coatings
Review
Application of Nanotechnology in Immunity against Infection
Jingxin Zhang 1 , Weiyue Shi 2 , Qiang Ma 1 , Haixin Cui 1 and Liang Zhang 1, *






Citation: Zhang, J.; Shi, W.; Ma, Q.;
Cui, H.; Zhang, L. Application of
Nanotechnology in Immunity against
Infection. Coatings 2021, 11, 430.
https://doi.org/10.3390/coatings
11040430
Academic Editor: Anton Ficai
Received: 17 March 2021
Accepted: 6 April 2021
Published: 8 April 2021
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Attribution (CC BY) license (https://
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4.0/).
Coatings 2021, 11, 430. https://doi.org/10.3390/coatings11040430
1 Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural
Sciences, Beijing 100000, China; mjingxinz@163.com (J.Z.); maqiang0430@163.com (Q.M.);
cuihaixin@caas.cn (H.C.)
2 College of Agriculture, Purdue University, West Lafayette, IN 47907, USA; shi497@purdue.edu
* Correspondence: zhangliang02@caas.cn; Tel.: +86-10-82107045
Abstract: The immune system has a physiological defense function, protecting the body from
infectious diseases. Antibiotics have long been one of the most important means to treat infectious
diseases, but in recent years, with the emergence of more and more multidrug-resistant (MDR)
bacteria, it has become urgent to find new ways or drugs to treat infectious diseases. Nanoparticles
(NPs) have attracted extensive attention owing to the special properties within the particle size range
of 1–100 nanometers. In addition, NPs also have special shape symmetry and relative structural
stability. The emergence of nanotechnology has brought new light to the widespread existence of
MDR by its different antibacterial mechanisms. In addition to antibiotic nanocarriers being able to
improve the antibacterial effect of antibiotics, some NPs also have certain antibacterial effect. What
is more interesting is that linking functional groups on the surface of NPS as coatings can improve
the stability of the whole system and improve the biocompatibility. The present review overviews
the development of antimicrobial agents, so as to better understand the causes and mechanisms
of antibiotic resistance in most microbial species, and to better think and explore new strategies to
solve the problem. At the same time, this review introduces how nanotechnology can be applied to
anti-infection immunity and its practical application and advantages in the treatment of infection.
Keywords: nanotechnology; multidrug resistance; Anti-Infective Immunity
1. Introduction
Nanotechnology is a technology capable of manipulating and controlling matter in
the range of 1–100 nanometers [1]. Nanoparticles (NPs) refer to zero-dimensional, one-
dimensional and two-dimensional materials with small size effect composed of ultrafine
particles smaller than 100 nm, or three-dimensional materials with their unit structure. As
early as 1959, the famous American physicist Richard P. Feynman mentioned in his speech
“There’s Plenty of Room at the Bottom: An Invitation to Enter a New Field of Physics” that
matter can be assembled by individual molecules or even atoms to meet requirements,
heralding the beginning of nanotechnology [2]. This brilliant conjecture heralded the new
age of nanotechnology, which gave us thorough and inexpensive control of the structure of
matter. In 1986, K. Eric-Drexler published a monograph called Engines of Creation: The
Coming Era of Nanotechnology, which brought nanotechnology into research focus and
established the revolutionary new field of nanotechnology [3]. The prediction and analysis
in these works have been proved and applied in recent years.
The development of nanotechnology has greatly promoted the development and
progress of various disciplines and has important applications in different disciplines. Nan-
otechnology has applications in cell biology, where it can mimic the complex extracellular
environment in vivo and dynamically monitor complex biological processes in real time at
the single-cell level [4]. Nanotechnology also has great potential in the field of medicine.
Its main applications include the use of NPs in disease diagnosis and pathogen screening,
DNA sequencing, tumor detection imaging and gene therapy [5]: such as fluorescent NPs
https://www.mdpi.com/journal/coatings
Coatings 2021, 11, 430 2 of 14

or dyed NPs which, since they almost do not interact with cellular proteins and optical
properties, are not affected by the outer proteins; and charged NPs’ surface and surface
chemical properties making it easier to internalize into cells and tissues compared with
common molecular probes; and more importantly, NPs produced by fluorescence detection
results are similar in the experiments in vivo and in vitro data, having good stability and
reference: all of these advantages give NPs a very high application prospect and application
value for imaging materials [6]. Nanotechnology also has wide applications in manufac-
turing. For example, NPs can be assembled on the surface of traditional textile materials,
which can change the color of the fabric and even give the fabric some antimicrobial proper-
ties [7]. In addition, studies have confirmed that nano-silver layered dihydroxide (Ag-LDH)
coating can be coated on the surface of metal, ceramic, glass and other different types of
substrates, and Ag-LDH coating shows excellent and lasting antibacterial activity against
both Gram-negative and Gram-positive bacteria [8]. Meanwhile, in medical immunology,
NPs can be used as an immune adjuvant to stimulate the immune response of the body or
as a carrier of entrap antigen for targeted delivery and activation induction. The application
of nanotechnology in pharmacy is more remarkable. On the one hand, some NPs have
their own medicinal effects. For example, metal or metal oxide NPs have a bactericidal
effect and can be used as a bactericide. At the same time, the surface coating of NPs can be
used to target the NPs, so as to improve the efficacy and reduce the toxic and side effects
of drugs. NPs are often coated with functional chemical groups to achieve better stability,
biocompatibility and active targeting [9]. On the other hand, NPs can be used as a drug
carrier to control the release rate while maintaining the slow and lasting release of drugs,
so as to reduce the frequency of drug use. The use of NPs loaded drugs can improve drug
solubility.
With the industrialization of antibiotics, infectious diseases have gone from being
untreatable and deadly to being curable and low-risk. However, the indiscriminate use of
antibiotics has led to widespread antibiotic resistance and even the emergence of multidrug-
resistance (MDR) in some bacteria. According to relevant statistics, bacterial resistance
relates to all currently known natural or synthetic antimicrobial agents [10]. Faced with a
serious situation, new methods, strategies or drugs continue to be found to remedy the
situation. Otherwise, as bacterial resistance becomes more and more severe, once a serious
bacterial infection occurs, there is nothing to do and infectious diseases will become highly
lethal again, which will seriously threaten the lives and health of the public around the
world. In the past few years, however, few new antibiotics have been discovered owing to
the high cost and complexity of drug development [11]. Therefore, it is a wise choice to
turn to the use of new technology to change the physical and chemical characteristics of
existing antibiotics to change the way drugs work, so as to effectively solve MDR.
The special size, properties and high specific surface area characteristics of NPs have
unsurpassable advantages in antibacterial and anti-MDR. Studies have shown that naked
NPs (NPs without any surface modification) have a relatively fragile inner shell structure,
which can be easily degraded and destroyed by the physiological environment in vivo
in the actual physiological experiments. Adding a surface coating to the naked NPs can
greatly improve stability, and the use of coated NPs-loaded antimicrobials can prevent
unnecessary interactions and drug degradation before reaching the target tissue or cell,
and maintain drug stability. More importantly, NPs can target diversity by changing their
surface coating. According to the specific target, the chemical groups connected on the
surface of NPs are changed so that the NPs can accurately identify the specific targeted
therapeutic site. After reaching the specified site, the treatment effect is achieved by the
sustained release of antibiotics. Meanwhile, nanotechnology can be used to optimize the
physical and chemical characteristics of drugs, change the way of drug administration and
reduce the discomfort of patients. What is more special is that NPs can wrap different
antibiotics in the same nanocarrier [12]. As is well-known in the treatment of infectious
diseases, a combination of multiple antibiotics is usually used to give faster action while
reducing the side effects of the drugs. NPs not only have a killing effect on MDR bacteria
 restore the antibacterial activity of older antibiotics to which microbes had developed re-
sistance [6]. Therefore, nanotechnology has high prospects in the treatment of infectious
diseases, and it has become a current research focus. Thousands of studies and papers
Coatings 2021, 11, 430 3 of 14
have been published. However, due to the side effect of NPs, their application in the hu-
man body is limited. At present, there are few researches on the pharmacokinetics of NPs
in the human body,themselves,
and there butare stillbesome
also can used as disputes abouttogether
an auxiliary agent, how withNPsantibiotics
are absorbed,
to which dif-
microbes have developed resistance, to enhance the antibacterial capacity. They helped
fused, metabolized and their toxic and side effects after entering the human body, which
restore the antibacterial activity of older antibiotics to which microbes had developed
needs further explorationresistanceand research.
[6]. Therefore, nanotechnology has high prospects in the treatment of infectious
diseases, and it has become
This review is based on the actual existence a current research focus. Thousands
of severe bacterial of studies and papers
resistance andhave the lack
been published. However, due to the side effect of NPs, their application in the human
of new antibiotics, combined
body is limited. with nanotechnology,
At present, known
there are few researches aspharmacokinetics
on the one of the breakthrough
of NPs in
technologies in the 21st century,
the human body, and tothere
consider the disputes
are still some combination
about howof NPsthearetwo to alleviate
absorbed, diffused, the
metabolized and their toxic and side effects after entering the human body, which needs
widespread bacterialfurtherresistance
explorationproblem in the world. Relying on the national agricultural
and research.
information system andThis the web
review of science
is based database,
on the actual existence ofwe referred
severe to a large
bacterial resistance number
and the lack of
of new antibiotics, combined with nanotechnology, known as one of the breakthrough
literature, includingtechnologies
on the composition and classification of bacteria, antibiotics antibac-
in the 21st century, to consider the combination of the two to alleviate the
terial principle, the mechanism
widespread bacterialof bacterial resistance,
resistance problem the special
in the world. Relying onadvantage of nanotech-
the national agricultural
information
nology, the classification system and
of NPs, thethe web of science of
application database, we referred to a large
nanotechnology number of liter- im-
in antibacterial
ature, including on the composition and classification of bacteria, antibiotics antibacterial
munity in as many as hundreds
principle, of articles.
the mechanism After
of bacterial careful
resistance, theclassification
special advantage and screening, sev-
of nanotechnology,
enty-eight articles were cited as theoretical
the classification support
of NPs, the application to emphasize
of nanotechnology the application
in antibacterial immunity ofinnano-
as many as hundreds of articles. After careful classification and screening, seventy-eight
technology in anti-infection
articles wereimmunity andsupport
cited as theoretical how it providestheaapplication
to emphasize new perspective for MDR
of nanotechnology
(Figure 1). in anti-infection immunity and how it provides a new perspective for MDR (Figure 1).

Figureof
Figure 1. The thought flow chart The thought
1. the review.flow chart of the review.

2. Current Situation of Antimicrobial Application

The immune system has a physiological defense function, which can resist the inva-
sion of pathogens and eliminate the invading pathogens and their harmful metabolites;
that is, anti-infection immunity. Abnormal increase of physiological defense response
Coatings 2021, 11, 430 4 of 14

2. Current Situation of Antimicrobial Application

The immune system has a physiological defense function, which can resist the inva-
sion of pathogens and eliminate the invading pathogens and their harmful metabolites;
that is, anti-infection immunity. Abnormal increase of physiological defense response
may lead to hypersensitivity reaction, while too low or deficient response may lead to
immunodeficiency disease or high susceptibility to pathogens. After the invasion of
pathogenic bacteria, taking antibacterial or antiviral drugs mobilizes the whole immune
system, including a variety of immune organs and immune cells to kill pathogens, to
maintain the normal operation of life activities. Antimicrobials can inhibit or kill bacteria
and be used to prevent and treat bacterial infections, including synthetic antimicrobials
(such as sulfonamides, furans, quinolones, etc.) and antibiotics (such as streptomycin,
cephalosporins, penicillin, etc.). Antibiotics are metabolites of microorganisms (bacteria,
fungi and actinomycetes), which can kill or inhibit other pathogenic microorganisms at a
certain concentration. British bacteriologist Alexander Fleming first discovered penicillin
in 1928. After further research and improvement, penicillin was successfully applied to
treat the human body’s anti-infection treatment. Since the discovery of penicillin, human
beings have found it a powerful bactericidal drug, ending the era of almost untreatable
infectious diseases. Since then, the search for new antibiotics has reached a climax, and the
human race has entered a new era of synthetic new drugs. Infectious diseases pose less
threat to human health and are easy to be cured.
However, with the increasing application of antibacterial drugs in clinical practice,
some patients do not strictly follow the prescribed way of medication and arbitrarily change
the frequency and time of medication, or stop the drug without authorization. Meanwhile,
there are some patients who lack awareness of correct medication, treat antibiotics as a
“panacea” and abuse them when encountering common cold fever and even non-infectious
inflammation antibiotics. Related studies have shown that 90% of colds are caused by viral
infections, so for most colds, antibacterials do not work but cause abuse of antibiotics. At
the same time, the abuse of broad-spectrum antibiotics further aggravates the resistance of
bacteria. Under normal circumstances, the human body’s oral cavity, respiratory tract and
intestinal bacteria are parasitic flora with mutual restriction to maintain the balance state.
If broad-spectrum antibiotics are used for a long period of time, the sensitive bacteria will
be killed, while the insensitive bacteria will take the opportunity to reproduce [13].
Relevant World Health Organization (WHO) reports show that after the elimination
of antibacterial drugs by a human or animal, the drug residues fermented in the soil and
contaminated wastewater will enter the soil and water, leading to the development of drug
resistance in the soil and water bacteria, and resistant components and genes will continue
to occur with horizontal and vertical transmission. This could lead to bacterial resistance
on a global scale. Antibacterial drugs have become less effective or even ineffective owing
extensive abuse in human. According to a World Health Organization, Escherichia coli,
klebsiella pneumoniae and staphylococcus aureus are more than 50% resistant to common
antibiotics. The relevant research statistics show klebsiella pneumoniae resistance to
carbapenems as being as high as 54% [14]. As a result, infectious diseases remain one of the
world’s biggest health challenges; they may become a lethal disease, as bacteria develop
resistance to many common antimicrobials.
The problem of antibiotics fighting pathogens is the underlying reason why most
drugs are now resistant. Antimicrobial resistance in pathogens has different mechanisms,
including chromosomal mutations, changes in membrane permeability, development of
efflux pumps that expel multiple kinds of antibiotics, activation of enzymes that degraded
the antibiotic, increased intracellular life cycle [15]. One of the most important things is
that pathogens not only exist in the cytosol, but also in the organelles and even in the
nucleus [16]. However, most antibiotics cannot penetrate the host cell and enter the cell,
and only stay outside the cell; meanwhile, they will be degraded quickly before they are
exposed to the pathogen or will not reach the effective therapeutic dose after exposure to
the pathogen [17].
Coatings 2021, 11, 430 5 of 14

Antibiotics kill bacteria and also cause damage to the body. Drug resistance increases
the dose of antibiotics, often producing toxic side effects. Quinolones, for example, can
cause cartilage damage in young animals and joint pain and inflammation in a small num-
ber of patients. Tetracycline makes children’s teeth yellow. Rifampicin and erythromycin
can cause liver damage. Chloramphenicol is difficult to inactivate after taking, can cause
cardiovascular failure in children, “gray baby syndrome”, and serious cases can be fatal.
Penicillin can cause anaphylactic shock, which can be life-threatening. The problems now
facing the use of antimicrobial drugs to treat infectious diseases include not only bacterial
resistance, but also the unbearable side effects of increased drug dosage or frequency in
order to be effective. Therefore, it has become an urgent matter to find an effective solution.

3. Nanotechnology and Anti-Infection Immunity

While looking for new antimicrobial drugs, scientists envision the use of new tech-
niques to modify the way antibiotics act, drug dosage forms, particle sizes, and so on
to promote the bactericidal effect. Several types of antibacterial NPs and nano-antibiotic
carriers have been shown to be effective in treating infectious diseases, including in drug-
resistant ones, in vitro and in animal models [18]. The applications of nanotechnology
in anti-infection immunity mainly include the direct bactericidal effect of some NPs [19];
the loading of antibiotics by nanocarriers, particularly in overcoming antibiotic-resistant
pathogens, have been explored as a promising alternative to current antibiotic-based
approaches [20].

3.1. Antibacterial NPs

NPs provide a new strategy for dealing with MDR bacteria. Recent studies have
shown that some metal (e.g., silver [21], golds [22]) and metallic oxide nanostructures are
known to have antibacterial activity and can be used to control infectious disease. Inorganic
fungicides such as metal oxide NPs can destroy bacteria locally without causing toxicity
to surrounding tissues [23]. Experiments have shown that zinc oxide (ZnO) NPs [24] and
iron oxide (Fe3 O4 ) NPs [25] have excellent antibacterial effects, although the antibacterial
mechanism of some NPs is still unclear, and it is worth noting that these antibacterial
effects can only occur in the range of nanoscale [26]. Among them, the main mechanism
of the cytotoxicity of zinc oxide NPs may be mediated by inducing the production of
reactive oxygen species (ROS) responsible for inducing apoptosis, and zinc oxide NPs
induce toxicity in a cell-specific and proliferation-dependent manner [27]. The antibacterial
mechanisms of other metal oxide NPs are not fully understood. Some metal oxide NPs
exhibit a bactericidal effect, destroying the cell membrane of bacteria, usually associated
with their physical structure and metal ion release [28]. Different researchers have given
different explanations for the mechanism of NPs. Mritunjal Singh et al. believe that the
main mechanism by which AgNPs exhibit antibacterial properties is to induce cell death
by anchoring and penetrating the bacterial cell wall and damaging the outer membrane
barrier components, such as liposolysaccharide or pore proteins [29], resulting in increased
bacterial cell membrane permeability. In addition, metal NPs have an affinity to interact
with biological materials containing sulfur and phosphorus in the bacterial cell; for exam-
ple, AgNPs can interact with phosphorous compounds such as sulfur-containing proteins
and DNA in bacterial membranes; therefore, metal NPs can act on bases to destroy DNA
and cause cell death [30]. Yan Cui et al. speculated that the antibacterial effect of AuNPs is
mainly through two ways: one is to change the membrane potential, inhibit the activity
of ATP synthase, reduce the level of ATP; the other is to inhibit the binding of ribosomal
subunits to tRNA, through the above two kinds of process, destroying the normal physio-
logical function of the cell [31]. The study of Chun-Nam Lok et al. showed that nano-silver
seemed to have a membrane targeting effect and might target the bacterial membrane,
leading to proton power dissipation, causing a large amount of loss of potassium ions in
the cell, thereby blocking the oxidative phosphorylation process of bacteria and leading to
cell death [32]. According to Siddhartha Shrivastava et al., the main mechanism by which
 Coatings 2021, 11, 430 6 of 14
Coatings 2021, 11, x FOR PEER REVIEW

AgNPs exhibits antimicrobial performance is to regulate cellular signaling by dephospho-

rylating the assumed key peptide substrates on tyrosine residues, thereby leading to signal
thereby leading
transduction totosignal
inhibition inhibittransduction inhibition
bacterial growth, to inhibit effects
and the antimicrobial bacterial growth,
of NPs are and
microbial
not related toeffects
bacterialofresistance
NPs aretonot related[33].
antibiotics to bacterial resistance
Jun Sung Kim to antibiotics
et al. believe that the [33].
Kim et al. believe that the mechanism of the bactericidal activity of metal
mechanism of the bactericidal activity of metal NPs is due to the free radical produced on NPs
the surface
the of NPs, which
free radical produced then destroys
on the the cell membrane
surface and eventually
of NPs, which leads to cell
then destroys the cell m
death [34] (Figure 2).
and eventually leads to cell death [34] (Figure 2).

NPs NPs Capsule NPs NPs

NPs Cytomembrane
NPs NPs Cytoderm NPsNPs
NPs NPs
NPs
NPs

NPs NPs
NPs
NPs
LPS
Inhiibit
NPsNPs
Ribosome
DN Signaling cell
A
tRNA Signal molecule
NPs NPs
P
NPs
Target cell
ATP synthase

ADP ATP

OXPHOS

Metal ion
Radical
NPs NPs
NPs
ROS
R

NPs
el

NPs
ea

NPsNPs
se

Apoptosis NPs
NPs
NPsNPs
NPs

Figure
Figure 2. Antibacterial
2. Antibacterial mechanism
mechanism of nanoparticles
of nanoparticles (NPs). (NPs).

Many different types of metallic and metal oxide NPs work against bacteria, viruses
Many different types of metallic and metal oxide NPs work against bacteri
and other eukaryotic microorganisms, of which AgNPs have been shown to be the most
and other
effective [35]. eukaryotic
Metallic silver microorganisms, of whichhave
or related silver compounds AgNPs beenhave beenancient
used since shown to be
effective
times to treat[35].
burnsMetallic
and several silver or infections.
bacterial related silver compounds
With the emergence ofhave beensuch
antibiotics used sinc
astimes
penicillin, the use of silver in the field of antibacterial gradually declined.
to treat burns and several bacterial infections. With the emergence of a However, the
use of metallic silver and silver compounds as fungicides has again attracted extensive
such as penicillin, the use of silver in the field of antibacterial gradually declin
attention due to the widespread problem of drug resistance [21]. AgNPs combined with
ever, the
different typesuse of metallic
of antibiotics, suchsilver and silver
as penicillin, compounds
erythromycin as fungicides
and vancomycin, has again
can enhance
extensive attention due to the widespread problem of drug resistance
the bactericidal effect on gram-positive bacteria and gram-negative bacteria [36]. Four [21]. AgN
bined with
different different
formulations types of antibiotics,
of silver–carbon complexes such(SCCs),asincluding
penicillin, erythromycin
micelles and NPs, areand van
effective in the range of 0.0005–0.09 kg/m 3 against medically established MDR bacteria
can enhance the bactericidal effect on gram-positive bacteria and gram-negative
such as MDR Acinetobacter baumannii (-), methicillin-resistant Staphylococcus aureus and
[36]. Four different formulations of silver–carbon complexes (SCCs), including
klebsiella pneumoniae (-) [37]. In addition, the current applications of silver NPS mainly
and NPs,
include externalaremedical
effective in the range
antibacterial dressings,of 0.0005–0.09 kg/m3material
implantable medical againstcoatings
medically es
MDR
and so on bacteria such as[39],
[38]. Dressings MDR Acinetobacter
creams and gels made baumannii
from silver(-),
NPsmethicillin-resistant
can effectively S
reduce
coccusbacterial
aureus infections in chronic pneumoniae
and klebsiella wounds [40]. Silver NPs wound
(-) [37]. dressings
In addition, containing
the current applic
poly vinyl nano-fibers also have high antibacterial properties [41]. NPs coatings play
silver NPS mainly include external medical antibacterial dressings, implantable
an important role in implanted medical devices and materials besides being used as
material coatings
antibacterial andexternal
materials for so onuse.
[38].It is
Dressings [39],exogenous
inevitable that creams and gelsmaterials
medical made from si
can effectively reduce bacterial infections in chronic wounds [40]. Silver NP
dressings containing poly vinyl nano-fibers also have high antibacterial prope
NPs coatings play an important role in implanted medical devices and material
being used as antibacterial materials for external use. It is inevitable that exogen
Coatings 2021, 11, 430 7 of 14

will be used in implant surgery. The most common problems in this type of surgery are
body rejection and bacterial infection. With their excellent antibacterial effect, NPs can be
coated on the surface of exogenous medical materials through technical means to achieve
a lasting anti-infection effect. Some researchers used the plasma immersion ion injection
method to synthesize zero valent iron NPs (FeNPs) and iron oxide NPs on the surface
and subsurface of titanium oxide coatings (TOCs); the synthetic Fe-NPs/TOC system
has excellent cell compatibility, and the system under the condition of the dark effect on
staphylococcus aureus has the specificity, and is considered to be an excellent implants
coating material [42]. Similarly, AgNPs were modified on tantalum oxide coating by plasma
immersion ion implantation. The results showed that the coating destroyed Staphylococcus
epidermidis cell integrity in the dark, thus producing a bactericidal effect [43].
Nonetheless, when silver compounds are administered in vivo, they may have toxic
effects due to prolonged exposure to soluble silver compounds. In addition to causing
argyria, they can cause permanent blue-gray discoloration of the skin or eyes, liver and kid-
ney damage, eye, skin, respiratory and intestinal irritation and changes in blood cells [44].
Studies have shown that AgNPs have significantly reduced or no toxic side effects on
humans compared to metallic silver or silver compounds. However, some studies have
pointed out that the particle size of AgNPs may lead to the accumulation of Ag+ in vivo
and the environment, resulting in certain toxic and side effects [45]. It is suggested that
adding appropriate coating on the surface of AgNPs can avoid aggregation in high salt
medium and improve the stability of NPS. Researchers have succeeded in preparation of
glutathione (GSH) coated silver NPs, confirmed that GSH capped AgNPs (GSH Ag NPs)
are more antibacterially active against Gram-negative bacteria than Gram-positive bacteria,
and speculated that this is due to the increased water-solubility of NPs by the GSH coating,
which allows Ag to penetrate more easily into the cytoplasm, subsequently releasing silver
and interacting with the local components of the cell to produce bactericidal action [46]. It
has been proven that immobilizing AgNPs on the plasma coating of hexamethyldisiloxane
by liquid flame spray technology can limit the escape of Ag+ to the environment on the
premise of ensuring the antibacterial effect [47]. Overall, although NPs have a wide range
of applications, they also have the potential to cause adverse effects at the cellular, subcel-
lular and protein levels. While some NPs may appear nontoxic, they may cause disruption
to cellular signal transduction and other normal cellular functions [48]. The AgNPs as
antibacterial drug in the body also need further research, and some knowledge of the acute
toxicity of metal NPs in vivo, such as metabolic processing, clearance, bioaccumulation
and long-term effects, remains to be elucidated [49].

3.2. Antibiotic Nanocarrier

Using nanotechnology to load antibacterial drugs can not only improve the antibacte-
rial effect of drugs, but also reduce the side effects of drugs [50]. The main pharmacokinetic
characteristics of nanocarrier-encapsulated antibiotics include increased solubility [51],
controlled and relatively uniform distribution in target tissues targeted delivery, sustained
and controlled release, and enhanced cell internalization [52]. Nanocarriers can encap-
sulate hydrophilic or lipophilic drugs, increase the solubility of drugs, and promote the
absorption of antibiotics in the human body. Specific drug delivery can be carried out
through appropriate nanocarriers, and antibiotics can be transported to the target through
nanocarriers, so as to reduce the toxic and side effects in the medication process, improve
the efficacy [53]. By controlling the surface aperture of the nanocarrier, the drug release rate
and amount can be controlled. Common antimicrobial drug delivery vehicles include lipo-
somes, solid lipid NPs (SLN), polymer NPs, etc. (Figure 3) [14]. Among them, liposomes
are the most widely used [54].
 Coatings 2021, 11, 430 8 of 14
Coatings 2021, 11, x FOR PEER REVIEW

Figure
Figure 3. Commonly
3. Commonly used antimicrobial
used antimicrobial delivery
delivery vectors: vectors:
liposome liposome
(A), solid lipid(A),
NPssolid
(SLN)lipid
(B), NPs (S
polymer
polymer NPsNPs including
including nanosphere
nanosphere (C) and nanocapsule
(C) and nanocapsule (D). (D).
3.2.1. Liposomes
3.2.1. Liposomes
Liposomes are nanoscale to micron vesicles formed by encapsulating drugs in a
Liposomes
phospholipid bilayer,arewhichnanoscale
is similar toto amicron
membrane vesicles
structure formed by to
and is easy encapsulating
fuse with dr
infectious microorganisms [55]. Moreover, both hydrophilic and
phospholipid bilayer, which is similar to a membrane structure and is easy to f hydrophobic antibiotics
can be encapsulated and retained in an aqueous core and phospholipid bilayer without
infectious microorganisms [55]. Moreover, both hydrophilic and hydrophobic a
chemical modification [56]. The surface of the liposomes is usually linked to polyethylene
can be
glycol, encapsulated
which is a hydrophilic and andretained
pliablein an aqueous
polymer that formscorea hydration
and phospholipid
film on the bilayer
chemical
surface of themodification [56]. The
liposomes. It inhibits surface ofofthe
the adsorption liposomes
plasma componentsis usually linked to poly
to the liposome
glycol,thereby
surface, whichreducing
is a hydrophilic
the uptake of and pliableby
liposomes polymer that forms a system.
the reticuloendothelial hydration The film on
time of the liposome in systemic circulation is prolonged,
face of the liposomes. It inhibits the adsorption of plasma components which indirectly increases the to the
time of drug action in vivo and improves the efficacy. There are many researches about
surface, thereby reducing the uptake of liposomes by the reticuloendothelial sys
liposomes encapsulating antibiotics as carriers. Studies have shown that liposomes encap-
time ofenhanced
sulation the liposome in systemic
the stability of ampicillin.circulation is prolonged,
Free ampicillin lost 50% of which
its initialindirectly
activity incr
intime of drugsolution
an aqueous actionstored
in vivo anddegrees
at four improves thefor
Celsius efficacy.
five weeks,There
whileareliposomes
many research
encapsulation of ampicillin (released from unencapsulated
liposomes encapsulating antibiotics as carriers. Studies have shown that drugs) lost only 17% of its
liposom
initial activity under the same conditions. Ampicillin, which is wrapped in liposomes, is
sulation enhanced the stability of ampicillin. Free ampicillin lost 50% of its initia
active in bacterial colonies, independent of other cells [57]. Ciprofloxacin is an effective
in an aqueous
treatment for systemicsolution stored
salmonella at fourLiposome-incorporated
infection. degrees Celsius for ciprofloxacin
five weeks, (LIC)while lipos
iscapsulation
more effective ofthan
ampicillin (released A
free ciprofloxacin. from unencapsulated
single drugs) lost only 17% of
injection of Liposome-incorporated
activity under the same conditions. Ampicillin, which is wrapped
ciprofloxacin was ten times more effective in preventing mortality than in liposomes,
a single injection
ofinfree drugs [58]. Liposomes encapsulation can significantly
bacterial colonies, independent of other cells [57]. Ciprofloxacin enhance the uptake ofis van-
an effect
comycin and teicolanin by macrophages. Vancomycin and teicolanin by entrapment in
ment for systemic salmonella infection. Liposome-incorporated ciprofloxacin
liposomes leads to increased availability of antibiotics, effectively eliminating intracellular
more effective than
methicillin-resistant free ciprofloxacin.
staphylococcus aureus (MRSA) A single injection
infection of Liposome-incorporate
[59]. Liposome encapsulating
loxacin was
streptomycin wastenmore
times morethan
effective effective in preventing
free streptomycin in themortality
treatment of than a single injectio
experimental
drugs [58]. Liposomes encapsulation can significantly enhance the uptake of van
and teicolanin by macrophages. Vancomycin and teicolanin by entrapment in li
leads to increased availability of antibiotics, effectively eliminating intracellular
lin-resistant staphylococcus aureus (MRSA) infection [59]. Liposome encapsulati
Coatings 2021, 11, 430 9 of 14

abamia complex infection in beige mice [60]. Direct injection of liposome polymyxin B into
the lung can enhance the retention of pulmonary antibiotics and is an effective method
for the treatment of Pseudomonas aeruginosa pulmonary infection [61]. Amikacin, an
aminoglycoside antibiotic wrapped in liposomes, has recently entered clinical trials. Lipo-
somes encapsulating aminoglycosides may increase the therapeutic index of these drugs by
increasing the concentration of aminoglycosides at the site of infection and/or by reducing
the toxicity of these drugs [62]. When cationic liposomes encapsulate benzyl penicillin
(penicillin G (pen-G)) on the pen-G-sensitive strain of Staphylococcus aureus immobilized
in the biofilm, liposome administration is most effective compared to the free drug at lower
overall drug concentration and shorter exposure time [63].

3.2.2. Solid Lipid NPs (SLN)

SLN are a new submicron drug delivery system developed in the early 1990s. Its
particle size is 10–1000 nm, and it is a new generation of nanoparticle drug delivery system
made by adsorption or encapsulation of drugs in lipid membrane with low toxicity, good
biocompatibility and biodegradable solid natural or synthetic lipids (such as lecithin, tria-
cylglycerin, etc.) as carriers [64]. SLN is improved on the basis of combining the advantages
of solid NPs and liposomes [65]. Aerosolized solid lipid particles (SLPs) combined with
rifampicin, isoniazid and pyrazinamide to act on experimental tuberin were shown to in-
crease the mean residence time and bioavailability of the drug several times with solid lipid
particles, and drug loaded solid lipid particle atomization treatment was given to infected
guinea pigs every 7 days; after 7 times of treatment, pulmonary/spleen tuberculosis bacilli
could not be detected, and most importantly, there is no evidence of biochemical hepatotox-
icity in the administration of solid lipid particle atomization. Atomized inhalation of solid
lipid particle-based antituberculosis drugs is an important means to improve the bioavail-
ability and reduce the frequency of drug administration [66]. Tobramycin-loaded SLN has
a much higher bioavailability of tobramycin (TOB) in body fluids than the equivalent dose
of tobramycin used with standard commercial eye drops [67]. In vivo studies using SLN as
a carrier for local delivery of econazole nitrate, a broad-spectrum antifungal with antibacte-
rial properties, have shown that compared with marketed reference gels, SLN promotes
rapid penetration of oxyconazole nitrate through the cuticle after 1 h and improves drug
diffusion in deeper skin layers after 3 h [68]. Five ciprofloxacin hydrochloride-loaded NPs
of albumin, gelatin, chitosan (CS) and solid lipid were prepared to control the prolonged
release of antibiotics in a single dose delivery system based on nanotechnology, which
demonstrated that chitosan NPs and SLNs can be used as promising vectors for sustained
release of ciprofloxacin to treat infections [69].

3.2.3. Polymer NPs

Biocompatible and biodegradable polymer NPs are used to control drug release.
Two main types of polymer NPs are used in antimicrobial delivery: linear polymers and
amphiphilic block copolymers. Most polymer NPs prepared from linear polymers are
typically nanocapsules or solid nanospheres [53]. The use of biodegradable polymer NPs
loaded antibacterial drugs has many advantages, such as the large molecular weight of
the polymer, being able to extend the drug in the lesion site residence time and enhanc-
ing the antibacterial effect. At the same time, antimicrobials can be used to control their
release by diffusion or by self-degradation of the polymer. Polymer molecular surface
can be connected with some functional components with targeting effect by means of
chemical bonds, which has achieved the targeting effect of antibacterial drugs. In the
existing literature, the morphology and structure of polymer nanoparticles commonly
used as drug carriers mainly include microspheres and microcapsules. The combination
of ampicillin with polyisohexylcyanoacrylate (PIHCA) NPs greatly improved the efficacy
of ampicillin in the treatment of salmonella typhimurium infection in C57BL/6 mice [70].
The experiments of emulsifying NPs formed by covalent binding of penicillin antibiotics
on polyacrylate proved that the NPs had the same in vitro antibacterial properties against
Coatings 2021, 11, 430 10 of 14

methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and had infinite

stability toward β-lactamase [71]. N-thiolated β-lactam antibiotic was covalently bound to
polyacrylate polymer matrix to produce nanoemulsion, which had strong in vitro antibac-
terial properties against methicillin-resistant staphylococcus aureus and better biological
activity than non-polymerized antibiotics [72]. This method allows the water-insoluble
drug to be directly incorporated into the nanoparticle framework, and more importantly, it
does not require post-synthetic modifications in the process. The combination of ampho-
tericin B (AmB) and poly (1-caprolactone) nanospheres increased the activity of the free
drug against leishmaniasis [73]. Studies have shown that the use of NPs as drug carriers
may significantly increase the activity of antibiotics in phagocytes, and that NPs may be
used in the treatment of intracellular infections [74].
However, in practical application, liposomes have problems such as short shelf life
and poor stability. Liposomes stored in solution may delamination or even mildew at
room temperature. In addition, liposomes have a relatively low encapsulation rate for
antimicrobial agents. It is easily removed by the reticuloendothelial system and can interact
with cells in the physiological environment [75]. Compared with liposomes, SLN is the solid
state of its granular matrix, so it has the ability to protect chemically unstable components
from chemical decomposition and the possibility of regulating drug release, and is also
considered as the next generation delivery system after liposomes. However, due to the
small particle size, complex system and dynamic phenomenon of SLN, the characterization
of SLN is a severe challenge [65]. For polymer NPs, there may be a certain toxic effect,
mainly because polymer NPs will stimulate the internalization effect of macrophages, and
the internalized NPs will be degraded in the cell, resulting in cytotoxicity. In addition,
there are still some problems in the large-scale production of polymer NPs [76]. In practical
application, different NPs have some problems. It may be a new way to solve the above
problems by combining the two different carriers, giving full play to their advantages
and complementing their deficiencies. Excitingly, lipid–polymer hybrid NPs have been
prepared and demonstrated to enhance cell delivery in vivo, and a simpler and better mass-
production method has been developed that can be industrialized based on experimental
conditions [77].

4. Conclusions
The emergence of antibiotics has greatly reduced the mortality of infectious diseases,
but the accompanying proliferation of drug-resistant bacteria has put public health at risk.
The direct causes of drug resistance are due to the misuse of antibiotics, the lack of proper
management measures and the awareness of drug use. The fundamental reason is the
change in the physiological nature of bacteria. Of course, there are many mechanisms for
bacteria to develop drug resistance. Researchers should follow different paths and take
the mechanism of drug resistance as a reference to actively find new strategies and new
drugs to fight against drug-resistant bacteria after fully understanding the mechanism of
drug resistance. The advent of nanotechnology has indeed shed light on the epidemic of
drug-resistant bacteria. It is difficult for bacteria to develop resistance to metal and metal
oxide NPs due to their multiple antimicrobial mechanisms. Because the metal in the human
body can produce toxicity, though, metal and metal oxide NPs in modern medical practice
are widely used as a topical antibacterial dressing or implantation surgery material surface
coating; in addition, small doses of metal and metal oxide NPs used together with the
existing antibiotics, on the one hand, ensure that small doses of metal and metal oxide
do not produce toxic effects to the human body, and on the other hand, can enhance the
antibacterial function and alleviate MDR. What is more promising is that antibacterial
drugs can be wrapped by a nanocarrier, and even different chemical groups or specific
substances can be connected on the surface of the carrier as coatings for different bacterial
species, so as to achieve a specific targeting effect. In this way, the efficacy can be improved
while the side effects caused by antibacterial drugs can be greatly reduced. It also increases
the stability of the antimicrobial and prevents it from breaking down before reaching the
Coatings 2021, 11, 430 11 of 14

target site. Due to the small size effect of NPs, they can enter and deposit into bacterial
hiding places that are inaccessible to ordinary drug particles, providing a new approach to
combatting MDR.
However, they also have disadvantages. The pharmacokinetic characteristics of NPs
in vivo are not fully understood, especially the distribution and metabolism of NPs in vivo,
as well as how they are excreted from the body after the corresponding drug effect is exerted,
which requires further study. For the possible toxicity of NPs, researchers should focus on
how the metal and metal oxide NPs are in relation to absorption, distribution, metabolism
and excretion, determine the rest of the toxic effects of particles in the metabolism of
the body’s organs, to record and calculate dose, and measure its titer parameter median
effective dose (ED50 ) and the median lethal dose (LD50 ) toxicity index. It is considered
that in future research, it is a promising direction to find new and effective targets for
bacteria and to use nanocarriers loaded with functional groups to attack them specifically.
It is an idea to use nanotechnology to change the dosage form and mode of action of
existing antibacterial substances to alleviate MDR. The authors believe that in addition
to the existing antibiotics, the antibacterial substances in natural plants are also worth
exploring and studying. At present, bacteria have not produced widespread resistance
to the antimicrobial substances in natural plants, and natural plants are rich in species
and have a variety of active ingredients, which is of research value. Although the existing
studies emphasize that the antimicrobial substances in natural compounds are far less
effective than antibiotics when used alone, is it not a new idea to use nanotechnology to
improve their antimicrobial activity? Nanotechnology is used to change the solubility of
natural antibacterial ingredients and improve their bioavailability to improve their effect.
However, the medicinal ingredients of natural plants are relatively complex and
their toxic and side effects are unknown. Therefore, future research should focus on the
pharmacokinetic analysis of the extracted active ingredients to understand the active dose
and the exact toxic and side effects. While scientists are trying to find a new way to combat
MDR, in order to prevent the further growth of drug-resistant bacteria, the government
should strengthen the management of antibiotics, require all drug use units to do a good
job of registration and statistics, the use of antibiotics should be strictly in accordance with
the principle of not using more antibiotics and not abusing them on the premise of not
threatening life and health. At the same time, the public should have the correct awareness
of drug use, strictly follow the doctor’s advice and not arbitrarily change the dosage of
drug use.

Author Contributions: Conceptualization, J.Z. and L.Z.; methodology, J.Z.; software, W.S. and Q.M.;
validation, L.Z. and H.C.; formal analysis, J.Z.; investigation, J.Z. and W.S.; writing—original draft
preparation, J.Z. and L.Z.; writing—review and editing, J.Z., L.Z., W.S., Q.M., and H.C.; visualization,
J.Z.; project administration, J.Z. and L.Z. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data sharing not applicable. No new data were created or analyzed in
this study. Data sharing is not applicable to this article.
Conflicts of Interest: The authors declare no conflict of interest.

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