Characterization and potential applications of silver nanoparticles: an insight on different mechanisms


 
published by Ural Federal University 

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REVIEW  

2022, vol. 9(4), No. 20229402 

DOI: 10.15826/chimtech.2022.9.4.02 
 

1 of 20 

Characterization and potential applications of silver 
nanoparticles: an insight on different mechanisms 

Anton N. Kodintcev *  

Institute of High Temperature Electrochemistry of the Ural Branch of the Russian Academy of Sciences, 

Ekaterinburg 620066, Russia 

* Corresponding author: antonkodintsev@mail.ru 

This invited review belongs to a Regular Issue. 

© 2022, the Authors. This article is published in open access under the terms and conditions of the Creative  

Commons Attribution (CC BY) license (http:creativecommons:licenses/by/4.0/). 

 

  

Abstract 

In the 21st century, a great interest is devoted to biomedical applica-

tion of various nanoparticles, particularly, as a means of improving 

the effectiveness of therapy for different diseases. Silver nanoparti-

cles (AgNPs) are among the most studied types of nanoparticles. Due 

to the wide spectrum of their action, silver nanoparticles may be 

used both to influence pathogenic microorganisms and to improve 

the treatment of cancer. The basic physicochemical characteristics 

and stabilizing agents play an important modifying role in the phar-

macokinetics and pharmacodynamics of nanoparticles, determining 

the severity of the caused effect and their potential toxicity. This re-

view summarizes the main physicochemical properties of AgNPs and 

their impact on the biological effects. Additionally, biochemical and 

pathophysiological mechanisms of silver nanoparticles activity 

against various microorganisms and tumor cells are considered. Fi-

nally, we address the problems associated with determining the op-

timal characteristics of nanoparticles in order to increase their effi-

ciency and reduce their toxicity for the macroorganism.  

Keywords 

silver nanoparticles 

physicochemical properties 

biological effects 

toxicity 

Received: 23.06.22 

Revised: 25.06.22 

Accepted: 25.06.22  

Available online: 11.07.22 

 

1. Introduction 

Currently, the research on biomedical properties of vari-

ous nanoparticles, synthesized from gold or silver, attracts 

a considerable interest. Despite the lack of data on the 

mechanisms of silver toxicity in vivo, the nanoparticles 

obtained from it are widely used as antibacterial sub-

stances in medical, cosmetic, food and textile industries. 

Silver nanoparticles (AgNPs) have unique binding proper-

ties, including internal antimicrobial activity and poten-

tially low toxicity. Silver, and, in particular, its ions have 

the strongest antibacterial effect among metals; AgNPs 

may be used in wound dressings, local drug delivery sys-

tems, orthopedic and orthodontic materials, antiseptic 

solutions, catheters, bandages, tissue scaffolds and protec-

tive clothing [1–3]. Thus, AgNPs can be an effective alter-

native to local antibacterial drugs because of special phys-

icochemical properties and wide spectrum of action 

against various Gram-negative (Escherichia coli, Neisseria 

gonorrhea, P. aeruginosa) and Gram-positive (S. aureus, 

including MRSA) bacteria, as well as intracellular micro-

organisms (Chlamydia trachomatis) and different viruses 

[3–5]. AgNPs may be considered as a means to modernize 

the treatment regimens for Mycobacteria, such as tubercu-

losis [6]. The systematic review of Fakhruddin et al. 

demonstrates the existence of the evidence of antimicrobi-

al properties of silver nanoparticles against cariogenic 

flora in vitro and prevention of the dentin destruction [7]. 

Moreover, there is evidence of synergistic action of 

nanoparticles and various antibiotics. Combining AgNPs 

with these class of drugs could increase the antibacterial 

activity of imipenem, tetracycline, aminopenicillins, met-

ronidazole, gentamicin, kanamycin, streptomycin, and 

vancomycin [8–14]. 

Silver nanoparticles may interact with bacterial 

membranes and penetrate into the cell with the subse-

quent initiation of vital malfunction and structural 

changes leading to destruction and death of pathogenic 

microorganisms [15]. The key factor is the activation of 

oxidative stress processes leading to dysfunction of cellu-

lar structures such as DNA (genotoxic effect). Disturb-

ance of protein structure occurs due to the formation of 

Ag–S complexes, which leads to malfunction of mem-

brane pumps and respiratory chain. Activation of lipid 

peroxidation processes is another important factor of 

cellular dysfunction [16]. 

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A comparative analysis of the antibacterial effective-

ness of silver ions and silver nanoparticles elucidated that 

they boost the development of many pores in the cell 

membrane and, consequently, cause the outside leakage of 

the cytoplasm and macromolecules. Besides, there is a 

significant damage of the flagella, which impairs the mo-

bility of bacteria [19, 20, 21]. 

AgNPs have an antifungal effect (Candida albicans, As-

pergillus niger) when adding material to silicone-

containing linings and resins. In addition, there are data 

on their effectiveness against Penicillium citrinum and 

Trichophyton mentagrophytes [20–22]. Beyond antibacte-

rial and antifungal activity, AgNPs demonstrate anti-

inflammatory and antitumor properties [2, 3, 21, 22]. It is 

assumed that AgNPs are able to enhance the immunogen-

icity of vaccines, have an antidiabetic effect and also con-

tribute to bone regeneration and wound healing [3]. 

Despite the large number of studies indicating antibacte-

rial properties of silver, there is evidence of the possible phe-

notypic resistance of bacteria to AgNPs. During repeated ap-

plying of nanoparticles, the increasing aggregation under the 

influence of flagellin protein was detected. This process leads 

to subsequent loss of beneficial antibacterial effect. Inhibition 

of flagellin, for example, with pomegranate peel extract, 

helps to overcome this resistance mechanism [23, 24]. 

It should be noted that the bactericidal and bacterio-

static functions of AgNPs could be changed in the bacte-

rial environment. For example, oxidation processes can 

induce the changes of nanoparticles in oxygen-containing 

liquids, which distinguishes AgNPs from the potentially 

stable gold nanoparticles. However, the synthesis of 

AgNPs is much cheaper and more affordable, so it is very 

important to find new ways to prevent any loss of basic 

silver characteristics in solutions. For example, the po-

tential instability of AgNPs could be improved by stabili-

zation with organic, inorganic, synthetic, natural, biotic, 

and abiotic substrates [15]. 

Silver nanoparticles are zero-dimensional materials 

with particle sizes ranging from 1 to 100 nm. Currently, 

special synthetic methods have been developed to obtain 

particles with certain shapes and sizes. For example, 

chemical (reduction of ions to atoms), physical (mechani-

cal and pear-shaped) and biological (extracts of microor-

ganisms and plants) methods of production are actively 

used (Figure 1). The most common approach is chemical 

synthesis; however, this method is characterized by high 

toxicity and pollution. Biological methods are cheaper and 

more ecologically friendly. Moreover, the substrates ob-

tained during biological synthesis can be used as stabi-

lizers for the nanoparticles [3].  

2. Materials and methods 

2.1. Data sources 

A literature review on the properties of silver nanoparti-

cles was performed using the following databases: 

MEDLINE (PubMed interface), SCOPUS, Cochrane Library, 

Google Scholar. The published data on the in vitro and in 

vivo studies were accessed between January 1990 and De-

cember 2021. Backward and forward reference searching 

was applied to find the most relevant articles. 

2.2. Inclusion and exclusion criteria 

The current review includes predominantly full-text arti-

cles presented in English language and focused on silver 

nanoparticles chemical/physical/biological properties. The 

selected articles were original studies (observational and 

experimental), systematic reviews, narrative reviews and 

meta-analyses. The studies were excluded if they were not 

consistent with the research objectives and the actual 

purposes of the current review. All studies were carried 

out in vitro (cell lines) or on mice/rats due to ethic issues.  

2.3. Search strategy 

Search terms included the following: silver nanoparticles, 

AgNP, physical, chemical, biological, biocidal, properties, 

effects, toxicity, microorganism, virus, bacteria, fungi, 

protozoa, parasites, cancer and tumor. The main search 

structures consisted of keywords according to each objec-

tive of the review: ((silver nanoparticle*) OR AgNP*) AND 

synth*; ((silver nanoparticle*) OR AgNP*) AND (chemic* 

OR physic* OR bio*); ((silver nanoparticle*) OR AgNP*) 

AND microorg*; ((silver nanoparticle*) OR AgNP*) AND 

propert*; ((silver nanoparticle*) OR AgNP*) AND (anti-

bacter* OR bacter*); ((silver nanoparticle*) OR AgNP*) 

AND antivirus*; ((silver nanoparticle*) OR AgNP*) AND 

(protoz* OR parasite*); ((silver nanoparticle*) OR AgNP*) 

AND (anticancer* OR tumor*); ((silver nanoparticle*) OR 

AgNP*) AND toxic*. Grey literature and unpublished in-

formation were neither considered nor used. After refer-

ence screening the duplicates were excluded.  

The key research objectives were: 

1. Studying different chemical and physical properties 

of AgNPs, which can change biological effects. 

2. Uncovering some important biological and bio-

chemical mechanisms of AgNPs effects and toxicity against 

bacteria, viruses, fungi, protozoa, and cancer. 

 
Figure 1 Characteristics of silver nanoparticles. Different ways of 
AgNPs synthesis. Adapted from refs [17, 18]. 



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3. Elucidating potential harm and toxicity of AgNPs 

for a macroorganism and a host. 

The current review was prepared according to a scale 

for the quality assessment of narrative review articles – 

SANRA [25]. 

3. Results and discussion 

3.1. Physical and chemical properties of silver nano-

particles 

3.1.1. Size  

The antibacterial activity of silver nanoparticles is closely 

related to their size. Agnihotri et al. have investigated an-

tibacterial activity of silver nanoparticles of different size 

(5, 7, 10, 15, 20, 30, 50, 63, 85, and 100 nm) against Esch-

erichia coli MTCC 443 (E. сoli) and Staphylococcus aureus 

NCIM 5201. Antibacterial activity of AgNPs was enhanced 

with decreasing size. The smallest nanoparticles of 5 nm 

demonstrated the best results and the highest bactericidal 

activity against all tested strains [26]. Baker et al. studied 

the antibacterial activity of nanoparticles with different 

sizes ranging from 5 to 70 nm (average size 15 nm) and 

from 50 nm to more than 100 nm (average size 75 nm), 

respectively. The results showed that smaller AgNPs 

(15 nm) were more effective against E. coli [27]. Conse-

quently, the smaller size results in the higher antibacterial 

activity. This rule is explained by the fact that small AgNPs 

have larger specific surface area and more surface-acting 

centers, resulting in the increase in Ag+ release rate and, 

therefore, toxicity [28, 29]. Dobias et al. demonstrated 

that in natural ponds, the dissolution of 5 nm AgNPS oc-

curred faster than that of 10 nm silver nanoparticles. 

Smaller nanoparticles released more silver ions than 50 

nm AgNPs [30]. Morones et al. showed that only nanopar-

ticles with a diameter of 10 nm or less could penetrate 

through the bacterial cell membrane [31]. In addition, ap-

plying the nanoparticles with the size of 8.3±1.9 nm in-

creases the damage of cellular DNA by influencing the nu-

cleotide excision repair [32]. Conversely, Bélteky et al. 

noticed that in spite of the fact that nanoparticles with the 

smallest diameter have the greatest toxicity, an increase 

in the size of the nanoparticles promotes colloidal stability 

and also provides greater resistance to environmental 

conditions and aggregation [33]. 

3.1.2. Shape 

Another property that determines the antibacterial activi-

ty of silver nanoparticles is their shape. There are quasi-

spheres, nanotubes, rods, disks, cubes, prisms, octahedral, 

and triangular nanoplates [34–37] (Figure 2). Pal et al. 

investigated the antibacterial activity of spherical, rod-

shaped, and triangular silver nanoparticles against E. coli. 

Truncated triangular nanoplates demonstrated the highest 

bactericidal activity compared to nanospheres and nano-

rods. The result could be explained by the presence of spe-

cial active faces that determine their high reactivity. This 

triangular structure of nanoplates promotes more effec-

tive interaction with the bacterial cell, leading to its lysis 

[38]. On the contrary, in one of the latest studies, triangu-

lar nanoplates showed a smaller antibacterial effect com-

pared to nanospheres against E. coli, S. aureus, P. aeru-

ginosa. This can be put down to the fact that the surface 

area of the nanospheres (1.307±5 cm2) exceeded the sur-

face area of triangular nanoplates (1.028±35 cm2) [39]. In 

the other studies, the greatest bactericidal activity was 

also demonstrated by nanoparticles with the largest sur-

face area, which caused the accelerated formation of ions 

on the nanoparticle surface during their dissolution, there-

fore, increasing the antibacterial effect [40, 41]. 

 
Figure 2 Different shapes of silver nanoparticles. Adapted from 

ref [42]. 

3.1.3. Concentration of nanoparticles 

The dissolution of silver nanoparticles depends on their 

initial concentration. If this concentration is lower than 

the solubility of AgNPs (which depends on the size of the 

nanoparticles, the presence of ligands forming a complex 

with silver (I) and the physicochemical properties of the 

solution), all nanoparticles will eventually dissolve. Ag-

gregation also explains why the initial concentration of 

AgNPs affects the release kinetics of silver ions. For exam-

ple, if other parameters are fixed, the higher initial con-

centration of nanoparticles results in the slower initial 

release of silver ions. [43]. This is explained by the fact 

that at the high initial concentration AgNPs tend to aggre-

gate more rapidly, which decreases the soluble AgNPs sur-

face area [44]. The initial concentration of AgNPs ranging 

from 300 to 600 μg/L increases the  aggregation rate for 

all three sizes of AgNPs (20, 40 and 80 nm) [45]. The an-

tibacterial activity of AgNPs is also determined by the con-

centration of nanoparticles. Panáček et al. found that 

AgNPs are able to exhibit antibacterial activity at a very 

low concentration of 1.69 μg/ml [46]. Shu et al. demon-

strated that the antibacterial activity of AgNPs of 13.8 nm 

against E. coli depended on their concentration. The 

growth inhibition analysis illustrated a complete suppres-

sion of the E. coli growth at AgNPs concentrations above 



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20.0 μg/ml [47]. Ugwoke et al. found that bactericidal 

activity enhanced as the dose of silver nanoparticles in-

creased from 2 to 8 μg/ml. The smallest AgNPs 

(3.4±1.2 nm) demonstrated high sensitivity to bacterial 

strains (Coliform) at lower concentrations (8 μg/ml), 

compared with 30 μg of gentamicin [48]. In addition, the 

minimal concentration of AgNPs for antibacterial proper-

ties is mainly determined by their shape. Thus, truncated 

triangular silver nanoparticles showed the inhibition of 

bacterial growth at the 1 μg concentration, while nano-

spheres and nanorods induce an inhibiting effect at con-

centrations of 12.5 μg and 50-100 μg, respectively [31, 38]. 

But, the shape cannot be considered as a single factor that 

affects antibacterial activity, because the particle size var-

ies with the form, which influences the overall rate of par-

ticles dissolving [34]. 

3.1.4. Stabilizing agents 

As a rule, stabilizing agents are used during AgNPs syn-

thesis to provide an electrostatic repulsion between indi-

vidual particles and to prevent their aggregation [43]. As 

opposed to other silver forms, nanoparticles exhibit high 

surface energy values due to their small size and, there-

fore, they are more likely to clump and to form agglomer-

ates. Choosing a suitable stabilizing agent is an important 

requirement for the nanoparticles stabilization, because 

coating agent affects the structural properties of the na-

noparticle, including its size, shape, surface charge, and 

interaction with environment [49]. It is worth noting that 

coatings probably detach from the surface after interact-

ing with environment [50]. Among stabilizing mechanisms 

of coating agents, there are electrostatic stabilization, ste-

ric stabilization, and stabilization by hydration forces, 

depletion stabilization and stabilization by the Van der 

Waals forces [51]. Organic coating agents are widely used 

as stabilizers for silver nanoparticles. In some cases, the 

stabilizing agent acts simultaneously as a reducing agent 

of Ag+ ion to Ag0 [52]. Also, organic molecules contribute 

to the complexation of silver ions, thereby accelerating 

their dissolution [53]. 

The most common coating agents for silver nanoparti-

cles are citrate, polyvinyl alcohol (PVA), sodium dodecyl 

sulfate (SDS), polyvinylpyrrolidone (PVP), Tween 80 [54–

58]. Citrate is one of the most commonly used stabilizers 

and reducing agents used for the AgNPs synthesis. Citrate-

coated particles are electrostatically stabilized by nega-

tively charged anions. However, as the pH value decreas-

es, the citrate-anion protonates, which causes the loss of 

stabilization [59]. In vivo AgNPs capped by citrate or PVP 

demonstrate the greater antibacterial activity against 

Salmonella, compared to uncapped AgNPs, which could be 

explained by minimal interaction with serum proteins. 

Uncapped AgNPs, by contrast, lose their antibacterial ac-

tivity due to interaction with bovine serum albumin (BSA) 

[58]. Kvítek et al. proved that any of three mentioned sta-

bilizing agents (Twin-80, sodium dodecyl sulfate (SDS) or 

polyvinylpyrrolidone (PVP)) increased the antibacterial 

activity and excellent stabilization of silver nanoparticles 

dispersion against aggregation. Among all AgNPs ligands, 

SDS-modified AgNPs proved to be the most stable due to 

the electrostatic repulsion and steric effect. SDS-modified 

AgNPs demonstrated the highest antibacterial activity as-

sociated with good silver nanoparticles dispersibility and 

effective interaction with the cell membrane [60]. Ajitha 

et al. found that PVA-coated AgNPs had the smallest size 

and demonstrated high stability and antibacterial activity, 

compared to nanoparticles stabilized by other coatings [49]. 

Currently, the biosynthesis of metals and metal oxide 

nanoparticles, using biological agents such as bacteria, 

fungi, yeast, plant and algae extracts, has gained popu-

larity in the field of nanotechnology [61]. Thus, AgNPs, 

which are synthesized by various microorganisms, pro-

vide high stability due to the fact that microbes produce 

large amounts of protein [62]. AgNPs, which are synthe-

sized using cyanobacterial extract of Oscillatoria lim-

netic, have high antibacterial activity against multidrug-

resistant bacteria (Escherichia coli and Bacillus cereus) 

as well as cytotoxicity against breast cancer and colon 

cancer cells at low concentrations of 6.147 μg/ ml and 

5.369 μg/ml, respectively [63]. Plants contain carbohy-

drates, fats, proteins, nucleic acids, pigments and several 

types of secondary metabolites that act as stabilizers and 

reducing agents in the biosynthesis of silver nanoparti-

cles [64]. Caffeine and theophylline are widely used as 

stabilizing agents and could be found in water-alcohol 

extracts of Coffea arabica and Camellia sinensis as well 

as in extracts of black tea [65, 66]. Utilization of fungi as 

reducing and stabilizing agents in the biogenic synthesis 

of silver nanoparticles is also attractive because they 

produce large amounts of protein. During biological syn-

thesis, nanoparticles are coated with biomolecules de-

rived from the fungus, which leads to improved stability 

and increased biological activity [17, 67]. Konappa et al. 

capped silver nanoparticles with secondary metabolites 

secreted by the T. Harzianum fungus. The obtained 

AgNPs had high stability as well as a wide range of anti-

bacterial activity against two gram-positive bacteria (S. 

aureus and B. subtilis) and two gram-negative bacteria 

(E. coli and R. solanacearum) [68]. 

Silver nanoparticles also could be stabilized with pol-

ymeric carbohydrates such as starch, sodium alginate and 

chitosan [69–71]. Muhammad et al. used sericin (a protein 

that is a part of silk) as a stabilizing agent. Sericin-coated 

nanoparticles proved to be highly effective against bacte-

ria and maintained stability over a wide range of tempera-

tures and pH concentrations. The authors suggested wide 

use of sericin in the future because of low cost and high 

stability [72]. Hydroxyl groups of sericin form complexes 

with silver ions, thus preventing their aggregation and 

deposition [71]. Azócar et al. used diclofenac (d) and ke-

torolac (k) as stabilizing agents, which are widely used as 

anti-inflammatory drugs in medicine. The results demon-



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strated that AgNPs-k were more stable than the uncoated 

nanoparticles. Under the influence of UV light (wavelength 

of 365 nm), capped nanoparticles generated anion radi-

cals. This effect is probably associated with capping 

agents, because bare nanoparticles do not promote the 

formation of superoxide anion [73]. 

3.1.5.  Surface charge of the nanoparticles 

Gao et al. found that dispersion and stability of AgNPs are 

related to their surface charge. The negative surface 

charge contributes to the electrostatic stabilization of the 

nanoparticles against aggregation. However, the disper-

sion charge of particle can change depending on the pH 

value. The surface charge of AgNPs becomes more nega-

tive at higher pH, as confirmed by the high zeta potential 

value equal to –32.5 mV, which promotes the stability of 

the suspension. Conversely, lower pH values of 5 and 3 are 

characterized by a decrease in zeta potential to –22.5 and 

–18.2 mV, which, therefore, reduces the repulsive forces 

and stability [59]. Moreover, small AgNPs have lower zeta 

potentials than large AgNPs; thus, small particles have 

less electrostatic repulsion and more rapid aggregation. 

Surface charge is one of the most important factors of 

AgNPs toxicity. Recently, the antibacterial activity of posi-

tively and negatively charged AgNPs has been studied. 

Some studies demonstrated that positively charged AgNPs 

have a higher bactericidal activity against all microorgan-

isms compared with negatively or neutral charged AgNPs 

[74, 75]. El Badawy et al. found out that positively charged 

BPEI-AgNP were more toxic against bacteria, compared 

with negatively charged citrate-AgNP. It could be ex-

plained by negative membrane charge of both gram-

positive and gram-negative bacteria. Consequently, there 

is an electrostatic barrier between negatively charged cit-

rate-AgNP and bacterial membranes that limits interaction 

between the cell and nanoparticles, thus reducing toxicity 

[76, 77]. Qiao et al. synthesized zwitterion-modified 

AgNPs, which could change the charge depending on the 

environmental pH. These AgNPs demonstrated a pH-

dependent transformation of negative charge into positive 

charge. Therefore AgNPs were innocuous for healthy tis-

sue cells (pH=7.4), while interacted effectively with nega-

tively charged bacterial surfaces in foci of infection 

(pH=5.5) [78]. 

3.2. Influence of biological conditions on the nanopar-

ticles properties  

Such factors as pH, presence of dissolved oxygen, electro-

lytes and organic substances, in particular, proteins affect 

significantly the physicochemical properties and antibac-

terial activity of silver nanoparticles [79, 80]. 

3.2.1. Oxygen availability 

The dissolution of the nanoparticles occurs in the presence 

of dissolved oxygen. The surface of AgNPs is easily oxi-

dized by O2 and other molecules in ecological and biologi-

cal systems, resulting in the release of Ag+ and defining 

their toxicity [81]. However, silver nanoparticles do not 

dissolve completely in the presence of molecular oxygen. A 

complete dissolution requires a stronger oxidizer such as 

H2O2. The AgNPs aggregation in oxygenated water is  

3–8 times faster than under anaerobic conditions, indicat-

ing that dissolved molecular oxygen can also significantly 

affect this process [45]. 

3.2.2. Interaction with proteins 

It is well known that nanomaterials can interact with 

various biomolecules of living organisms, primarily with 

proteins that are able to adsorb on the nanoparticles sur-

face, forming the biomolecular corona [82]. About 300–

500 human plasma proteins could be bound to different 

nanoparticles. Nanomaterials are rapidly coated by pro-

teins in physiological fluids. The formation of the protein 

corona leads to the change in the physicochemical prop-

erties of nanoparticles, including hydrodynamic size, 

surface charge, and aggregation [84]. The structure of 

protein corona depends primarily on the nanoparticle 

material, size and surface properties, as well as on the 

composition of protein environment and experi-

mental/physiological conditions [84–86]. Tai et al. and 

Alarcon et al. demonstrated that the protein corona 

serves as a kind of biological identity of the nanoparticle. 

In addition, it contributes to the colloidal stability of the 

particle, that presents the aggregation of the nanoparti-

cles and protective from aggressive environmental condi-

tions  [87, 88]. Functionalization of silver nanoparticles 

surface significantly affects the formation dynamics of 

protein corona. The presence of a protein coating on the 

surface of the nanoparticles strongly reduces the binding 

degree to the protein. On the contrary, the formation of 

the corona on the uncoated nanoparticles improved sig-

nificantly their stability in biological environment. The 

in vitro experiments showed that the physiological sta-

bility of AgNps caused by the corona formation may be 

directly associated with their binding to the cell, capture 

and toxicity [89]. The interaction between nanoparticles 

and different cells is determined by the composition of 

protein corona [90]. 

3.2.3. pH 

The solution pH affects significantly the surface charge 

and oxidative dissolution of AgNPs. The behavior of nano-

particles differs under acidic and alkaline conditions. 

AgNPs are found to destabilize in acid and neutral pH, 

which results in higher aggregation rate. Under alkaline 

conditions, negatively charged hydroxyl ions promote the 

stabilization of nanoparticles [91]. Bélteky et al. found 

that AgNPs are more stable at alkaline and neutral values 

of pH than under acid conditions. An increase in the pH 

level leads to higher deprotonation degree of free organic 

functional groups and increasing negative charge on the 

nanoparticles surface. It facilitates the increasing electro-

static repulsion between particles and reduces the degree 

of aggregation [82]. Sivera et al. showed that gelatin-



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stabilized AgNPs have robust resistance to aggregation in 

a wide range of pH (2 to 13). Moreover, these AgNPs 

demonstrated long-term stability against aggregation and 

maintained high antibacterial activity under environmen-

tal conditions for several months [92]. 

3.2.4. Electrolyte concentration 

An increase in the electrolyte concentration leads to an 

increase in the AgNPs aggregation rate [43]. Stebounova 

et al. concluded that AgNPs aggregate in solutions with 

high ionic strength regardless of stabilization [79]. Bé-

lteky et al. found that in solutions containing 50 mm of 

NaCl, the aggregation is slow and the size of AgNPs ag-

glomerates does not change significantly. However, the 

addition of 150 mm of NaCl induces the rapid aggrega-

tion of AgNPs up to micrometer size range. Sudden 

changes in aggregation occur due to an increase in the 

concentration of Na+, because in large quantities these 

ions can shield negatively charged surface groups, which 

provide electrostatic stabilization. With reduced repul-

sion, the particles form larger aggregates during colli-

sions [82]. The presence of chloride ions in solution 

causes silver chloride deposition [53]. However, sulfide 

ligands significantly reduce the toxicity of AgNPs caused 

by generation of insoluble silver compounds [93]. The 

nanoparticle aggregation is very prominent in solutions 

with high concentration of divalent cations, such as Mg 2+ 

and Ca2+, due to the stronger neutralization of the sur-

face charge. On the other hand, monovalent cations (K+ 

and Na+) can also enhance the aggregation of AgNPs, but 

they are much less effective in the shielding of surface 

charge than divalent ones [43]. Finally, the effect of the 

ionic strength on the AgNPs aggregation is more signifi-

cant for smaller particles [93]. 

3.3. Mechanisms of AgNPs biological activity 

3.3.1. The main mechanisms of antibacterial activity 

The main antibacterial properties of silver nanoparticles 

are provided directly by silver ions; in other words, nano-

particles are a kind of transporters of the main active sub-

stance [97]. Moreover, AgNPs obtained by the "green" syn-

thesis are more toxic than AgNPs obtained by non-

biological approaches [64]. 

AgNPs release silver ions that interact with sulfa 

groups of membrane proteins, which disturb the mem-

brane integrity and thereby increase its permeability. 

AgNPs interact with the cytoskeletal protein MREB, which 

plays an important role in the survival and formation of 

the bacterial cell [98]. Active adhesion of silver ions to the 

cell membrane leads to the change in its charge (depolari-

zation and desensitization), lysis of cellular components 

and rupture of organelles. Moreover, silver ions partici-

pate in transduction processes by dephosphorylation of 

tyrosine residues, initiating the launch of the bacterial cell 

apoptosis program [13, 99].  

Once in the cell, free silver ions interact with respira-

tory chain enzymes (dehydrogenases) and bind to func-

tional electron donor groups (thiols, phosphates, imidaz-

ole, indoles, and hydroxyl groups), disrupting the ATP syn-

thesis and K+ transport [14, 98, 100]. 

In addition, the pathological effect of silver nanopar-

ticles is induced by the formation of reactive oxygen spe-

cies (ROS): superoxide anion radical (O2•−), peroxide 

(O2•−2), hydroxyl radical (•OH), hydrogen peroxide 

(H2O2), hydroxyl ions (OH−). Different ROS have various 

pathological effects, for instance: OH−, H2O2 and O2•− 

have the greatest antibacterial activity. OH− interacts 

with positively charged cell membranes, while H2O2 has 

the greatest penetrating effect. High concentration of 

ROS leads to a decrease in the concentration of glutathi-

one, an increase in lactate dehydrogenase, dysregulation 

of calcium channels, matrix metalloproteases and intra-

cellular redox homeostasis [101]. Actually, ROS interacts 

with the thioredoxin system of S. aureus, which is one of 

the most important disulfide reductase systems that 

counteract the processes of oxidative stress. Oligomeri-

zation and dysregulation of thiol-redox homeostasis due 

to the depletion of intracellular thiol leads to disruption 

of the protective components and to activation of the 

oxidative stress [102].  

Moreover, ROS interact with DNA, thereby triggering 

the processes of its modification. In addition to the indi-

rect effect through oxidative stress, silver ions interact 

with sulfur and phosphorus groups of DNAs, which leads 

to the rupture of hydrogen bonds between the chains; the 

processes of replication and reproduction are disrupted 

(i.e., genome splitting is observed) [103]. Unipolar charge 

of DNA and AgNPs leads to additional destabilization of 

the chains. Damage to DNA molecules occurs due to oxida-

tion and alkylation of its bases, which leads to the for-

mation of various compounds: 8-oxoguanine, 7,8-dihydro-

8-oxoguanine, 8-oxoadenine, unsubstituted and substitut-

ed with an imidazole ring of purines. These compounds 

are integrated into DNA under the influence of hydroxyl 

radicals [103, 104]. 

In addition to DNA, silver ions also interact with RNA 

and block the subunits of ribosomes (30S), which are nec-

essary for binding tRNA [105, 106]. Being in cytoplasm 

AgNPs induce the processes of ribosome denaturation, 

inhibition of translation, protein synthesis and carbohy-

drate metabolism [102, 107]. 

The disturbance of the signal transduction processes is 

equally important because suppressing the phosphoryla-

tion of tyrosine residues results in blocking the cell cycle, 

the synthesis of exopolysaccharides and capsular polysac-

charides, which ultimately leads to the interruption of the 

bacterial cell division [103]. 

Thus, the antibacterial activity of silver has a complex 

effect on the microorganism, disrupting various aspects of 

its vital activity.  



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Gram-negative bacteria are more sensitive to the ef-

fects of silver ions than Gram-positive bacteria, which is 

due to a thinner layer of peptidoglycans in the cell wall 

[108]. For example, S. aureus, a Gram-positive coccus with 

a cell wall width of 30 nm, can effectively prevent the in-

ward penetration of nanoparticles due to the high affinity 

of the peptidoglycan layer [109, 110].  

The antibacterial effect may depend not only on the 

size of the nanoparticles (nanoparticles smaller than 10 

nm have high penetrating power), but also on the physico-

chemical properties, in particular, surface characteristics. 

So, positively charged nanoparticles have a greater bind-

ing ability with a negatively charged cell membrane due to 

the electrostatic interaction, in contrast to the negatively 

charged AgNPs. The higher positive charge of the ions re-

sults in the lower severity of the electrostatic barrier [97, 

108, 109, 111]. 

Despite the fact that silver ions play a crucial role in 

disrupting the basic processes of microorganisms’ activity, 

nanoparticles also have an antibacterial effect due to the 

mechanism of the "contact destruction". 

The antibacterial properties of silver nanoparticles also 

depend on their shape. For example, spherical and trian-

gular AgNPs have greater activity against E. coli and S. 

aureus is than AgNPs of irregular shape, which may be due 

to a larger surface and increased release of silver ions [5, 

13]. However, Pal et al. elucidated that the triangular 

shape’s AgNPs have a greater antibacterial effectiveness 

against E. coli, compared to spherical and rod-shaped par-

ticles [38]. Moreover E.coli is more sensitive to AgNP ex-

posure than S. aureus regardless of AgNP size and surface 

properties [112]. 

There are published data indicating the ability of silver 

nanoparticles to suppress the formation of bacterial films 

on medical instruments without significant accumulation 

of silver ions in surrounding organs and tissues. The most 

promising direction is the approbation of this coating for 

catheters, drains and medical masks [5]. 

Moreover, numerous studies pinpoint the anti-

inflammatory properties of AgNPs, which are associated 

with a decrease in the pro-inflammatory cytokines synthe-

sis (TNF, IL-12, IL-1, NF-kb) and the induction of apoptosis. 

In addition, the modulation role of silver in the process of 

wound and periodontal healing has been discovered [104]. 

Thus, the main antibacterial mechanisms of AgNPs 

(Figure 3) are as follows: 

1. Interaction with the membrane, impairment of its 

permeability and change in charge. 

2. Disturbance of intracellular processes and organelles 

dysfunction.  

3. Inhibition of mitochondrial processes (respiratory 

chain malfunction), activation of oxidative stress, synthe-

sis of reactive oxygen species and lipid peroxidation. 

4. Interaction with DNA and RNA, blocking the replica-

tion, transcription, and translation. 

5. Inhibition of transduction of signals due to 

dephosphorylation of tyrosine residues. 

 

 

 
Figure 3 Antibacterial properties of AgNPs. General mechanisms 
of antimicrobial mode of action of silver nanoparticles (a); Bacte-
ricidal effect of green synthesized AgNPs on different bacterial 

strains. Dose-dependent activity of AgNPs synthesized using Allo-
phylus cobbe leaves. The bacterial strains were incubated at vari-
ous AgNPs concentrations ranging from 0.1 to 1.0 mg/ml and bac-

terial rate survival was estimated by colony forming unit (CFU) 
assay at 4 h (b); Zone of inhibition of silver nanoparticles against 
various pathogenic microorganisms compared to banana peel 

extract (BPE) (c). Presented from refs [61, 113].  

(a) 

(b) 

(c) 



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3.3.2. The main mechanisms of antiviral activity  

In vitro AgNPs could adhere to the virus surface, bind the 

viral ligand and therefore prevent its spreading in cell 

cultures (Figure 4a, 4b). Lv et al. indicate the property of 

silver nanoparticles to inhibit TGEV (transmissible gastro-

enteritis virus in pigs) induced apoptosis by binding to S 

glycoprotein. The suppression of the proapoptotic pathway 

is one of the possible mechanisms because TGEV causes an 

increase in concentration of protein BAX [114]. Based on 

the published data, there is assumption that the nanopar-

ticles can also be effective against the novel coronavirus 

infection (COVID-19) because they have a possibility to 

interact with the spike glycoprotein and to decrease pH of 

respiratory epithelium, which would effectively prevent 

intracellular invasion of the virus (Figure 4c) [98, 115]. 

There is a description of AgNPs possibility to bind the G-

protein of the respiratory syncytial virus in the hep-2 cell 

culture. AgNPs coated with polyvinylpyrrolidone inhibited 

the reproduction of RSC virus by 44%, while silver nano-

particles coated with biomolecules and RF-112 did not 

have a visible effect on the pathogen's life cycle [104, 116]. 

In addition to the binding to surface proteins, AgNPs 

interact with the viruses’ nucleic acids (for instance, of the 

hepatitis B virus) and disrupt their replication in the host 

cells [103]. The inhibition of HBV RNA/DNA synthesis and 

creation of extracellular virions are observed in the hu-

man hepatoma HepAD38 cell line [117]. 

Biologically synthesized AgNPs of small size (<20 nm) 

have greater effectiveness against herpes simplex virus 

type 1/2 and human parainfluenza virus type 3 due to a 

more pronounced blocking effect on the interaction be-

tween the virus and a cell of the Veroline cell line. Nano-

particles are able to interact non-covalently with the thy-

midine kinase ligand, thereby suppressing the activity of 

herpesviruses. In addition to inhibition of HPV 1 and type 

2, there is an inhibition of oncogenic herpesviruses, for 

example, Epstein-Barr virus [13, 120]. Moreover, AgNPs 

block the interaction of herpesviruses with heparan sul-

fate proteoglycans of cell membranes, preventing invasion 

processes. These properties could be enhanced by combin-

ing AgNPs with tannic acid [121, 122]. 

Particles smaller than 10 nm can prevent the spreading 

of influenza virus in cell culture MDCK [123]. In 2017, Lin 

et al. published the data about the activity of combination 

treatment with Zanamivir and AgNPs against the H1A1 

influenza virus in MDCK cell line. This combination not 

only demonstrated high thermodynamic and kinetic stabil-

ity, but also suppressed effectively the replication of the 

influenza virus by regulating neuraminidase activity [124]. 

There are published data about the ability of silver na-

noparticles to interact with HIV and inhibit significantly 

its reproduction by binding to the regions of disulfide 

bond (sulfur-containing residues of CD4-binding domain) 

of gp120 [125, 126]. Moreover, silver nanoparticles could 

prevent infection of cervical tissue with HIV type 1 with-

out cytotoxic effect in vitro [127]. 

 

 

 
Figure 4 Antiviral properties of AgNPs. Schematic model of a virus 

infecting an eukaryotic cell and antiviral mechanism of metal 
nanoparticles. (a); The activity of silver nanoparticles against the 
prevalent viruses (b); Mechanisms of antiviral activity against 

SARS-CoV2 (c). Adapted from refs [118, 119]. 

Silver nanoparticles have a wide antiviral spectrum of 

action against different viruses that spread through mos-

quito bites: dengue fever, West Nile fever, Zika virus and 

Chikungunya virus. Both uncoated AgNPs and polysaccha-

Influenza

inhibition of new virions 
formation and their 

spreading

Hepatitis B virus

inhibition of new virions 
formation and their 

spreading

Herpes virus

Inhibition of replication 
and invasion processes in 

a healthy cell

HIV

Binding to gp120 and 
preventing virus from 

entering the cell. Inhibition 
of virus reproduction

Respiratory syncytial 
virus

Binding to G-protein, 
inhibition of virus 

reproduction

(a)

))k

k)) 

(b) 

(c) 



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rides- coated AgNPs have a suppressing effect on the repli-

cation of Tacaribe virus and Monkeypox virus [13, 128, 129]. 

3.3.3. The main mechanisms of antifungal activity 

The mechanisms of AgNPs antifungal activity are not fully 

understood. There is a suggestion that the interaction of 

nanoparticles with the membrane leads to disruption of its 

function (the current of transmembrane ions, including 

protons) and division processes (especially in yeast). Also, 

AgNPs induce an inhibition of germ tube formation, 

growth of biofilm and secretion of hydrolytic enzymes 

[130, 131]. Beyond the membranotoxic effect, silver nano-

particles could initiate a cascade of intracellular patholog-

ical processes leading to the fungus death: oxidative 

stress, interaction with thiol groups and phosphorus-

containing molecules, blocking protein synthesis. Thus, 

the fundamental antifungal mechanisms are similar to 

antibacterial ones (Figure 5a) [132]. 

The majority of the published data was acquired by 

studying the activity of AgNPs against plant pathogens and 

mold fungi [133]. However, AgNPs have antifungal proper-

ties against pathogenic fungi that cause dermatophytosis: 

Candida sp. (including Candida albicans) and Tri-

chophyton mentagrophytes [134, 135]. Even amphotericin-

B resistant strains of Candida glabrate were found to be 

sensitive to nanoparticles [136]. Silver nanoparticles also 

have a biocidal effect on biofilms that are formed by Can-

dida spp. [137].  

There are data on the inhibition effect of particles on 

fungal keratitis pathogens (Fusarium spp., Aspergillus 

spp., Alternaria alternate) in vitro. At the same time, 

AgNPs had a potentially greater antifungal effect than an-

timycotic drug – natamycin [140]. 

AgNPs can enhance the effect of antifungal drugs. 

There are data about synergy of silver nanoparticles and 

ketoconazole against the main cause of seborrheic derma-

titis - Malassezia furfur. Combination therapy leads to a 

decrease in the frequency of drug use and the frequency of 

relapses not only of seborrheic dermatitis, but also of oth-

er malasesiosis [141]. Also, AgNPs suppress the growth of 

different pathogenic Aspergillus species (Aspergillus ni-

ger, Aspergillus flavus, Aspergillus fumigatus), which can 

cause a wide range of diseases. Due to this effect, silver 

nanoparticles can play an important role in the treatment 

of aspergillosis, especially in patients with drug-resistant 

strains [142]. It is worth mentioning that Aspergillus niger 

can be used to synthesize AgNPs (one of the directions of 

biological synthesis). The synthesized nanoparticles have 

the ability to inhibit the growth and development of Allo-

vahlkampfia spelaea, which causes resistant keratitis [143].  

Thus, silver nanoparticles can play an important role in 

the treatment of fungal infections, especially due to the 

scarcity of the antifungal drugs and increasing number of 

drug-resistant species (Figure 5b). The combination of 

nanoparticles and drugs can boost the effect of the latter 

and have an independent bactericidal action in the case of 

multiple resistance of pathogenic fungi. AgNPs can also be 

used to prevent the spreading of mold on different surfac-

es [133]. However, the inhibition of fungal growth by sil-

ver nanoparticles is less prominent than that of bacteria, 

which may be due to the presence of chitin in the wall of 

the fungus, rather than peptidoglycans [142]. 

 
 

 
Figure 5 Antifungal activity of silver nanoparticles. Schematic repre-
sentation for the proposed model for mechanism of action of AgNPs 
against Candida cells, depicting possible cellular targets and existence 

of ROS-dependent and ROS-independent pathways for fungicidal 
action of AgNPs (a); Antifungal activity of silver nanoparticles 
against: A.niger (1) and P.chrysogenum (2) at the concentrations of 

200, 300, 400 and 500 µg/ml(b); Colonies of Trichophyton tonsurans 
(1), Microsporum gypseum (2) and Trichophyton mentagrophytes (3). 
On PDA and PDA supplemented with different concentrations of 

AgNP. The bar charts represent the diameter of the colonies in the 
function of AgNP concentration (b). Reproduced from [138, 139]. 

3.3.4. Mechanisms of antiparasitic activity 

There are reliable data confirming the antiparasitic prop-

erties of silver nanoparticles, in particular, against the 

causative agent of cutaneous leishmaniasis (Leishmania 

tropica) (Figure 6a). AgNPs bind to the sulfo- and phos-

phorus-containing membrane and DNA proteins, blocking 

DNA synthesis and activation of oxidative stress. AgNPs 

have an anti-promastigote effect because of blocking the 

proliferation of promastigotes. In addition, AgNPs sup-

(a) 

(c) 

(b) 



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press the vital activity of amastigotes and reduce their 

survival in infected host cells. Anti-amastigote properties 

are boosted by additional exposure of ultraviolet light. 

Probably, when exposed to ultraviolet light, there is an 

increase in the concentration of monosulfide radicals, 

which are formed from complexes. These complexes are 

formed by interaction of silver ions and cysteine groups of 

parasitic proteins [144, 145]. 

 
Figure 6 Antiparasitic properties of AgNP. AgNPs leishmanicidal 
activity. L. amazonensis promastigotes forms were subjected to 
different concentrations of AgNPs-bio (0.125, 0.25 and 0.50 

μg/mL) and the parasite viability was assessed at 0, 24, 48 and 72 
h (a); Effect of AgNPs in Toxoplasma gondii morphology as as-

sessed by fluorescence microscopy. In the control sample, intact 
oocyst, in the presence AgNPs at 45 min and 60 min (b); Scanning 
electron microscopy (SEM) micrograph of protoscolices of E. 

granulosus. Protoscolices without nanoparticles and 1 mg/mL 
concentrations of Ag-NPs that covered protoscolex (c). Repro-
duced from [146–148].  

Apart from Leishmania, the antibacterial activity of 

silver nanoparticlesis was observed against oocysts Enta-

moeba histolytica, Cryptosporidium parvum and several 

other protozoa [131, 149]. For example, in the study of 

Costa et al. biogenic AgNPs inhibited the replication of 

Toxoplasma gondi (which causes toxoplasmosis) in cell 

cultures, such as BeWo, HTR-8/svneo, Hela and in villous 

explants. Moreover, the nanoparticles induced secretion of 

inflammatory cytokines in cells, for example, in the BeWo 

line: IL-4 and IL-10; in the HTR-8/SVneo line: IL-4 and the 

macrophage migration inhibitory factor (MIF). Toxoplas-

ma gondi increased the MIF concentration in the BeWo cell 

culture and IL-6 in HTR-8/SVneo line. In villous explants 

the synthesis of IL-4, IL-6 and IL-8 decreased after infest-

ing. In Hela cell line an increase in the NO concentration, 

oxidative stress and reduction of pro-inflammatory cyto-

kines, in particular, IL-8 were observed. Thus, silver na-

noparticles can significantly inhibit the spread of T. Gondi 

without developing dysfunction of the host cells (Figure 

6b) [150, 151]. In addition to the cell cultures and chorion-

ic villi, AgNPs suppresses toxoplasma’s replication in liver 

and spleen tissues [152]. One of the possible antiparasitic 

mechanisms includes the suppression of mitochondrial 

function, disturbing mitochondrial membrane potential, 

redox signaling and destruction of leucine aminopeptidase 

(LAP) [153]. 

The current data plays an important role in the devel-

opment of alternative approaches to the treatment of tox-

oplasmosis, particularly in pregnancy, because standard 

drugs used for the treatment of this pathology have tera-

togenic and myelosuppressive properties. Moreover, toxo-

plasmosis is part of the TORCH complex, which includes a 

group of intrauterine infections that lead to impaired fetal 

development and even death.  

The results of Younis et al. demonstrated the effective-

ness of AgNPs against Blastocystis hominis, which is the 

causative agent of blastomycosis. The most prominent an-

tiparasitic effect in vitro was observed with a combination 

of particles and metronidazole. The concentration of B. 

Hominis decreased by 71.69% in the metronidazole group, 

by 79.67% in the AgNPs group and by 62.65% in the com-

bination therapy group (AgNPs + metronidazole) after 3 

hours (p<0.05). The nanoparticles are likely to interact 

with and modify glycoprotein and lipophosphoglycan mole-

cules on the parasite surface they may induce oxidative 

stress, and inhibit ROS synthesis and DNA replication [154]. 

There are data on the possible sporicidal action of na-

noparticles against Echinococcus (Figure 6c). Moreover, 

AgNPs have a synergistic effect with albendazole and are 

able to prevent the development of adverse reactions in 

the liver associated with this drug. For example, they de-

crease the severity of necrosis, steatosis, and reduce the 

level of transaminase and IFN-γ. Combination therapy is 

associated with a greater degree of structural changes in 

echinococcal cysts (reduction of cyst size and cyst mass) 

[155, 156]. 

Additionally, silver nanoparticles are used for the devel-

opment of new directions in the treatment of giardiasis (Gi-

ardia lamblia). The combination with chitosan and curcu-

min leads to the complete eradication of giardia in the in-

testine and feces of rodents without the development of 

adverse reactions [157]. The study of tropical malaria 

(Plasmodium falciparum) using AgNPs for the treatment is 

ongoing [158]. Moreover, silver nanoparticles could be used 

in ophthalmology for prevention of Acanthamoeba adhesion 

on contact lenses (amoebic keratitis prophylaxis) [159]. 

3.3.5. Main mechanisms of anticancer activity  

Silver nanoparticles are promising for developing and 

modifying approaches to antitumor therapy. AgNPs can 

have a cytotoxic effect on tumor cells with subsequent 

suppression of the pathological process. The decreased 

lymphatic outflow in malignant tumors allows nanoparti-

cles to accumulate and act longer [160]. Moreover, tumor 

cells absorb AgNPs (by endocytosis) to greater than nor-

mal cells [2].  



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There are main mechanisms of anticancer activity: in-

duction of oxidative stress, changing the structural-

cellular morphology and activation of pro-apoptotic pro-

cesses (caspase 3 and 9, regulation of p53, p38 MAPK, 

HIF-1α, increase in BAX concentration and decrease in Bcl-

2 concentration) [161]. Apart from apoptosis, there are 

also necrosis and autophagy in cancer cells are activated 

by stimulation of autophagosomes formation through the 

PtdIns3K signaling pathway. Except direct pro-apoptotic 

effect, there is also an indirect activation of apoptosis 

through oxidative stress and synthesis of pro-

inflammatory cytokines (IL-6). An increase in the concen-

tration of TNF-alpha and "NF-kB" nuclear factor contrib-

utes to the activation of pro-inflammatory processes in the 

tumor cell [162]. The increased concentration of oxygen radi-

cals and significant depletion of glutathione leads to the dys-

function of mitochondria and the NADP/NAD system, im-

paired permeability of the outer mitochondrial membrane, 

destruction of the respiratory chain, blocking the ATP synthe-

sis and release of cytochrome C into cytosol, which are im-

portant activating factors of caspase 3 (through apaf-1) and 

caspase 9 (Figure 7) [3, 101, 163–165]. 

Besides inhibiting the mitochondrial activity, AgNPs af-

fect structural and functional characteristics of DNA. 

AgNPs provoke the DNA methylation, increasing the num-

ber of chromosomal aberrations and malfunction of the 

repair system. For example, they cause the downregula-

tion of proliferating cell nuclear antigen, i.e. the clamp of 

DNA polymerase, which plays an important role in the 

synthesis and reparation of DNA. As in bacterial cells, the 

released silver ions are able to disrupt the hydrogen bonds 

between the DNA bases, which leads to disorganization 

[3]. The activation of c-Jun NH2 terminal kinase (JNK) is 

an additional factor in DNA fragmentation and the atopic 

bodies formation [162]. 

Moreover, the action of AgNPs is characterized by the 

disturbance of metabolic processes and sensitization of the 

tumor cell, increasing its sensitivity to antitumor drugs, in 

particular, to 5-fluorouracil due to the modulating effect 

on expression of uracil phosphoribosyl transferase, which 

ultimately leads to active induction of apoptosis [166]. In 

addition, there are data on the pharmacological synergism 

of AgNPs and doxorubicin [167]. 

In lung fibroblasts and glioblastoma cells AgNPs in-

duce different processes, such as metallothionein up-

regulation, downregulation of the actin-binding protein 

and filamine, cell cycle arrest in phase G (2)/M [2, 168]. 

Biosynthesized AgNPs can block the cell cycle in G1 

phase. One possible mechanism of the cell cycle arrest is 

the downregulation of cyclin B and cyclin E, whose nor-

mal functioning is of the paramount importance for divi-

sion processes [162].  

AgNPs have antiangiogenic properties. In particular, 

AgNPs inhibit growth of blood vessels in tumor, limiting 

its progression. Probably, this effect is associated with 

VEGF (vascular endothelial growth factor) blocking and 

angiogenic FGF-2 (fibroblast growth factor 2) synthesis, as 

well as the inhibition of the transduction processes of the 

signaling pathways through the phosphorylation of KDR 

tyrosinekinase (VEGFR-2) and PI3K/Akt [169–171]. 

Another mechanism of inhibiting cancer cell prolifera-

tion, vascular growth, and tumor progression implies a 

disruption of signaling transduction by suppressing the 

effects of hypoxia-induced factor-1a (HIF-1α) and matrix 

metalloproteases. Active growth and progression of the 

tumor are accompanied by insufficiently active formation 

of the vascular network, which leads to the cell hypoxia 

and, consequently, an increase in the concentration of 

HIF-1α. HIF-1α regulates the expression of genes responsi-

ble for cellular activity: division, growth, and angiogenesis 

[172]. Matrix metalloproteases have similar functions. 

Resistance to the therapy is often accompanied with high 

activity of these signaling pathways, so their blocking 

plays a potentially important role in the modification of 

contemporary treatment approaches [3].  

The antitumor effect of nanoparticles can be enhanced 

by coating with nano transfers, for example, with chi-

tosan. Chitosan-coated nanoparticles have a greater inhib-

itory effect and cause apoptosis at a lower concentration 

than uncoated AgNPs [2, 173]. Smaller nanoparticles (10, 

20 nm) have the strongest antineoplastic effect compared 

to the large AgNPs (100 nm), which may be due to the 

greater penetrating capacity.  

 
Figure 7 Anticancer properties of AgNPs. AgNPs have a cytotoxic 
effect, inhibit the mitochondrial functions and boost the processes 

of oxidative stress and damage of tumor cell membrane. AgNPs 
also contribute to the suppression of the vascular growth factor 
(VEGF), which leads to the inhibition of the new vessels for-

mation. Moreover, processes of tumor cells division are disturbed 
and the phenomenon of autophagy is observed. Reproduced from 
refs [180, 181]. 



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Moreover, charge and electrostatic interaction also af-

fect internalization. For example, positively charged parti-

cles penetrate more quickly and have greater cytotoxicity 

than particles with a neutral or negative charge. 

A positive charge allows the interaction both with a 

negatively charged membrane and albumin, which leads to 

formation of a protein shell. The "protein corona" allows 

AgNPs to enter cells through receptor-mediated endocyto-

sis with further implementation of cytotoxic and genotoxic 

effects [75, 174, 175].  

There are published data on the antitumor activity of 

AgNPs against a wide spectrum of oncological diseases in 

vitro: blood cancer (acute myeloid leukemia), breast cancer, 

hepatocellular carcinoma, osteosarcoma, lung cancer, mela-

noma of the skin and mucous membranes, squamous cell 

carcinoma of the skin, colon cancer, osteosarcoma, cervical 

cancer, prostate cancer, adenocarcinoma of the stomach, 

bladder cancer and pancreas cancer [1, 3, 13, 176–179]. 

3.3.6. Potential toxicity of silver nanoparticles 

Despite the data indicating the broad therapeutic potential 

of AgNPs, it is important to assess their toxicity, since the 

main biochemical effects of nanoparticles do not have bio-

logical selectivity and can interact with the macroorgan-

ism cells. Studying of toxic effects allows us to determine 

the therapeutic properties of drugs contain AgNPs and to 

minimize adverse side effects. The toxic properties of 

AgNPs depend on their size, shape, surface feature (nega-

tively charged particles are less toxic), stabilizing agent 

and coating. Moreover, local environmental factors have 

an equally important role in toxicity: the strength of the 

ion interaction, presence of ligands, macromolecules and 

bivalent cations, as well as pH parameters [74, 182]. Toxic 

effects of nanoparticles have been studied either in vitro 

on cell cultures or in vivo on rodents. Different methodol-

ogies and approaches make it difficult to determine com-

mon parameters and characteristics of AgNPs toxicity. 

Pharmacokinetic features of AgNPs have wide distribu-

tion in organs and tissues (lungs, CNS, kidneys, heart, liv-

er, spleen, etc.), independent of the route of administra-

tion. The clearance of nanoparticles can differ from 

17 days to 4 months. In tissues containing natural physio-

logical barriers, for example, brain, excretion of silver 

proceeds more slowly (up to 260 days), which creates ad-

ditional conditions for its accumulation [183, 184]. Exces-

sive accumulation of AgNPs leads to disruption of cells 

activity in different organs and systems: skin (argyria, 

contact dermatitis), respiratory system (bronchitis, alveo-

litis, fibrosis, provocation of bronchial asthma exacerba-

tions) visual system (conjunctivitis, argyrias), gastrointes-

tinal tract (hepatobiliary and intestinal dysfunction), im-

mune system (dysregulation of cytokine synthesis and 

function of cells), CNS (cognitive impairment, Alzheimer's 

disease, epileptic seizures), urinary system (acute tubular 

necrosis, glomerular dysfunction), cardiovascular system 

(bradycardia, AV block, ventricular arrhythmias) (Fig-

ure 8) [3, 161, 185]. The possible nanoparticles accumula-

tion in the reproductive system and damage of the germ 

cells structures were discovered by studying the patholog-

ical effects of AgNPs in mice. Apart from the metabolic 

disturbances in germ cells and reduction of female oocyte 

fertility, the dysfunction of Leydig and Sertoli cells in 

males, which leads to infertility and a decrease in testos-

terone synthesis, was observed [3]. An embryotoxic effect 

was detected in mice and zebrafish. This effect depended 

on the size and coating of AgNPs nanoparticles. Smaller 

AgNPs of 20 nm have greater toxicity than large particles 

of 110 nm, and polypyrimidine-coated particles are more 

toxic than citrate-coated AgNPs [186]. AgNPs also have a 

genotoxic effect due to chromosome damage, oxidative 

stress, and interaction with DNA [185, 187].  

 
Figure 8 Main spectrum of AgNPs toxicity. AgNPs have a wide 
spectrum of toxicity, which has been studied in mice. The collect-

ed data made it possible to predict the different consequences of 
nanoparticles accumulation in various organs and systems. Re-
produced rom ref. [180].  

The process of the silver ions permutation and their in-

teraction with oxygen or sulfur, which induce a pathologi-

cal biochemical cascade in cell, are considered the main 

mechanism of potential AgNPs cytotoxicity. It is believed 

that formation of Ag+ plays a key role in activation of lyso-

somal acid phosphatases, dysfunction of the actin cyto-

skelet, inhibition of Na+/K+-ATPase, stimulation of apopto-

sis (through the protein p53, ACT, TP38), induction of oxi-

dative stress, depletion of glutathione and diffusion of 

cellular components [101, 185, 188]. However, according 

to another hypothesis, independent mechanisms of metal-

lic ions toxicity, which can be found for various nanoparti-

cles, cause the pathological effects [189]. Except the direct 

entering into cell through the membrane (diffusion, endo-

cytosis), it is supposed that AgNPs may penetrate through 

ion channels ("flip-flop" mechanism) and by the "Trojan 

horse" approach. The latter method consists of phagocyto-

sis and further induction of petrochemical changes in ac-

tive cells by silver ionization in the cytosol [101]. It is 



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worth mentioning that the most prominent morphological 

changes are observed in the liver, lungs, and kidneys, 

which may be due to the greatest participation of these 

organs in the clearance of nanoparticles [190]. 

AgNPs were found to induce oxidative stress in rat liv-

er cells due to disturbance of metabolism and mitochon-

drialal malfunction. These changes resulted in the focal 

liver necrosis, spleen edema and apoptosis in thymus cor-

tex [185, 191]. Exposure to the most effective small nano-

particles (10 nm or less) caused much more prominent 

pathological shifts [192]. The excretion of silver from the 

body is mostly carried out by the hepatobiliary system 

(more than 50%), which may be associated with more 

severe hepatotoxicity because of the greatest accumulation 

in hepatocytes, Kupffer cells and sinusoidal endothelio-

cytes [193]. Kidneys are the second important excretion 

system. Silver nanoparticles accumulate in all structural 

components of cortex and medulla in spite of a low uri-

nary excretion fraction (less than 0.01%) [161, 193].  

Beyond hepato- and nephrotoxicity, silver particles 

may provokepathological changes in the intestinal wall 

despite a rather low level of absorption in the intestine 

ranging from 0.12% to 0.88%, which can be caused by the 

binding of nanoparticles to undigested food [193]. Howev-

er, oral administration of silver nanoparticles in mice 

causes destruction of epithelial villi and glands. The impli-

cation of bowel dysfunction causes weight loss [194]. 

In addition, nanoparticles have toxic effect on hearing 

and retina due to the activation of oxidative stress in the 

mitochondria, which leads to the loss of hearing and vi-

sion [3, 190].  

The accumulation of AgNPs in the central nervous sys-

tem leads to disorganization of the cytoskeleton, activa-

tion of neuroinflammation and increase in the insoluble 

beta-amyloid concentration. These processes are im-

portant pathophysiological entity of Alzheimer's disease. 

Thus, it is possible to conclude that AgNPs can induce the 

development of neurodegenerative disorders, particularly 

due to low clearance and pathological accumulation [195]. 

Positively charged silver nanoparticles are known to 

have toxic effects on myocardial INA and IK1 channels, 

which leads to significantly increased risk of severe brad-

ycardia [196]. Prolonged inhalation of AgNPs causes re-

duction of tidal volume and enhancing of inflammatory 

processes in bronchopulmonary system [131, 197].  

Thus, it is necessary to study and compare different 

AgNPs in order to determine the possibilities to synthesize 

less toxic nanoparticles with the strongest therapeutic 

effect. The study of pharmacodynamics and pharmacoki-

netics properties of AgNPs to prevent pathological accu-

mulation is equally important. Moreover, it is necessary to 

conduct further research, devoted to direct comparison of 

coating agents and to selecting the optimal coating ap-

proach, because the coating and stabilization have been-

proved to have a huge modifying effect. 

4. Conclusion 

Given the wide range of biological, physical, and chemical 

properties of silver nanoparticles, a potential role of this 

compound in clinical medicine may be suggested. Appro-

bation and usage of AgNPs are highly promising, especially 

in the era of growing antimicrobial resistance. In addition 

to activity against pathogenic bacteria, viruses, protozoa 

and fungi, silver nanoparticles are able to inhibit the activ-

ity of tumor cells or play the role of drug carriers in the 

structures of malignant neoplasms in order to increase the 

effectiveness of chemotherapy [198]. Despite the promis-

ing results of the studies, most of them are conducted 

mainly in cell cultures or mice. Therefore, pharmacody-

namics and pharmacokinetics of silver nanoparticles in 

human have not been fully studied due to the reliable data 

on possible multisystem toxicity, which could restrict per-

forming these kinds of studies. Moreover, silver nanopar-

ticles are among the most toxic nanocompounds. There-

fore, it is of tremendous importance to develop and evalu-

ate potential AgNPs antidotes, such as sulfides [199]. A 

careful selection of the minimum toxic and at the same 

time the most effective dose of AgNPs is an important as-

pect of planning the clinical and paraclinical trials. The 

nanoparticles synthesized by the "green synthesis" meth-

ods are likely to have less toxicity and a wider biological 

spectrum against microorganisms, which makes this ap-

proach more preferable than chemical or physical synthe-

sis [200]. Further studies of different properties of nano-

particles are needed to determine the most optimal con-

centration, shape, structure and enveloping substance in 

vivo. These may be achieved by evaluating the dose-

response parameters via comparison of the equivalent val-

ues with the results from animal studies and extrapolated 

potential effects on humans [188].  

Thus, it can be concluded that the integration of nano-

technologies, AgNPs in particular, for various medical 

purposes is highly promising due to the clear biocidal ef-

fects. However, the lack of unified methodological ap-

proaches and the inconsistencies in the data leave a wide 

field for further research and development of unified algo-

rithms to prevent biases, trial heterogeneity, inaccurate 

data processing and compilation. 

Limitations 

The type of article is a narrative review. It means a more 

relaxed literature search strategy, and it is affected by 

subjective approach (in contrast with PRSIMA and multi-

ple search strategy by two or more authors), which limits 

the comprehensive data extraction and strict study selec-

tion. There is a high probability of heterogeneity among 

studies due to the lack of strict prespecified criteria (selec-

tion bias), which leads to the impossibility of generalizing 

results and performing the statistical summary effect as-

sessment. All studies are carried out in vitro (cell lines) or 



Chimica Techno Acta 2022, vol. 9(4), No. 20229402 REVIEW 

14 of 20 

on mice/rats which makes it difficult to extrapolate the 

obtained results to humans and assess a potential minimal 

clinical important difference. There is a high demand for 

systematic reviews and meta-analyses according to the 

PRISMA guidelines for every particular topic of the current 

review, including extensive analysis of the pub-

lished/unpublished literature and following the evidence-

based practice. Such approach could improve the accuracy 

and understanding of the research objective for the medi-

cal application of silver nanoparticles. 

Supplementary materials 

No supplementary materials are available. 

Funding  

This research had no external funding. 

Acknowledgments 

The author is grateful to Anastasia Vlasova for assitance in 

the preparation of the current review. 

Author contributions 

There is only one author. 

Conflict of interest 

The author declares no conflict of interest. 

Additional information 

Kodintcev Anton Nikolaevich – adult general neurologist at 

polyclinic of the Institute of High Temperature Electro-

chemistry of the Ural Branch of the Russian Academy of 

Sciences and a young scientist at the same institute. 

Education: (MD) at Ural State Medical University 

(USMU), Faculty of General Medicine.  

Postgraduate courses, 2019–2022 at Ural State Medical 

University (USMU), Department of Neurology, Neurosur-

gery and Medical Genetics 

Neurology residency: 2018–2020 at Yekaterinburg 

Medical Research Center for Prophylaxis and Health Pro-

tection in Industrial Workers is a Research Institute of the 

Russian Agency for Consumers Rights Protection (Rospo-

trebnadzor), Department of Neurology.  

Scientific interest: researching of new and cheap diag-

nostic methods of neurodegenerative disorders, in particu-

lar, Alzheimer’s disease based on different biomarkers of 

biofluids.  

 

Website: 

Institute of High Temperature Electrochemistry, 

http://www.ihte.uran.ru/?page_id=3106. 

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