synthetic methods according to the application area and desired fea­
Keywords: tures is their advantage in many applications. Green synthesis of silver nanoparticles has become one of the most
Silver nanoparticles potential synthesis methods. Because of their strong antibacterial activity, AgNPs have been used in a wide range
Synthesis
of applications, such as food packaging and medical products and devices. With the increasing application of
Applications
AgNPs, it is becoming necessary for a better understanding of the toxicity of AgNPs and their potential mech­
Toxicity
Main toxicity mechanisms anism of toxicity. In the review, we first describe the synthetic methods of AgNPs. The application of AgNPs in
the field is then briefly described. The toxicity of AgNPs and their potential toxicity mechanisms are discussed.

1. Introduction antibacterial property, non-drug resistance, and other characteristics

(Li, 2021). Thanks to the intrinsic versatility of Ag (Burdușel, 2018), the
Nanoscale materials have significant superiorities in physical and synthesis methods of AgNPs are diverse, including physical, chemical,
chemical properties, such as quantum size effect (Patil and Burungale, and biological synthesis approaches (Burdușel, 2018). The characteris­
2020), surface effect and macro quanta tunnel effect (Shehzad, 2016), tics of the different synthesis methods are not well known, and AgNPs
which are determined by the three-dimensional scale, special structure are synthesized in different ways for different applications(Beyene,
and surface structure (Shehzad, 2016; Cai, 2018). For these reasons, 2017); hence, it is necessary to summarize the synthesis of AgNPs.
nanoscale materials have long been of interest (Yin, 2020). Nowadays, Among them, green synthesis of AgNPs is an environmentally friendly
silver nanoparticles (AgNPs) have been one of the most popular mate­ and sustainable method (Remya, 2017) with the advantages of green,
rials and have been explored by nanotechnology-derived nanostructures low cost, low energy consumption (Rauwel, 2015)and mild reaction
in recent decades (Saravanan, 2018). AgNPs are particles consisting of conditions (Chung, 2016) that has become an intensive research topic in
simple silver with diameter of 1–100 nm and possessing high specific the field of AgNP synthesis and has shown great potential (Remya, 2017;
surface area, surface activity, surface energy, and catalytic performance Rafique, 2017).
(Beyene, 2017). Compared with ordinary silver, AgNPs have stronger Thanks to their properties, especially antibacterial properties (Patil

Abbreviation: AE-AgNPs, Anthocyanin extract derived from purple basil-silver nanoparticles; AgNO3, Silver nitrate; AgNPs, Silver nanoparticles; AKT, Protein
Kinase B, PKB; ALB, Albumin; ALT, Glutamic-pyruvic transaminase; AST, Aspartate transaminase; ATF6, Activated transcription factor 6; ATP, Adenosine triphos­
phate; ATPase, ATP synthase; BIP, Immunoglobulin binding protein; CAT, Catalase; CHOP, CCAAT/enhancer binding protein (C/EBP) homologous protein; CRE,
Cyclization Recombination Enzyme; CYP, Cytochrome P450 proteins; Drp1, Dynamin-related protein 1; eIF-2, Eukaryotic initiation factor-2; ER, Endoplasmic re­
ticulum; GLO, Globulin; GLU, Glucose; GPX, Glutathione peroxidase; GRP78/BIP, Glucose regulated protein78/immunoglobulin binding protein; GSH, Glutathione;
HepG2 cells, Human hepatocellular liver carcinoma cell line; HSP70, Heat stress protein 70; ICR mice, Institute of Cancer Research mice; IL-6, Interleukin-6; IRE1,
Iron-response element1; LDH, Lactate dehydrogenase; LHP, Lymphocyte helping protease; LOAEL, Lowest Observed Adverse Effect Level; MDA, Malondialdehyde;
Mfn1, Mitofusin 1; MRSA, Methicillin-resistant Staphylococcus aureus; mtTFA, Mitochondrial transcription factor A; NO, Nitric oxide; Nrf2, Nuclear factor erythroid 2-
related factor 2; OPA1, Optic Atrophy 1; PERK, ProteinkinaseR-likeERkinase; PGC-1α, Peroxisome proliferator-activated receptor-γ coactlvator-1α; P-IRE1, Phos­
phorylated inosiosinase 1; P-Perk, Phosphorylated kinase R-like endoplasmic reticulum kinase; RONS, Reactive oxygen and nitrogen species; ROS, Reactive Oxygen
Species; SD rats, Sprague-Dawley; SOD, Superoxide dismutase; TGF, Transforming growth factor; TGF-β, Transforming growth factor-β; TNF-α, Tumor necrosis factor;
TP, Total protein; TPX, Thioredoxin peroxidase; TXN, Thioredoxin; XBP-1 s, X-box binding protein 1.
* Correspondence to: State Key Laboratory of Food Science and Technology, Nanchang University, 235 Nanjing East Road, Nanchang 330047, China.
E-mail addresses: [email protected], [email protected] (H. Xu).

https://doi.org/10.1016/j.ecoenv.2023.114636
Received 11 November 2022; Received in revised form 7 February 2023; Accepted 8 February 2023
Available online 15 February 2023
0147-6513/© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

et al., 2021), AgNPs are widely used in a range of applications, such as spray pyrolysis results in particles with a narrow size distribution. In an
cotton fabrics (Maghimaa and Alharbi, 2020), food packaging (Kumar, oxygen-free environment, Ag+ is reduced by heating the material to
2018; He, 2021), medical products, medical devices (Xu, 2020; Mousavi, temperatures of 600–1000 ℃ to synthesize AgNPs. Therefore, ultrasonic
2018) and other fields (Lee and Jun, 2019; Verma and Maheshwari, spray pyrolysis is considered as a direct route to synthesize AgNPs. In
2019). With the increasing use of AgNP products, AgNPs can cause a addition, the particle size of AgNPs is dependent on the aerosol droplet
variety of environmental and human health problems (Prabhu and size (Pingali et al., 2005).
Poulose, 2012). Therefore, we need to have a better understanding of the
toxicity of AgNPs and their mechanisms of toxicity. 2.2. Physical methods
AgNPs can pass through biological membranes, directly enter cells
(Ema, 2017), and accumulates in brain, heart, liver, spleen, lungs, kid­ Electric energy, light energy, microwave plasma (Hattori, 2011) and
neys, etc.(Park, 2010), which may affect the physiology. It is important evaporation–condensation are common physical methods for synthe­
to gain an understanding of how these multiple factors affect the toxicity sizing AgNPs used to decompose synthetic media to produce reducing
of AgNPs. However, self-factors are often one of the most overlooked. In substances (O2-, ethanol, ethylene glycol) that react with silver ions to
addition, the exact toxicity mechanisms of AgNPs remain unclear. There synthesize AgNPs (Iravani, 2014). People can control the reaction con­
are many proposed mechanisms, such as oxidative stress (Flores-Lopez ditions to synthesize AgNPs of different particle sizes. There is no solvent
et al., 2019), endoplasmic reticulum stress (Huo, 2015). This review contamination in this process, and the distribution of synthesized
focuses on the methods of AgNP synthesis and applications of AgNPs. nanoparticles is homogeneous. However, the physical synthesis of
Moreover, recent advances regarding the toxicity of AgNPs and its main AgNPs also has some disadvantages, such as energy consumption and
mechanism are described. the requirement for high concentrations (Iravani, 2014). This synthetic
process can be considered as decomposing the synthetic medium to
2. Synthesis of silver nanoparticles produce AgNPs. One of the key conditions for the synthesis of AgNPs is
the synthesis medium (organic solvent or water). Ethanol, ethylene
In nanotechnology, the syntheses of AgNPs are categorized as glycol, and the like are common organic solvents (Huo, 2015). Because
chemical, physical, and biological methods (Yaqoob et al., 2020). of its low cost, safety, and high heat capacity, distilled or deionized
Among them, there are two synthetic approaches for metallic nano­ water is the most frequently used liquid medium (Yaqoob et al., 2020).
particles: top-down and bottom-up (Shanmuganathan, 2019). In the
top-down approach, a suitable bulk material is split into fine particles by 2.3. Biological methods
size reduction with different techniques. In the bottom-up approach,
through chemical and biological methods, nanoparticles can be syn­ Because of several disadvantages with the physical and chemical
thesized by the phenomenon of self-assembly of atoms into new nuclei synthesis of nanomaterials, there is a growing demand for the devel­
that grow into nanoscale particles (Daniel and Astruc, 2004). Therefore, opment of environmentally friendly synthetic methods. As a key branch
people can design controlled synthetic forms of specific nanomaterials of nanotechnology, green synthesis of AgNPs is evolving (Rafique,
and construct atomic or molecular nanostructures by analyzing the 2017). Green synthetic chemistry refers to chemical synthetic methods
structure of the reactants and target products (Ijaz, 2020). In this sec­ that do not use pollutants from the source through scientific research
tion, we have reviewed the various chemical, physical and biological and development (Nasrollahzadeh, 2019). Green synthetic chemistry
methods synthesized AgNPs. meets the need for simple and reliable synthesis of nanomaterials
without toxic chemicals, and it is an important aspect of nanotechnology
2.1. Chemical methods (Prabu and Johnson, 2015; Veerasamy, 2011). The main direction of the
green approach is the synthesis of AgNPs using raw materials and re­
2.1.1. Chemical reduction agents in line with the concept of green chemistry. Biosynthesis of
Chemical reduction is one of common methods, and it needs a AgNPs is in line with the concept of green chemistry (Dikshit, 2021;
reductant to transform Ag+ into AgNPs (Suriati et al., 2014). Common Rónavári, 2021; Kurhade et al., 2021). This section mainly reviews the
reductants such as citrate (Khatoon, 2017), ascorbic acid, sodium use of microorganisms, biological fermentation broth, or plant extracts
borohydride (Sholikhah, 2018) and block copolymers (Elgawady, 2022) to synthesize high-performance AgNPs.
play a role in ensuring the stability of AgNPs (Sotiriou, 2011). The
process of forming AgNPs starts with generating a neutral silver atom 2.3.1. Microbiologically synthesized AgNPs
used as a precursor to form silver ion. As more atoms gather, they form a Using fungi, bacteria, algae, yeast, and even fermentation liquor can
cluster that can control the shape and size of AgNPs formed (Quinter­ also be categorized as microbiological synthesis of AgNPs (Rónavári,
o-Quiroz, 2019). 2021). Microbial synthesis can occur either intracellularly or extracel­
As the chemical reduction method is investigated, the advantages of lularly (Banik, 2022). Intracellular synthesis of AgNPs often requires the
chemical reduction method have become apparent. The biggest advan­ use of cell lysis agents and acoustic waves to obtain AgNPs, whereas
tage in this approach is that a substantial number of nanoparticles can be extracellular synthesis of AgNPs does not require such agents and
synthesized easily (Rafique, 2017). Nevertheless, there are some short­ acoustic waves (Farooq, 2021). Therefore, extracellular synthesis of
comings of the chemical reduction method for synthesizing AgNPs. AgNPs is more common and practical.
Metal precursor, reductant, and stabilizing/capping agents, such as The mechanism underlying the synthesis of microbiologically syn­
polyvinylpyrrolidone, are required to ensure stable chemically synthe­ thesized AgNPs can be predicted (Banik, 2022; Gurunathan, 2013). The
tized colloids, which are all present in the synthetic solution. The sub­ possible synthetic path for synthesized extracellular AgNPs can be un­
strate and chemical waste solution are harmful to humans (Sportelli, derstood as follows: some microorganisms can release reductase into the
2018). However, considering the low cost, simple operation, conve­ solution, and the reductase can reduce silver ions to the corresponding
nience, and other factors, the chemical reduction method is still one of AgNP. At the same time, the related protein can play a stabilizing role.
the most used methods. Thus, AgNPs attach to the surface of microorganism, forming extracel­
lular AgNPs. The other path is separating microorganisms and solution
2.1.2. Pyrolysis after release masses of reductase. Here, the reductase reduces silver ions
Ultrasonic spray pyrolysis is capable of synthesizing nanoparticles to AgNPs, the particle size of which is relatively small as compared with
with controlled and uniform particle size (Yusuf, 2020). Aerosol gen­ the previous method (de Souza et al., 2019; Garg, 2020). Moreover,
eration from dilute aqueous solutions of metal salts using ultrasonic intracellular synthesis of AgNPs is uncommon and occurs mainly in

2
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

fungi. However, fungi can synthesize extracellular or intracellular the superior properties of AgNPs, they have been used extensively in
AgNPs, and most of the AgNPs they synthesize are extracellular. None­ cotton fabrics (Maghimaa and Alharbi, 2020), food packaging (Kumar,
theless, this method of synthesis is not universal. The pathway of 2018; He, 2021), medical products, medical devices (Xu, 2020; Mousavi,
intracellular synthesis of AgNPs is relatively clear: metal ions are trap­ 2018), and other fields. Various certification bodies have approved the
ped on the surface of the fungi by electrostatic interactions with nega­ use of products made with AgNPs (Link and El-Sayed, 2003). Because of
tively charged carboxyl groups in the enzymes of the mycelium their biocompatibility and easy functionalization, AgNPs are applied in
cytoderm. Subsequently, metal ions are reduced by the enzymes within different products that can be endowed with sterilization ability (Bruna,
the cytoderm; this leads to the aggregation of metal ions and forms 2021). In this section, we briefly review the application of AgNPs in food
nanoparticles. Some of the produced nanoparticles penetrate the cyto­ packaging and medical products and devices.
derm and undergo reduction by the enzymes present on the cytoplasmic
membrane and cytoplasm, while the smaller nanoparticles penetrate the 3.1. The application of silver nanoparticles in food packaging
cytoderm and get trapped within the cytoplasm (de Souza et al., 2019;
Garg, 2020). Therefore, the mechanism of microorganisms’ synthesis of With increased awareness of safety, people are placing higher de­
AgNPs is increasingly being researched after the understanding of the mands on food safety. Food packaging with antimicrobial properties has
synthetic pathway of AgNPs. Ali (2014) used Penicillium citreonigrum to the capability of releasing active substances to improve the quality of
synthesize extracellular AgNPs. Results based on TEM micrographs used food, extend shelf life, and prevent spoilage, which can be achieved by
to observe extracellular AgNPs showed that the majority of AgNPs are using organic materials or by adding inorganic materials to the surface
spherical and range in size from 10 to 50 nm. Ali (2014) used Fusarium of food packaging (Sanches-Silva, 2014; Otoni, 2016). Organic polymers
moniliforme to synthesize intracellular AgNPs. There were 10–50 nm such as polyethylene and polypropylene are common food packaging
AgNPs detected within the cells, existing both in the cell wall and the material (Maddah, 2016). Recent studies have shown that microplastics
cytoplasmic membrane. Bhatnagar (2019) used Talaromyces purpur­ are formed when these organic materials are continuously broken down
ogenus to extracellularly synthesize AgNPs. The shape of the nano­ and decomposed into countless tiny plastic fragments in the environ­
particles were spherical, hexagonal, rod-shaped, and triangular, and the ment. Microplastics can enter the body through the food chain, water
particle size ranged from 4 to 41 nm. Seshadri et al. (2012) used a sources, etc. and are potentially harmful to humans (Hwang, 2019;
marine bacterium, Idiomarina sp. PR58–8, to intracellularly synthesize Rubio et al., 2020). In addition, nanocomposites material is unstable at
AgNPs. The size of AgNPs was about 26 nm. high temperature, and some have strong odors that affect the sensory
Because microorganisms are highly adaptable, fast-growing, and characteristics of food. Therefore, compared with organic materials
abundant, and have low requirements for growth conditions (tempera­ (Dhall, 2013), the use of inorganic materials seems to be more promising
ture, oxygenation, and incubation time), more researchers have focused (Metak, 2015). On account of the antibacterial property of AgNPs, they
on studying the bacteria used to synthesize nanoparticles (Li, 2011). have been used on fresh fruit, meat and other food packaging (Istiqola
Microbial synthesis of nanomaterials will possibly become mainstream and Syafiuddin, 2020).
in the future.
3.2. The application of silver nanoparticles in medical products and
2.3.2. Use of plants or plant extracts to synthesize AgNPs devices
Natural phytochemical compounds such as terpenes, flavonoids, al­
kaloids, phenol ketones, aldehydes, amides, and carboxylic acids are Compared to conventional antimicrobial materials, the specific
effective antioxidants. These are good sources of reducing agents and physical and chemical properties of AgNPs make them and their com­
stabilizers for nanoparticle synthesis (Jeevanandam et al., 2016). posites quite promising for applications in the medical industry. AgNPs
Furthermore, flavonoids can inhibit the release of inflammatory bio­ are already being used in many medical applications such as wound
logical enzymes, improve wound healing and pain relief, improve blood dressings (Kalantari, 2020), dental materials (Yin, 2020), bone implants
circulation, and reduce blood sugar and blood lipids (Dias et al., 2021). (Cheng, 2018), coated medical equipment (Marassi, 2018), and so forth.
AgNPs synthesized using green plant extracts (Prunus persica (Kumar, Here, we review some applications of AgNPs in the medical field.
2017), turmeric (Alsammarraie, 2018), Boerhaavia diffusa (Kumar,
2014), etc.) can have the properties of both plant extract and AgNPs, 3.2.1. Wound healing
exerting their synergistic effects. Using plants and plant extracts to The skin is the largest organ, and it has the capacity to protect
synthesize AgNPs has developed into a significantly innovative various tissues and organs in the body from physical, mechanical,
biotechnology. chemical and pathogenic microbial attacks. Therefore, it can be easily
More studies have shown that by choosing different plant extracts to impaired by different harmful external factors (You, 2017). Physically or
synthesize AgNPs, the properties of the synthesized AgNPs differ, mainly chemically induced cutaneous wounds may significantly disturb skin
depending on the nature of the plant or plant extract. Saratale (2018) structural and functional integrity (Zulkifli, 2017). Skin injuries leading
used Punica granatum green leaves to synthesize AgNPs. Most standard to wound infection with pathogenic microorganisms have been an
AgNPs are spherical, with size range of 20 – 45 nm, though some are important issue in the past few years (Gong et al., 2018). Because of the
variable. Haider et al. (Abbasi, 2019) synthesized AgNPs, using antho­ intrinsic physicochemical characteristics and biological peculiarities of
cyanin extract derived from purple basil (AE-AgNPs). The average size of AgNPs, AgNPs have a wide range of efficient anti-microbial activities.
AE-AgNPs was about 41.85 nm. The study indicated that AE-AgNPs have Ionized silver can provide specific antimicrobial effects under physio­
high anticancer activity. logical conditions. Inside the cell, Ag+ can merge with and act on en­
Although the property of a single extract is limited, previous studies zymes and structural proteins (Konop, 2016). Wound dressings
have given us good enlightenment by adding other substances to make containing AgNPs or Ag+ interact with and destroy bacteria in the
up for the lack of properties of green synthesized AgNPs. Therefore, in exudate (Yang and Hu, 2015). AgNPs have been used as a dressing for
the future, we may use composite extracts to obtain non-toxic, anti- wound healing in a wide range of domestic and medical applications
bacterial AgNPs through green synthesis. (Krishnan, 2020).

3. Applications of silver nanoparticles 3.2.2. Dental materials

The oral cavity is an active ecosystem. Microorganisms, including
AgNPs have exhibited highly antibacterial action against multiple pathogenic microorganisms, often colonize the mouth, thus causing
Gram-positive and Gram-negative bacteria (Cavassin, 2015). Because of contamination of dental materials and implants, as well as increase the

3
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

risk during the colonization processes (Pokrowiecki, 2017). In the dental more stable is the system. The fewer active sites are exposed on the
field, silver-based nanostructures are commonly added to modify or surface, and the weaker is the cellular response in the organism. Po­
embed dental materials (Zhang, 2016). Fluorinated diamine silver is a tential of hydrogen (pH) plays an important role in the zeta potential
typical material with favorable effects in caries prevention. The smaller (Kowalczyk and Kaminska, 2020; Takahashi, 2005), and the stability of
is the size of AgNPs, the larger is the specific surface area, thus AgNPs depends on pH (Velgosová et al., 2016). When the pH of AgNPs
improving the antibacterial property of AgNPs (Santos, 2013). The solution changes, the number of acidic or basic groups on the surface of
addition of silver-based nanosystems to adhesive resins (Lee, 2018), nanoparticles changes, leads to a change in the zeta potential of the
orthodontic cements (Paiva, 2018), and dental composites (Gunputh, particle(Badawy, 2010). When the particle surface charge repulsion is
2018; Natale, 2017) has been reported to be effective. low, suspended particles will agglomerate or flocculate; when the par­
ticle surface charge density is high, the electrostatic repulsion between
3.2.3. Bone healing the particles is greater, and the suspension solution maintains a high
Bone is an active tissue with regenerative and restorative capabil­ stability (Tantra et al., 2010). Usually, the surface of the cell membrane
ities. Bacterial infection will obviously affect the self-repair ability of is negatively charged, and there are many proteins and polysaccharides
bones. Most of these bacterial infections occur in the process of bone in the intercellular matrix, and so the amount of charge directly affects
grafts. Bone grafts are commonly used to replace or restore large defects the size of the particle’s ability to act with the cell in the biological tissue
in bone that have been severely damaged (Burdușel, 2018). Therefore, it (Chen, 2022).
is of great significance to add antibacterial agents or use antibacterial
materials in bone transplantation. Compared with common antibiotics, 4.2. Size
AgNPs have a broader spectrum of intrinsic antibacterial activity.
Especially for antibiotic-resistant bacteria such as MRSA (methi­ The size of AgNPs has long been a topic of interest. Particle size as a
cillin-resistant Staphylococcus aureus), AgNPs showed strong antibacte­ basic property affects the surface effect of nanomaterials. At the same
rial properties (Lu, 2016). The antibacterial mechanism of AgNPs is that dose, different sizes even have different effects. Specifically, the toxicity
AgNPs can interact with peptidoglycan and plasma membrane in the cell of small-size AgNPs is much higher than that of large particle size
wall (Kim, 2011) and then inhibit or weaken the development of biofilm (Scherer, 2019). One of reasons could be biological transport (Kim,
or mature biofilm (Guo, 2019). In addition, AgNPs can cause DNA 2012). AgNPs with larger diameters may enter/exit cells through ion
damage and inhibit cell respiration through Reactive Oxygen Species channels, while AgNPs with small diameters can directly pass through
(ROS) and non-ROS pathways (Khorsandi, 2021; Fatima et al., 2021; Ji, the cell membrane and act in the cells. On the other hand, small particle
2020). Therefore, AgNPs play an important role as an antibacterial agent size has a larger specific surface area, which can better play the role of
in bone healing. In addition, AgNPs can help to promote the value-added AgNPs. Therefore, in this section, we have reviewed the toxicity of
and differentiation of bone cells. Recently, it has been found that AgNPs AgNPs of different diameters.
can promote the proliferation and differentiation of MC3T3–1 pre­ To investigate different size of AgNPs, (Park, 20100 used on ICR mice
osteoblasts and improve the subsequent mineralization of osteoid tissue for six weeks after oral exposure. This finding shows that the AgNPs with
(Qing, 2018). small diameter are distributed in organs such as brain, liver, kidney, etc.
The group of 323 nm was not observed in those tissues. In addition, the
4. Factors influencing the toxicity of AgNPs levels of transforming growth factor (TGF) were significantly increased in
the groups of 22, 42, and 71 nm but not in the 323 nm group, and the
Because of their anti-inflammatory and antimicrobial properties, the distribution of B cells was increased in the treated group of 22, 42, and
unique properties of AgNPs make them widely used in life. However, 71 nm but not in the 323 nm group. We think that it may be because the
studies have shown that AgNPs can have a negative impact on humans smaller is the diameter, the easier they are to distribute in the target
as well as the environment. Therefore, an exploration of the toxicity of organ and the more severe is the damage to the organ. (Cho, 2018) used
AgNPs was initiated. The factors affecting the toxicity of AgNPs are BALB/c mice for intraperitoneal administration of 0.3 mL AgNPs, which
divided into endogenous and exogenous factors. The toxicity of AgNPs were measured at 10, 60, and 100 nm and then sacrificed at 1, 3, or 6 h
themselves is relevant to their shape, size, and surface modification after treatment. The results were only observed in the treated group of
(Yaqoob et al., 2020; Pryshchepa et al., 2020). Except for endogenous 10 nm AgNPs. The activity of mice decreased after 5 h of intraperitoneal
factors, there are also external factors, such as dosage. To sum up, these administration, and the body temperature lowered after 6 h, with his­
main factors must be fully considered when exploring the toxicity of topathological changes of congestion, vacuolation, single-cell necrosis,
AgNPs to ensure the effectiveness and feasibility of the experiment. On and focal necrosis in the liver.
this basis, this chapter reviews other main factors relative to AgNPs
themselves, and briefly outlines the influence of external factors on the 4.3. Surface modification
toxicity of AgNPs.
AgNPs could be synthesized with surface modification via chemical
4.1. Shape and/or physical methods. This modification can be in the form of AgNPs
attached to a group or substance, or encapsulation of AgNPs in a number
The shape of the nanomaterials includes spheres, flakes, tubes, rings, of surface modifiers. The AgNPs synthesized by these methods are
lines, and irregularities (Roy, 2017). Differences in particle shape cause different from traditional AgNPs; the synthesized AgNPs have some
differences in their specific surface area (Singh, 2018), surface charge, unique properties and their own characteristics (Wigginton, 2010;
zeta potential (Metwally and Stachewicz, 2019), and chemical interfaces Zahran et al., 2014). (Wang, 2019) used PVP-AgNPs and AgNPs to verify
(Capron et al., 2017), which in turn cause different interactions with the effect on Human hepatocellular liver carcinoma cell line (HepG2
cells, cell membranes, organelles, proteins, and DNA. Furthermore, cells). The particle sizes are both 20 nm. The results showed that two
irregular particles are more likely to cause physical damage to cells types of AgNPs can cause genotoxicity in HepG2 cells. However, the
(Choi, 2021). degree of DNA damage in HepG2 cells in the AgNP group was higher
Of these, zeta potential is the potential of a colloidal nanoparticle than that in the PVP-AgNPs group, while the group treated with
between the shear surface and the solution, which is an important in­ PVP-AgNPs showed chromosomal aberration more seriously than that of
dicator related to the stability of colloidal dispersion (Serrano-Lotina, the AgNPs group. A recent study found that AgNPs exhibit less toxicity
2022). The smaller is the molecule or dispersive particle, the higher is through green synthesis. (Amooaghaie et al., 2015) used Nigella sativa
the absolute value of the zeta potential (positive or negative) and the leaf extract for green synthesis of AgNPs. The size of green synthesized

4
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

Fig. 1. Chemical, physical and biological methods to synthesized AgNPs.

Fig. 2. AgNPs synthesized by microorganism in vitro and possible synthetic path on synthesized AgNPs in different locations.

5
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

Fig. 3. AgNPs or silver ions entering cells induce the levels of ROS increasingly, which combine with NO to produce RONS causing oxidative stress damage.

Fig. 4. AgNPs affects endoplasmic reticulum stress by affecting ER stress sensing proteins and markers in cells.

AgNPs is about 15 nm. The authors used six different plants and 4.4. Others
bone-building stem cells to study the toxicity of green synthesized
AgNPs compared with chemically synthesized AgNPs. The results indi­ External factors will affect the toxicity of AgNPs. Among them, the
cated that the cytotoxicity and phytotoxicity of AgNPs synthesized by most typical is the dosage of AgNPs. Some substances are beneficial at
the chemical method were significantly higher than that of the green low doses(Yin, 2020; Cheng, 2018). (Reshi, 2017) found that AgNPs at
synthesis group. Therefore, in view of their unique properties, re­ non-toxic dosages (50, 100, and 150 μg/kg) have potential to protect
searchers should currently consider using different surface modifiers to against acetaminophen-induced hepatotoxicity by regulating markers of
reduce the toxicity of AgNPs and improve their biocompatibility and to liver function, cellular biomolecules, and activities of metabolic en­
obtain a kind of AgNPs with good effect, low toxicity, and high zymes. AgNPs showed significant dose-dependent protection against
biocompatibility. acetaminophen-induced hepatocellular injury. However, with the dose
increase, the toxicity of the substance will become increasingly severe.

6
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

Fig. 5. AgNPs enters the inner membrane of mitochondria, destroys its structure and affects the fission/fusion of mitochondria, resulting in the reduction of ATP
or ATPase.

Table 1
Synthesis methods, reduction conditions, characterization and size for AgNPs using various methods.
Method Components responsible Conditions Characterization Size Reference
for the reduction of silver
nitrate

Chemical reduction Trisodium citrate 0.002 M AgNO3 solution was added into 0.02 M XRD, TEM, UV-Vis, DLS 20–30 nm (Khatoon, 2017)
C6H5Na3O7 solutions up to 10:1 ratio under 70 ◦ C and zeta potential
Chemical reduction Sodium borohydride Silver nitrate (1 mL, 0.001 N), reductor NaBH4 (1 mL, TEM, PSA and zeta 21.2 ± (Sholikhah,
0.002 N), 40 mL PVP 0.3% (w/v) and 20 mL NaCl 1.5 N, potential 5.6 nm 2018)
without stirring and temperature setting
Chemical reduction Polysulfone-poly(ethylene- 48 mg AgNO3 dissolved in 3 mL ethylene glycol TEM, GPC, GPC, FT-IR, 50–100 (Elgawady,
glycol) block copolymer DLS, TGA, DSC and DMA nm 2022)
Pyrolysis - Aqueous silver nitrate solution atomized and maintained TEM and SEM Less than (Pingali et al.,
above 650 ◦ C. 20 nm 2005)
Microwave plasma Oxide or hydroxide species Silver rods of 1–2 mm in diameter submerged by MW UV-Vis, TEM and XRD About 6 (Hattori, 2011)
generated from water plasma in pure water at 20 kPa nm
Microbiologically Enzyme within the cell The concentration of Ag+ over 10− 3 M was reacted with UV-Vis, TEM, SEM and X- 10–50 nm (Ali, 2014)
synthesized AgNPs wall in Penicillium biomass in in dark condition at 10, 27 and 40 ◦ C ray microanalysis
citreonigrum
Microbiologically Enzyme in Fusarium The concentration of Ag+ over 10− 3 M was reacted with UV-Vis, TEM, SEM and X- 10–50 nm (Ali, 2014)
synthesized AgNPs moniliforme biomass in in dark condition at 10, 27 and 40 ◦ C ray microanalysis
Microbiologically The extracellular pigment Mixture containing 0.5 g/L pigment and 2 mM of AgNO3 SEM, DLS, zeta potential 4–41 nm (Bhatnagar,
synthesized AgNPs of T. purpurogenus was adjusted to 12 using a 5 N sodium hydroxide solution, and FT-IR 2019)
and incubated at 28 ◦ C with 2000 lux of light for 48 h
Microbiologically Idiomarina sp. PR58–8 Idiomarina sp. PR58–8 was grown containing 5 mM silver UV–vis, XRD and TEM About 26 (Seshadri et al.,
synthesized AgNPs nitrate for 48 h under agitation at 120 rpm nm 2012)
Plant extract Prunus persica extract 10 mL of a 0.01 M aqueous solution of silver nitrate was X-ray diffractometer, About 40 (Kumar, 2017)
synthesized AgNPs added into Prunus persica extract at room temperature FTIR, UV-Vis, FESEM nm
Plant extract Turmeric extract 2 mL of turmeric powder were mixed with 8 mL of 1 mM UV-Vis, TEM, EDS and 18 ± 0.56 (Alsammarraie,
synthesized AgNPs AgNO3 aqueous solution under moderate stirring at room FT-IR nm 2018)
temperature
Plant extract Boerhaavia diffusa 10 mL of Boerhaavia diffusa extract was added to 90 mL of SEM-EDX, XRD, FTIR and About 25 (Kumar, 2014)
synthesized AgNPs 0.1 M AgNO3 solution and incubated for 24 h UV-Vis nm
Plant extract Punica granatum leaf Punica granatum leaf extract was mixed with an aqueous UV-Vis. XRD, XPS, FT-IR, 30–60 nm (Saratale, 2018)
synthesized AgNPs extract solution of AgNO3 (1 mM) (1:10 mixing ratio) at pH 5.0, FESEM, EDS and DLS
at room temperature
Plant extract Anthocyanin extracts AgNO3 (1 mM) was added to anthocyanin extracts and FT-IR, UV-Vis, SEM, XRD About (Abbasi, 2019)
synthesized AgNPs stored at 25 ◦ C for 24 h and EDX 41.85 nm

Meanwhile, AgNPs are a material with a significant dose dependence, was dose-dependent. AgNPs also induced obvious DNA strand breaks.
especially in terms of the toxicity of AgNPs. Wang et al. (Wang, 2017) Even at small doses, long-term exposure can lead to accumulation of
used HepG2 cells treated with different concentrations of AgNPs for 24 the substance in the body, resulting in chronic toxicity. AgNPs are the
h. This study showed that the genotoxic effect of AgNPs on HepG2 cells same. Park et al. (Park, 2010) investigated the toxicity of AgNPs in mice

7
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

Table 2
Effect of silver nanoparticles.
Material Size Model Treatment Effect Ref

AgNPs 22, 42, 71 ICR mice Mice were orally administrated AgNPs of 22, 22, 42 and 71 nm AgNPs were distributed to (Park, 2010)
and 323 42, 71 and 323 nm in a 1 mg/kg dose for 14 the organs including brain, lung, liver,
nm days kidney, and testis while 323 nm AgNPs were
not observed in those tissues. In addition, the
levels of TGF in serum were significantly
increased in the 22 nm, 42 nm and 71 nm
AgNPs group but not in 323 nm AgNPs
group, and B cell distribution was increased
in 22, 42 and 71 nm AgNPs but not in 323 nm
AgNPs
AgNPs 10, 60, BALB/c mice BALB/c mice intraperitoneally administered Only observed in mice in 10 nm AgNPs group (Tantra
and 100 0.3 mL AgNPs and sacrificed at 1, 3, or 6 h that activity and piloerection reduced at 5 h, et al., 2010)
nm after treatment and body temperature lowered at 6 h, with
histopathological changes of congestion,
vacuolation, single cell necrosis, and focal
necrosis in the liver
Polyvinylpyrrolidone- Both 20 Human hepatoma Different doses of AgNPs solution were Two types of AgNPs, in doses of 20–160 μg/ (Kim, 2012)
coated AgNPs and AgNPs nm cell HepG2 added to HepG2 cells at 1 × 105 cells per mL mL, could cause genetic toxicological
changes on HepG2 cells. The DNA damage
degree of HepG2 cells in 20 nm AgNPs was
higher than that in 20 nm PVP-AgNPs, while
the 20 nm PVP-AgNPs caused more serious
chromosomal aberration than 20 nm AgNPs
Nigella sativa leaf extract 15 nm, 30 Mesenchymal stem 103 cells per mL mesenchymal stem cells Both chemical and green synthesized AgNPs (Cho, 2018)
synthesized AgNPs and nm cells were plated into 0.1, 0.2 and 0.4 mg/mL reduced cell viability but toxicity of green
AgNPs AgNPs solution at 37 ◦ C in present of CO2 for synthesized AgNPs was significantly less than
4h chemical synthesized AgNPs
Nigella sativa leaf extract 15 nm, 30 Six different plants 10 mL of 0, 100, 200, 400, 800, 1000 and Six different plants were clearly restricted (Cho, 2018)
synthesized AgNPs and nm 1200 mg/L concentration of AgNPs with increasing concentration of both
AgNPs suspensions were added at a culture room at chemical and green synthesized AgNPs. But
25 ± 1 ◦ C under a 12 h light/dark cycle at a IC50 for seed germination, root and shoot
light intensity of 300 μmol/(m2 s) for 10 days length of seedlings in seeds or seedling
exposed to green synthesized AgNPs were
higher than one in chemical synthesized
exposures
AgNPs 3–5 nm Wistar albino rats Rats were orally exposed with APAP at a AgNPs at 50, 100 and 150 μg/kg have (Wigginton,
dose of 2 g/kg. After 24 h, rats were treated potential to protect acetaminophen induced 2010)
with 50, 100 & 150 μg/kg of AgNPs and were hepatotoxicity by regulating markers of liver
sacrificed after 24 h of the last treatment function, cellular biomolecules and activities
of metabolic enzymes, and AgNPs had
significant dose-dependent protection
against acetaminophen induced
hepatocellular injury
AgNPs < 100 nm Human liver HepG2 Stable HepG2- and A549-luciferase cells The dose-dependent genotoxic effects (Zahran
and lung epithelial were then exposed to AgNPs for 24 h over a elicited by AgNPs in HepG2-luciferase cells et al., 2014)
A549 cells 5-point concentration range of 12.5–200 μg/ which may probably be due to the obvious
mL DNA strand breaks induced by AgNPs.
Compared with the A549-luciferase cells, the
HepG2-luciferase cells seemed to be more
susceptible to AgNPs as higher levels of
genotoxicity were induced
AgNPs 42 nm ICR mice Mice were treated with AgNPs (0.25 mg/kg, Adverse impacts on liver and kidney were (Park, 2010)
0.5 mg/kg and 1 mg/kg) by oral observed in a high dose-treated group (1.00
administration for 28 days mg/kg). Cytokines including IL-1, IL-6, IL-4,
IL-10, IL-12, and TGF-β were also increased in
a dose-dependent manner by repeated oral
administration. In addition, B cell
distribution in lymphocyte and IgE
production were increased
AgNPs 87–230 Wistar rats Female Wistar rats 60 days orally exposed AgNPs treatment led to decrease in kidney (Wang,
nm AgNPs at doses of 50 and 200 ppm weight and some loss of renal function. 2019)
Significant mitochondrial damage, loss of
brush border membranes, pronounced
swelling of podocytes and degeneration of
their foot processes were observed.
Prolonged treatment of AgNPs also led to the
activation of cell proliferative, survival and
pro-inflammatory factors (Akt/mTOR, JNK/
Stat and Erk/NF-κB pathways and IL1β, MIP-
2, IFN-γ, TNF-α and RANTES) and
dysfunction of normal apoptotic pathway

8
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

by repeated oral administration for 28 days. The results indicated that and Kuo, 2010; Sánchez-Valle, 2012; Chen, 2003). AgNPs can also
cytokines were increased in a dose-dependent manner. (Tiwari, 2017) penetrate liver cell membrane, induce the production of reactive oxygen
experimented on female Wistar rats for 60 days by oral exposure to species, as well as cause lipid and protein oxidation and DNA damage,
AgNPs at doses of 50 and 200 ppm, which are below Lowest Observed which result in the injury of cellular components and function (Grzelak,
Adverse Effect Level (LOAEL). The result showed that long-term expo­ 2018; Jiravova, 2016; Yao, 2019).
sure to AgNPs can promote renal ultrastructural damage, cause renal
inflammation, and expression of cell survival factors, thereby leading to 5.2. Endoplasmic reticulum stress
and promoting the death of renal necrotic cells. The toxic effect of AgNPs
on organs is dose-dependent, and a higher dosage is associated with Endoplasmic reticulum, as a biosynthesis site, is used to produce
greater organ damage. Furthermore, although the dosage of AgNPs is far lipids, membrane proteins, and secreted proteins (Han, 2010). However,
below LOAEL, long-term low-dose repeated exposure to AgNPs can still some stimuli can disrupt the homeostasis of the endoplasmic reticulum,
induce damage and pathology of related organs. Therefore, we must thereby affecting correct protein folding and leading to the accumula­
minimize contact with AgNPs and carefully choose the dosage of AgNPs tion of unfolded and misfolded proteins in the endoplasmic reticulum
to prevent its toxicity in our daily life. lumen. ER stress is a protective stress response, the purpose of which is
to reduce the concentration of unfolded protein in the cell, thereby
5. Main toxicity mechanisms of AgNPs preventing the unfolded protein from agglutinating. However, excessive
endoplasmic reticulum stress may cause damage to cells or even organs
The toxicity mechanism of AgNPs is mainly due to its ability to (Bhattarai, 2021; Malhotra and Kaufman, 2007).
release a large amount of ROS, which can damage the cell membrane Three ER proteins act as stress-sensing proteins, which are regulated
and lead to cell apoptosis (Tang and Zheng, 2018; Bressan, 2013; Akter, by glucose regulated protein78/immunoglobulin binding protein
2018). Specifically, AgNPs easily undergo oxidation by O2 and other (GRP78/BIP), including iron-response element1 (IRE1), proteinkina­
molecules (El-Habit et al., 2014), producing Ag+(Li, 2017). Further seR—likeERkinase (PERK), and activated transcription factor 6 (ATF-6),
amounts of ROS produced and excessive ROS activates oxidative stress which activate unfolded protein response target genes during endo­
(Blanco, 2018; Mao, 2018). Endoplasmic reticulum stress is also a cell plasmic reticulum stress (Lee, 2005). AgNPs may affect these
signal transduction system and an important defense mechanism (Bet­ stress-sensing proteins to restrain unfolded protein from folding.
tigole and Glimcher, 2015) that is inextricably linked to oxidative stress Moreover, the main possible toxicity mechanisms of AgNPs on the
(Bhandary, 2012). Endoplasmic reticulum stress is a protective stress endoplasmic reticulum affect its markers. ER stress makers are signifi­
response, the purpose of which is to reduce the concentration of cantly upregulated in a dose-dependent manner (Chen, 2016). Among
unfolded protein in the cell to prevent the unfolded protein from ER stress makers, CCAAT enhancer binding protein-homologous protein
agglutinating (Lai et al., 2007). However, AgNPs can disrupt endo­ (CHOP) is a pro-apoptotic transcription factor (Yang, 2017). Therefore,
plasmic reticulum (ER) homeostasis (Mao, 2016), affect correct protein the reason for the decrease in DNA content is caused by apoptosis. Apart
folding, and lead to the accumulation of unfolded and misfolded pro­ from this, AgNPs induced changes in many ER-stress-related proteins,
teins in the endoplasmic reticulum lumen, inducing excessive endo­ including phosphorylation of PERK and its downstream eukaryotic
plasmic reticulum stress (Samutrtai et al., 2020). Some experiments initiation factor-2 (eIF-2) and phosphorylated IRE1,
have found that AgNPs can damage mitochondrial functions through endoplasmic-reticulum-stress-specific splicing of x-box transcription
non-ROS pathways (Das, 2021). Therefore, in response to research on factor-1, and cleavage of activated transcription factor 6 (ATF6), splices
the potential toxicity mechanisms of AgNPs, we have discussed three X-box binding protein 1 (XBP-1 s), and BIP. These altered proteins
main mechanisms of AgNPs toxicity (oxidative stress, endoplasmic re­ accumulate in the ER, resulting in changes in the homeostasis of the
ticulum stress, and mitochondrial function damage through non-ROS endoplasmic reticulum and further aggravating ER damage (Lee et al.,
pathways). 2003; Asselah, 2010).

5.1. Oxidative stress 5.3. Mitochondrial damage

Oxidative stress is identified as the imbalance between the produc­ Mitochondria are the main place for aerobic respiration of cells,
tion and clearance of oxygen free radicals in the cells, which leads to the oxidative phosphorylation, and formation of adenosine triphosphate
accumulation of ROS and Reactive oxygen and nitrogen species (RONS) (ATP) in cells. They provide the energy or ATP for the body and cells,
in the cells and causes oxidative stress damage (García-Sánchez et al., which are needed for life activities. Therefore, mitochondria are called
2020). cell power factories (Scheffler, 2011).
More studies showed that the toxicity of AgNPs is relevant to Ag+. Some studies have shown that mitochondria are one of the most
The specific process is as follows: AgNPs is oxidized by O2 and other sensitive targets for the toxicity of AgNPs (Maurer and Meyer, 2016;
molecules in the organism (El-Habit et al., 2014), which produces Ag+. Chichova, 2014), and AgNPs can damage mitochondrial functions
Ag+ forms stable bonds with S and N through the formation of free through non-ROS pathways(Das, 2021). AgNPs can penetrate the inner
radicals, and sulfhydryl groups interact with sulfur-containing proteins mitochondrial membrane, resulting in the swelling of mitochondria and
and peptides such as glutathione (GSH), thioredoxin (TXN), thioredoxin damage to the ridge structure of mitochondria, and even influencing
peroxidase (TPX), and superoxide dismutase (SOD)(Buglak et al., 2019). mitochondrial fusion and fission(Akter, 2018; Li, 2020). In the mito­
After a large amount of Ag+ combines with functional protein, which chondrial fission/fusion events, mitogenic proteins, fusogenic proteins,
can resist the damage due to ROS, the level of functional protein and other proteins are co-regulated. In the studies, the dephosphoryla­
changes, inducing reduction reactions. On the one hand, altered func­ tion of Drp1, which is induced by AgNPs, led to the translocation of
tional protein affects the inactivation of IRP-1, leading to disassembly of dynamin-related protein 1 (Drp1) to the mitochondria, which could
Fe–S clusters in the protein, release of iron, and alterations of -SH resi­ trigger mitochondrial fission (Li, 2020). In addition, AgNPs reduced the
dues (Lill, 2009; Outten and Theil, 2009; MladĚNka, 2006). On the other expression of Recombinant Mitofusin 1 (Mfn1) and Optic Atrophy 1
hand, the content of antioxidant substances significantly decreased. ROS (OPA1) and inhibited the expression of peroxisome proliferator-activated
as superoxide anion reacts with nitric acid (NO) to form RONS (1O2, receptor-γ coactlvator-1α (PGC-1α). Defects in mitochondrial fission/fu­
O2⋅− , H2O2,⋅OH, OH-HO2, NO⋅, and ONOO− ). ONOO- is one of the toxic sion affect mitochondrial function, resulting in reduced production of
peroxynitrite products, and⋅OH may play a significant role in overall energy, which directly affects the activity of mitochondrial ATP syn­
toxic manifestations (Guzik et al., 2003; Svegliati-Baroni, 2001; Diesen thase (ATPase), inhibits the respiratory chain, and reduces the

9
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

production of ATP (Chichova, 2014; Silva, 2014; Teodoro, 2016). On Alsammarraie, F.K., et al., 2018. Green synthesis of silver nanoparticles using turmeric
extracts and investigation of their antibacterial activities. Colloids Surf. B-
this basis, energy production, mitochondrial fission/fusion, and
Biointerfaces 171, 398–405.
biogenesis play a significant role in cytotoxicity that is produced by Amooaghaie, R., Saeri, M.R., Azizi, M., 2015. Synthesis, characterization and
AgNPs. biocompatibility of silver nanoparticles synthesized from Nigella sativa leaf extract
in comparison with chemical silver nanoparticles. Ecotoxicol. Environ. Saf. 120,
400–408.
6. Conclusion and outlook Asselah, T., et al., 2010. In vivo hepatic endoplasmic reticulum stress in patients with
chronic hepatitis C. J. Pathol.: A J. Pathol. Soc. Gt. Br. Irel. 221 (3), 264–274.
Badawy, A.M.E., et al., 2010. Impact of environmental conditions (pH, ionic strength,
The synthesis of AgNPs is mainly through chemical and physical and electrolyte type) on the surface charge and aggregation of silver nanoparticles
methods, which were followed over the decades. However, it has been suspensions. Environ. Sci. Technol. 44 (4), 1260–1266.
found that the cost is expensive with the use or production of various Banik, A., et al., 2022. Molecular Mechanisms that Mediate Microbial Synthesis of Metal
Nanoparticles, in Microbial Metabolism of Metals and Metalloids. Springer,
toxic chemicals in the synthetic process, which makes biosynthesis a pp. 135–166.
preferable option. However, bacteria and fungi can be used in the syn­ Bettigole, S.E., Glimcher, L.H., 2015. Endoplasmic reticulum stress in immunity. Annu.
thesis of AgNPs. Using plant or plant extracts is regarded as an excellent Rev. Immunol. 33, 107–138.
Beyene, H.D., et al., 2017. Synthesis paradigm and applications of silver nanoparticles
choice for synthesizing AgNPs. The advantages of using plant extracts (AgNPs), a review. Sustain. Mater. Technol. 13, 18–23.
are followed because of the availability, the nontoxic nature, and the Bhandary, B., et al., 2012. An involvement of oxidative stress in endoplasmic reticulum
various options available. Furthermore AgNPs are used in a variety of stress and its associated diseases. Int. J. Mol. Sci. 14 (1), 434–456.
Bhatnagar, S., et al., 2019. Biosynthesis of silver nanoparticles mediated by extracellular
ways, in which the antibacterial and anti-inflammatory properties of
pigment from Talaromyces purpurogenus and their biomedical applications.
AgNPs are one of the most exploited aspects. However, AgNPs can Nanomaterials 9 (7), 1042.
induce toxicity to some extent. The concentration of AgNPs above Bhattarai, K.R., et al., 2021. The aftermath of the interplay between the endoplasmic
LOAEL is toxic and can induce various health problems. Hence, it is reticulum stress response and redox signaling. Exp. Mol. Med. 53 (2), 151–167.
Blanco, J., et al., 2018. Oral exposure to silver nanoparticles increases oxidative stress
essential to study the factors (internal and external) that influence the markers in the liver of male rats and deregulates the insulin signalling pathway and
toxicity of AgNPs. External factors can be controlled through human p53 and cleaved caspase 3 protein expression. Food Chem. Toxicol. 115, 398–404.
intervention, while internal factors are related to the nature of AgNPs Bressan, E., et al., 2013. Silver nanoparticles and mitochondrial interaction. Int. J. Dent.
2013.
themselves. Therefore, in the future, it is necessary to strengthen the Bruna, T., et al., 2021. Silver nanoparticles and their antibacterial applications. Int. J.
research on the influencing factors of AgNPs in order to avoid the harm Mol. Sci. 22, 13.
caused by AgNP toxicity to humans and the environment. In the Buglak, A.A., Ramazanov, R.R., Kononov, A.I., 2019. Silver cluster–amino acid
interactions: a quantum-chemical study. Amino Acids 51 (5), 855–864.
meantime, by studying the mechanisms of toxicity of AgNPs, it is hoped Burdușel, A.-C., et al., 2018. Biomedical applications of silver nanoparticles: an up-to-
that in the future, any toxicity caused by AgNPs to humans and the date overview. Nanomaterials 8 (9), 681.
environment can be eliminated in order to use the unique properties of Cai, X., et al., 2018. Multi-hierarchical profiling the structure-activity relationships of
engineered nanomaterials at nano-bio interfaces. Nat. Commun. 9 (1), 1–12.
this substance for the betterment of humanity without any controversy. Capron, I., Rojas, O.J., Bordes, R., 2017. Behavior of nanocelluloses at interfaces. Curr.
Figs. 1–5. (Tables 1 and 2). Opin. Colloid Interface Sci. 29, 83–95.
Cavassin, E.D., et al., 2015. Comparison of methods to detect the in vitro activity of silver
nanoparticles (AgNP) against multidrug resistant bacteria. J. Nanobiotechnology 13.
Credit authorship contribution statement Chen, R., et al., 2016. Silver nanoparticles induced oxidative and endoplasmic reticulum
stresses in mouse tissues: implications for the development of acute toxicity after
Penghui Nie: Conceptualization, Investigation, Project administra­ intravenous administration. Toxicol. Res. 5 (2), 602–608.
Chen, T., et al., 2003. Role of nitric oxide in liver injury. Curr. Mol. Med. 3 (6), 519–526.
tion, Writing – original draft, Writing – review & editing. Yu Zhao: Chen, W., et al., 2022. Chitosan improves storage stability of wheat-embryo globulin. Int.
Conceptualization, Investigation, Writing – review & editing. Hengyi J. Biol. Macromol. 199, 287–297.
Xu: Conceptualization, Investigation, Project administration, Funding Cheng, L., et al., 2018. Potential antibacterial mechanism of silver nanoparticles and the
optimization of orthopedic implants by advanced modification technologies. Int. J.
acquisition, Writing – review & editing. Nanomed. 13, 3311.
Chichova, M., et al., 2014. Influence of silver nanoparticles on the activity of rat liver
mitochondrial ATPase. J. Nanopart. Res. 16 (2), 1–14.
Cho, Y.-M., et al., 2018. Size-dependent acute toxicity of silver nanoparticles in mice.
Declaration of Competing Interest J. Toxicol. Pathol. 31 (1), 73–80.
Choi, D., et al., 2021. In vitro toxicity from a physical perspective of polyethylene
The authors declare that they have no known competing financial microplastics based on statistical curvature change analysis. Sci. Total Environ. 752,
142242.
interests or personal relationships that could have appeared to influence Chung, I.-M., et al., 2016. Plant-mediated synthesis of silver nanoparticles: their
the work reported in this paper. characteristic properties and therapeutic applications. Nanoscale Res. Lett. 11.
Daniel, M.-C., Astruc, D., 2004. Gold nanoparticles: assembly, supramolecular chemistry,
quantum-size-related properties, and applications toward biology, catalysis, and
Data Availability
nanotechnology. Chem. Rev. 104 (1), 293–346.
Das, N.C., et al., 2021. Surface-modified noble metal nanoparticles as antimicrobial
No data was used for the research described in the article. There is no agents: biochemical, molecular and therapeutic perspectives, in Nanotechnology for
Advances in Medical Microbiology. Springer, pp. 165–205.
data associated with the manuscript.
Dhall, R.K., 2013. Advances in Edible Coatings for Fresh Fruits and Vegetables: a Review.
Crit. Rev. Food Sci. Nutr. 53 (5), 435–450.
Acknowledgement Dias, M.C., Pinto, D.C., Silva, A.M., 2021. Plant flavonoids: chemical characteristics and
biological activity. Molecules 26 (17), 5377.
Diesen, D.L., Kuo, P.C., 2010. Nitric oxide and redox regulation in the liver: Part I.
This work was supported by National Natural Science Foundation of General considerations and redox biology in hepatitis. J. Surg. Res. 162 (1), 95–109.
China (82060606). Dikshit, P.K., et al., 2021. Green synthesis of metallic nanoparticles: applications and
limitations. Catalysts 11 (8), 902.
Elgawady, Y., et al., 2022. In situ synthesized amphiphilic polysulfone-poly(ethylene-
References glycol) block copolymer/silver nanocomposite for separating oil/water emulsion.
J. Appl. Polym. Sci. 139, 15.
El-Habit, O.H., Mousa, E.A., Hassan, B.N., 2014. Cytotoxicity of silver nanoparticles in
Abbasi, B.H., et al., 2019. A comparative evaluation of the antiproliferative activity
mice liver cells: an ultrastructure study. J. Hosp. Med. 57 (1), 554–564.
against Hepg2 liver carcinoma cells of plant-derived silver nanoparticles from basil
Ema, M., et al., 2017. A review of reproductive and developmental toxicity of silver
extracts with contrasting anthocyanin contents. Biomolecules 9 (8), 320.
nanoparticles in laboratory animals. Reprod. Toxicol. 67, 149–164.
Akter, M., et al., 2018. A systematic review on silver nanoparticles-induced cytotoxicity:
Farooq, U., et al., 2021. Cell lysis induced by nanowire collision based on acoustic
physicochemical properties and perspectives. J. Adv. Res. 9, 1–16.
streaming using surface acoustic waves. Sens. Actuators B: Chem. 345, 130335.
Ali, F.T., et al., 2014. Silver nanoparticles synthesized by Penicillium Citreonigrum and
Fusarium moniliforme isolated from El-Sharkia, Egypt. Int J. Sci. Eng. Res 5 (4),
181–186.

10
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

Fatima, F., Siddiqui, S., Khan, W.A., 2021. Nanoparticles as novel emerging therapeutic Lee, A.-H., Iwakoshi, N.N., Glimcher, L.H., 2003. XBP-1 regulates a subset of
antibacterial agents in the antibiotics resistant era. Biol. Trace Elem. Res. 199 (7), endoplasmic reticulum resident chaperone genes in the unfolded protein response.
2552–2564. Mol. Cell. Biol. 23 (21), 7448–7459.
Flores-Lopez, L.Z., Espinoza-Gomez, H., Somanathan, R., 2019. Silver nanoparticles: Lee, A.S., 2005. The ER chaperone and signaling regulator GRP78/BiP as a monitor of
electron transfer, reactive oxygen species, oxidative stress, beneficial and endoplasmic reticulum stress. Methods 35 (4), 373–381.
toxicological effects. Mini review. J. Appl. Toxicol. 39 (1), 16–26. Lee, S.H., Jun, B.-H., 2019. Silver nanoparticles: synthesis and application for
García-Sánchez, A., Miranda-Díaz, A.G., Cardona-Muñoz, E.G., 2020. The role of nanomedicine. Int. J. Mol. Sci. 20 (4), 865.
oxidative stress in physiopathology and pharmacological treatment with pro-and Lee, S.J., et al., 2018. Preparation and characterization of antibacterial orthodontic resin
antioxidant properties in chronic diseases. Oxid. Med. Cell. Longev. 2020. containing silver nanoparticles. Appl. Surf. Sci. 432, 317–323.
Garg, D., et al., 2020. Synthesis of silver nanoparticles utilizing various biological Li, G., et al., 2011. Fungus-mediated green synthesis of silver nanoparticles using
systems: mechanisms and applications—a review. Prog. Biomater. 9 (3), 81–95. Aspergillus terreus. Int. J. Mol. Sci. 13 (1), 466–476.
Gong, C.-P., Li, S.-C., Wang, R.-Y., 2018. Development of biosynthesized silver Li, J., et al., 2020. Silver nanoparticles modulate mitochondrial dynamics and biogenesis
nanoparticles based formulation for treating wounds during nursing care in in HepG2 cells. Environ. Pollut. 256, 113430.
hospitals. J. Photochem. Photobiol. B: Biol. 183, 137–141. Li, X., et al., 2021. Development of pH-responsive nanocomposites with remarkably
Grzelak, A., et al., 2018. Crucial role of chelatable iron in silver nanoparticles induced synergistic antibiofilm activities based on ultrasmall silver nanoparticles in
DNA damage and cytotoxicity. Redox Biol. 15, 435–440. combination with aminoglycoside antibiotics. Colloids Surf. B: Biointerfaces 208,
Gunputh, U.F., et al., 2018. Anodised TiO2 nanotubes as a scaffold for antibacterial silver 112112.
nanoparticles on titanium implants. Mater. Sci. Eng.: C. 91, 638–644. Li, Y., et al., 2017. Differential genotoxicity mechanisms of silver nanoparticles and silver
Guo, J., et al., 2019. Silver nanoparticles exert concentration-dependent influences on ions. Arch. Toxicol. 91 (1), 509–519.
biofilm development and architecture. Cell Prolif. 52, 4. Lill, R., 2009. Function and biogenesis of iron–sulphur proteins. Nature 460 (7257),
Gurunathan, S., et al., 2013. Cytotoxicity of biologically synthesized silver nanoparticles 831–838.
in MDA-MB-231 human breast cancer cells. BioMed. Res. Int. 2013. Link, S., El-Sayed, M.A., 2003. Optical properties and ultrafast dynamics of metallic
Guzik, T., Korbut, R., Adamek-Guzik, T., 2003. Nitric oxide and superoxide in nanocrystals. Annu. Rev. Phys. Chem. 54 (1), 331–366.
inflammation. J. Physiol. Pharm. 54 (4), 469–487. Lu, H., et al., 2016. Biomaterials with antibacterial and osteoinductive properties to
Han, S., et al., 2010. Orm1 and Orm2 are conserved endoplasmic reticulum membrane repair infected bone defects. Int. J. Mol. Sci. 17 (3), 334.
proteins regulating lipid homeostasis and protein quality control. Proc. Natl. Acad. Maddah, H.A., 2016. Polypropylene as a promising plastic: a review. Am. J. Polym. Sci. 6
Sci. 107 (13), 5851–5856. (1), 1–11.
Hattori, Y., et al., 2011. Continuous synthesis of magnesium-hydroxide, zinc-oxide, and Maghimaa, M., Alharbi, S.A., 2020. Green synthesis of silver nanoparticles from Curcuma
silver nanoparticles by microwave plasma in water. Mater. Chem. Phys. 131 (1–2), longa L. and coating on the cotton fabrics for antimicrobial applications and wound
425–430. healing activity. J. Photochem. Photobiol. B: Biol. 204, 111806.
He, Y., et al., 2021. Carboxymethyl cellulose/cellulose nanocrystals immobilized silver Malhotra, J.D., Kaufman, R.J., 2007. The endoplasmic reticulum and the unfolded
nanoparticles as an effective coating to improve barrier and antibacterial properties protein response in. Seminars in cell & developmental biology. Elsevier,.
of paper for food packaging applications. Carbohydr. Polym. 252, 117156. Mao, B.-H., et al., 2016. Mechanisms of silver nanoparticle-induced toxicity and
Huo, L., et al., 2015. Silver nanoparticles activate endoplasmic reticulum stress signaling important role of autophagy. Nanotoxicology 10 (8), 1021–1040.
pathway in cell and mouse models: the role in toxicity evaluation. Biomaterials 61, Mao, B.-H., et al., 2018. Silver nanoparticles have lethal and sublethal adverse effects on
307–315. development and longevity by inducing ROS-mediated stress responses. Sci. Rep. 8
Hwang, J., et al., 2019. An assessment of the toxicity of polypropylene microplastics in (1), 1–16.
human derived cells. Sci. Total Environ. 684, 657–669. Marassi, V., et al., 2018. Silver nanoparticles as a medical device in healthcare settings: a
Ijaz, I., et al., 2020. Detail review on chemical, physical and green synthesis, five-step approach for candidate screening of coating agents. R. Soc. Open Sci. 5 (1),
classification, characterizations and applications of nanoparticles. Green. Chem. 171113.
Lett. Rev. 13 (3), 223–245. Maurer, L., Meyer, J., 2016. A systematic review of evidence for silver nanoparticle-
Iravani, S., et al., 2014. Synthesis of silver nanoparticles: chemical, physical and induced mitochondrial toxicity. Environ. Sci.: Nano 3 (2), 311–322.
biological methods. Res. Pharm. Sci. 9 (6), 385. Metak, A.M., 2015. Effects of nanocomposite based nano-silver and nano-titanium
Istiqola, A., Syafiuddin, A., 2020. A review of silver nanoparticles in food packaging dioxide on food packaging materials. Int. J. Appl. Sci. Technol. 5 (2), 26–40.
technologies: regulation, methods, properties, migration, and future challenges. Metwally, S., Stachewicz, U., 2019. Surface potential and charges impact on cell
J. Chin. Chem. Soc. 67 (11), 1942–1956. responses on biomaterials interfaces for medical applications. Mater. Sci. Eng.: C.
Jeevanandam, J., Chan, Y.S., Danquah, M.K., 2016. Biosynthesis of metal and metal 104, 109883.
oxide nanoparticles. ChemBioEng Rev. 3 (2), 55–67. MladĚNka, P., et al., 2006. The role of reactive oxygen and nitrogen species in cellular
Ji, H., et al., 2020. Size-controllable preparation and antibacterial mechanism of thermo- iron metabolism. Free Radic. Res. 40 (3), 263–272.
responsive copolymer-stabilized silver nanoparticles with high antimicrobial Mousavi, S.M., et al., 2018. Green synthesis of silver nanoparticles toward bio and
activity. Mater. Sci. Eng. C. Mater. Biol. Appl. 110. medical applications: review study. Artificial cells. Nanomed. Biotechnol. 46 (sup3),
Jiravova, J., et al., 2016. The effect of silver nanoparticles and silver ions on mammalian S855–S872.
and plant cells in vitro. Food Chem. Toxicol. 96, 50–61. Nasrollahzadeh, M., et al., 2019. Green Nanotechnology, in Interface Science and
Kalantari, K., et al., 2020. Wound dressings functionalized with silver nanoparticles: Technology. Elsevier,, pp. 145–198.
promises and pitfalls. Nanoscale 12 (4), 2268–2291. Natale, L.C., et al., 2017. Synthesis and characterization of silver phosphate/calcium
Khatoon, U.T., et al., 2017. Antibacterial and antifungal activity of silver nanospheres phosphate mixed particles capable of silver nanoparticle formation by
synthesized by tri-sodium citrate assisted chemical approach. Vacuum 146, photoreduction. Mater. Sci. Eng.: C. 76, 464–471.
259–265. Otoni, C.G., et al., 2016. Trends in antimicrobial food packaging systems: emitting
Khorsandi, K., et al., 2021. A mechanistic perspective on targeting bacterial drug sachets and absorbent pads. Food Res. Int. 83, 60–73.
resistance with nanoparticles. J. Drug Target. 29 (9), 941–959. Outten, F.W., Theil, E.C., 2009. Iron-based redox switches in biology. Antioxid. Redox
Kim, S.-H., et al., 2011. Antibacterial activity of silver-nanoparticles against Signal. 11 (5), 1029–1046.
Staphylococcus aureus and Escherichia coli. Korean. J. Microbiol. Biotechnol. 39 (1), Paiva, L., et al., 2018. Antibacterial properties and compressive strength of new one-step
77–84. preparation silver nanoparticles in glass ionomer cements (NanoAg-GIC). J. Dent.
Kim, T.H., et al., 2012. Size-dependent cellular toxicity of silver nanoparticles. J. Biomed. 69, 102–109.
Mater. Res. Part A 100 (4), 1033–1043. Park, E.-J., et al., 2010. Repeated-dose toxicity and inflammatory responses in mice by
Konop, M., et al., 2016. Certain aspects of silver and silver nanoparticles in wound care: a oral administration of silver nanoparticles. Environ. Toxicol. Pharmacol. 30 (2),
minireview. J. Nanomater. 2016. 162–168.
Kowalczyk, D., Kaminska, I., 2020. Effect of pH and surfactants on the electrokinetic Patil, A.P., Kapadnis, K.H., Elangovan, S., 2021. Antibacterial applications of
properties of nanoparticles dispersions and their application to the PET fibres biosynthesized AgNPs: a short review (2015-2020). Mater. Sci. Res. India 18 (2),
modification. J. Mol. Liq. 320, 114426. 143–153.
Krishnan, P.D., et al., 2020. Silver nanomaterials for wound dressing applications. Patil, S.P., Burungale, V.V., 2020. Physical and chemical properties of nanomaterials, in
Pharmaceutics 12, 9. Nanomedicines for Breast Cancer. Theranostics. Elsevier,, pp. 17–31.
Kumar, P.P.N.V., et al., 2014. Green synthesis and characterization of silver Pingali, K.C., Rockstraw, D.A., Deng, S.G., 2005. Silver nanoparticles from ultrasonic
nanoparticles using Boerhaavia diffusa plant extract and their anti bacterial activity. spray pyrolysis of aqueous silver nitrate. Aerosol Sci. Technol. 39 (10), 1010–1014.
Ind. Crops Prod. 52, 562–566. Pokrowiecki, R., et al., 2017. In vitro studies of nanosilver-doped titanium implants for
Kumar, R., et al., 2017. Rapid green synthesis of silver nanoparticles (AgNPs) using oral and maxillofacial surgery. Int. J. Nanomed. 12, 4285.
(Prunus persica) plants extract: exploring its antimicrobial and catalytic activities. Prabhu, S., Poulose, E.K., 2012. Silver nanoparticles: mechanism of antimicrobial action.
J. Nanomed. Nanotechnol. 8 (4), 1–8. Synth., Med. Appl., Toxic. Eff. Int. Nano Lett. 2 (1), 1–10.
Kumar, S., et al., 2018. Biodegradable hybrid nanocomposites of chitosan/gelatin and Prabu, H.J., Johnson, I., 2015. Plant-mediated biosynthesis and characterization of silver
silver nanoparticles for active food packaging applications. Food Packag. shelf life nanoparticles by leaf extracts of Tragia involucrata, Cymbopogon citronella,
16, 178–184. Solanum verbascifolium and Tylophora ovata. Karbala Int. J. Mod. Sci. 1 (4),
Kurhade, P., Kodape, S., Choudhury, R., 2021. Overview on green synthesis of metallic 237–246.
nanoparticles. Chem. Pap. 75 (10), 5187–5222. Pryshchepa, O., Pomastowski, P., Buszewski, B., 2020. Silver nanoparticles: Synthesis,
Lai, E., Teodoro, T., Volchuk, A., 2007. Endoplasmic reticulum stress: signaling the investigation techniques, and properties. Adv. Colloid Interface Sci. 284, 102246.
unfolded protein response. Physiology 22 (3), 193–201. Qing, T., et al., 2018. A genomic characterization of the influence of silver nanoparticles
on bone differentiation in MC3T3–E1 cells. J. Appl. Toxicol. 38 (2), 172–179.

11
P. Nie et al. Ecotoxicology and Environmental Safety 253 (2023) 114636

Quintero-Quiroz, C., et al., 2019. Optimization of silver nanoparticle synthesis by Sportelli, M.C., et al., 2018. The pros and cons of the use of laser ablation synthesis for
chemical reduction and evaluation of its antimicrobial and toxic activity. Biomater. the production of silver nano-antimicrobials. Antibiotics 7 (3), 67.
Res. 23 (1), 1–15. Suriati, G., Mariatti, M., Azizan, A., 2014. Synthesis of silver nanoparticles by chemical
Rafique, M., et al., 2017. A review on green synthesis of silver nanoparticles and their reduction method: effect of reducing agent and surfactant concentration. Int. J.
applications. Artif. Cells, Nanomed., Biotechnol. 45 (7), 1272–1291. Automot. Mech. Eng. 10, 1920.
Rauwel, P., et al., 2015. A review on the green synthesis of silver nanoparticles and their Svegliati-Baroni, G., et al., 2001. Involvement of reactive oxygen species and nitric oxide
morphologies studied via TEM. Adv. Mater. Sci. Eng. 2015. radicals in activation and proliferation of rat hepatic stellate cells. Liver 21 (1), 1–12.
Remya, V., et al., 2017. Silver nanoparticles green synthesis: a mini review. Chem. Int. 3 Takahashi, M., 2005. ζ potential of microbubbles in aqueous solutions: electrical
(2), 165–171. properties of the gas− water interface. J. Phys. Chem. B 109 (46), 21858–21864.
Reshi, M.S., et al., 2017. Silver nanoparticles protect acetaminophen induced acute Tang, S., Zheng, J., 2018. Antibacterial activity of silver nanoparticles: structural effects.
hepatotoxicity: a biochemical and histopathological approach. Regul. Toxicol. Adv. Healthc. Mater. 7 (13), 1701503.
Pharmacol. 90, 36–41. Tantra, R., Schulze, P., Quincey, P., 2010. Effect of nanoparticle concentration on zeta-
Rónavári, A., et al., 2021. Green silver and gold nanoparticles: biological synthesis potential measurement results and reproducibility. Particuology 8 (3), 279–285.
approaches and potentials for biomedical applications. Molecules 26 (4), 844. Teodoro, J.S., et al., 2016. Low-dose, subchronic exposure to silver nanoparticles causes
Roy, E., et al., 2017. Shape effect on the fabrication of imprinted nanoparticles: mitochondrial alterations in Sprague–Dawley rats. Nanomedicine 11 (11),
comparison between spherical-, rod-, hexagonal-, and flower-shaped nanoparticles. 1359–1375.
Chem. Eng. J. 321, 195–206. Tiwari, R., et al., 2017. Oral subchronic exposure to silver nanoparticles causes renal
Rubio, L., Marcos, R., Hernandez, A., 2020. Potential adverse health effects of ingested damage through apoptotic impairment and necrotic cell death. Nanotoxicology 11
micro- and nanoplastics on humans. Lessons learned from in vivo and in vitro (5), 671–686.
mammalian models. J. Toxicol. Environ. Health-Part B-Crit. Rev. 23 (2), 51–68. Veerasamy, R., et al., 2011. Biosynthesis of silver nanoparticles using mangosteen leaf
Samutrtai, P., Krobthong, S., Roytrakul, S., 2020. Proteomics for toxicological pathways extract and evaluation of their antimicrobial activities. J. saudi Chem. Soc. 15 (2),
screening: a case comparison of low concentration ionic and nanoparticulate silver. 113–120.
Anal. Sci. 20P018. Velgosová, O., Mražíková, A., Marcinčáková, R., 2016. Influence of pH on green
Sanches-Silva, A., et al., 2014. Trends in the use of natural antioxidants in active food synthesis of Ag nanoparticles. Mater. Lett. 180, 336–339.
packaging: a review. Food Addit. Contam. Part a-Chem. Anal. Control Expo. Risk Verma, P., Maheshwari, S.K., 2019. Applications of Silver nanoparticles in diverse
Assess. 31 (3), 374–395. sectors. Int. J. Nano Dimens. 10 (1), 18–36.
Sánchez-Valle, V., et al., 2012. Role of oxidative stress and molecular changes in liver Wang, J., et al., 2017. Comparative genotoxicity of silver nanoparticles in human liver
fibrosis: a review. Curr. Med. Chem. 19 (28), 4850–4860. HepG2 and lung epithelial A549 cells. J. Appl. Toxicol. 37 (4), 495–501.
Santos, V.E., et al., 2013. Antimicrobial activity of silver nanoparticles in treating dental Wang, X., et al., 2019. Genotoxic effects of silver nanoparticles with/without coating in
caries. Rev. da Fac. De. Odontol. -UPF 18, 3. human liver HepG2 cells and in mice. J. Appl. Toxicol. 39 (6), 908–918.
Saratale, R.G., et al., 2018. Exploiting antidiabetic activity of silver nanoparticles Wigginton, N.S., et al., 2010. Binding of silver nanoparticles to bacterial proteins
synthesized using Punica granatum leaves and anticancer potential against human depends on surface modifications and inhibits enzymatic activity. Environ. Sci.
liver cancer cells (HepG2). Artif. Cells, Nanomed., Biotechnol. 46 (1), 211–222. Technol. 44 (6), 2163–2168.
Saravanan, M., et al., 2018. Synthesis of silver nanoparticles from Bacillus brevis (NCIM Xu, L., et al., 2020. Silver nanoparticles: synthesis, medical applications and biosafety.
2533) and their antibacterial activity against pathogenic bacteria. Microb. Pathog. Theranostics 10 (20), 8996.
116, 221–226. Yang, Y., et al., 2017. Transcription factor C/EBP homologous protein in health and
Scheffler, I.E., 2011. Mitochondria. John Wiley & Sons. diseases. Front. Immunol. 8, 1612.
Scherer, M.D., et al., 2019. Cytotoxic and genotoxic effects of silver nanoparticles on Yang, Y., Hu, H., 2015. A review on antimicrobial silver absorbent wound dressings
meristematic cells of Allium cepa roots: A close analysis of particle size dependence. applied to exuding wounds. J. Microb. Biochem. Technol. 7, 228–233.
Sci. Total Environ. 660, 459–467. Yao, Y., et al., 2019. The toxicity of metallic nanoparticles on liver: the subcellular
Serrano-Lotina, A., et al., 2022. Zeta potential as a tool for functional materials damages, mechanisms, and outcomes. Int. J. Nanomed. 14, 8787.
development. Catal. Today. Yaqoob, A.A., Umar, K., Ibrahim, M.N.M., 2020. Silver nanoparticles: various methods of
Seshadri, S., Prakash, A., Kowshik, M., 2012. Biosynthesis of silver nanoparticles by synthesis, size affecting factors and their potential applications–a review. Appl.
marine bacterium, Idiomarina sp. PR58-8. Bull. Mater. Sci. 35 (7), 1201–1205. Nanosci. 10 (5), 1369–1378.
Shanmuganathan, R., et al., 2019. Synthesis of silver nanoparticles and their biomedical Yin, I.X., et al., 2020. The antibacterial mechanism of silver nanoparticles and its
applications-a comprehensive review. Curr. Pharm. Des. 25 (24), 2650–2660. application in dentistry. Int. J. Nanomed. 15, 2555–2562.
Shehzad, K., et al., 2016. Three-dimensional macro-structures of two-dimensional Yin, I.X., et al., 2020. The antibacterial mechanism of silver nanoparticles and its
nanomaterials. Chem. Soc. Rev. 45 (20), 5541–5588. application in dentistry. Int. J. Nanomed. 15, 2555.
Sholikhah, U., et al., 2018. Critical parameters of silver nanoparticles (AgNPs) You, C., et al., 2017. Silver nanoparticle loaded collagen/chitosan scaffolds promote
synthesized by sodium borohydride reduction. Res. J. Chem. Environ. Vol. 22 (Spec. wound healing via regulating fibroblast migration and macrophage activation. Sci.
Issue II) August (2018) 22 (2), 179–183. Rep. 7 (1), 1–11.
Silva, R.G.Td, The effect of silver nanoparticles: a chronic in vivo study for the evaluation of Yusuf, M., 2020. Silver nanoparticles: synthesis and applications. Handb. Ecomater.
hepatic mitochondrial toxicity. 2014. 2343.
Singh, P., et al., 2018. Gold nanoparticles in diagnostics and therapeutics for human Zahran, M., Ahmed, H.B., El-Rafie, M., 2014. Surface modification of cotton fabrics for
cancer. Int. J. Mol. Sci. 19 (7), 1979. antibacterial application by coating with AgNPs–alginate composite. Carbohydr.
Sotiriou, G.A., et al., 2011. Nanosilver on nanostructured silica: antibacterial activity and Polym. 108, 145–152.
Ag surface area. Chem. Eng. J. 170 (2–3), 547–554. Zhang, N., et al., 2016. Novel dental cement to combat biofilms and reduce acids for
de Souza, T.A.J., Souza, L.R.R., Franchi, L.P., 2019. Silver nanoparticles: an integrated orthodontic applications to avoid enamel demineralization. Materials 9 (6), 413.
view of green synthesis methods, transformation in the environment, and toxicity. Zulkifli, F.H., et al., 2017. A facile synthesis method of hydroxyethyl cellulose-silver
Ecotoxicol. Environ. Saf. 171, 691–700. nanoparticle scaffolds for skin tissue engineering applications. Mater. Sci. Eng.: C.
79, 151–160.

12