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SYSTEMATIC REVIEW ARTICLE
ISSN: 1573-4137
eISSN: 1875-6786

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Zinc Oxide Nanoparticles as a Potential Agent for Antiviral Drug Delivery

Development: A Systematic Literature Review

Mahda S. Nasrollahzadeh1,*, Razieh Ghodsi1, Farzin Hadizadeh2, MahdiFaal Maleki1,

Mohammad Mashreghi3 and Donya Poy4

1
Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran;
2
Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences,
Mashhad, Iran; 3Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical
Sciences, Mashhad, Iran; 4College of Life Science and Biotechnology, Department of Biotechnology, Shahid Beheshti
University, Tehran, Iran

ARTICLE HISTORY
Received: January 17, 2021
Revised: February 28, 2021
Accepted: April 02, 2021
DOI:
10.2174/1573413717666210618103632
Current Nanoscience
Abstract: Viral infection is a worldwide health problem, which has negatively affected global activ-
ity in recent years. There is no specific medication for most of the viral infections and the treatments
are based on symptom management. Nanoparticles (NPs) in recent years have shown promising anti-
bacterial and antiviral properties, among which metal oxide NPs have shown superiority. In the pre-
sent study, we aimed to systematically review all available literature supporting the efficiency of zinc
oxide (ZnO)NPs in the treatment of viral infections. For this purpose, a systematic literature search
was performed in scientific literature databases, including PubMed, Scopus, Web of Science, Science
Direct, Ovid, Embase, and Google Scholar by using “viral infections”, “antiviral effects” and “ZnO
NPs” in addition to all their equivalent terms as keywords. Due to the lack of human studies, no strict
inclusion criteria were defined and all available relevant studies were included. A total of 14 docu-
ments that fully met the inclusion criteria were retrieved and used for data synthesis. The results
showed that ZnO NPs due to specific physicochemical properties can be a promising approach in
developing antiviral agents and nano vaccines, especially against RNA viruses, such as human im-
munodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus. The most probable

antiviral mechanistic pathways of ZnO NPs include blocking the virus entry into the cells and deacti-
vation of the virus through virostatic potential. Based on the findings of the included studies, it is
suggested that ZnO NPs and other metal oxide-based NPs may be potential antiviral agents; how-
ever, further human studies are required to confirm such efficiency in clinical practice.
Keywords: Zinc oxide, viral infection, ZnO NPs, nanoparticle, vaccines, immune system.

1. INTRODUCTION biomedical applications [5, 6]. Recent studies have sug-

Viral infections are a global health problem that has an
enormous economic burden on society. The global health
community is facing a great challenge in terms of morbidity
and the related mortality of various viral infections [1, 2].
Since there is no specific cure, most of the viral infections
can only be treated by supportive therapy; however, some
vaccines have been developed for few viruses that can help
to boost the immune system [3]. Currently, it has been sug-
gested to use nanotechnology in vaccine development.
Nowadays, nanotechnology has introduced a new approach
in science, resulting in significant progress in various scien-
tific fields, especially pharmaceutical technology [4]. Differ-
ent nanoparticles (NPs) having various sizes, shapes, and
chemical and surface properties have different biological and
*Address correspondence to this author at the Department of Medicinal
Chemistry, School of Pharmacy, Mashhad University of Medical Sciences,
Mashhad, Iran; E-mail: Nasrollahzadehm961@mums.ac.ir
gested the potent antibiofilm activity of a variety of NPS and
recommended their use for various medical purposes, such
as drug delivery, or antibacterial medical devices [6]. NPs,
due to their high surface-to-volume ratio and small size, have
good penetrating ability into the microorganisms and have
strong antibacterial and antiviral properties [4, 7]. Many
studies have reported antibacterial and antiviral effects of
some nanomaterials, because nanomaterials, particularly
heavy metal oxides NPs, tend to inactivate viruses or bacte-
ria by directly affecting them or interacting with their intra-
cellular target molecules [8, 9].
Among the various types of metal oxide nanoparticles,
(ZnO), due to great biocompatibility, being cost-effective,
reasonable cytotoxicity, and specific physical and chemical
properties, is considered as a multifunctional agent that is
used in various industrial and pharmaceutical applications,
such as electronics, optoelectronics, lasers, ceramic, textile,
agriculture, and cosmetics [10-14]. Also, ZnO due to its low

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148 Current Nanoscience, 2022, Vol. 18, No. 2 Nasrollahzadeh et al.

toxicity and biodegradability is a suitable nanomaterial for
biomedical purposes. ZnO has antimicrobial and antiseptic
properties and is widely used in the production of various
pharmaceuticals. Recently performed in silico study has also
evaluated the 77 factors (core size, exposure dose, coordina-
tion number, etc.) which affect the cytotoxicity (safety) of
metal oxide nanoparticles, including ZnO. According to the
results, it is necessary to find a suitable balance between core
size and exposure dose [15]. Studies have shown that ZnO
NPs with a size of less than 100 nm have antimicrobial
properties against gram-positive and gram-negative bacteria
due to their high cellular internalization capacity. Also, the
activity of ZnO NPs against Staphylococcus aureus and Es-
cherichia coli increases with the reduction in particles size
ranging from 250 to 40 and 20 nm, which may be due to
increased production of reactive oxygen species (ROS) and
membrane damage of bacteria [16, 17]. Various studies have
been performed on the antibacterial properties of ZnO NPs,
but its antiviral effects are less considered [18, 19]. In the
present study, a systematic literature review was performed
to collect all evidence supporting the antiviral properties of
ZnO NPs. Also, we will discuss the possible effects of ZnO
and ZnO NPs on new Coronavirus disease (COVID-19).
necrosis factor (TNF), lymphocyte activation, and expression
of viral antigens.
3. RESULTS
3.1. Literature Search Results
Of the total of 234 articles found in the first step of data-
base search, 11 articles were found from Scopus, and 217
were from PubMed. Also, 6 articles were retrieved through
search in Google Scholar and other databases. Two addi-
tional documents were also found through a manual refer-
ence list search of previously included articles. After remov-
ing 222 articles due to subject and language irrelevancy, 14
articles were selected, which were completely relevant to the
main purpose of this study and were used for data synthesis
(Fig. 1). However, all collected articles were animal or in
vitro studies, therefore, quality assessment was not per-
formed for individual studies.

2. METHODS

2.1. Database Search and Inclusion Criteria

In the present study, we systematically reviewed the ap-
plication of ZnONPs in preventing viral infections. For this
purpose, a systematic search was performed in Scopus,
PubMed, Web of Science, Science Direct, Embase, Ovid,
and Google Scholar in January 2021. The keywords used for
this purpose were “zinc oxide nanoparticle”, “viral infec-
tion”, “antiviral effects” and all other equivalents. Accord-
ingly, the following search method was used in the PubMed:
zincoxide nanoparticle OR zinc oxide nanoparticle OR ZnO
nanoparticle OR zincoxide nano-particle OR zinc oxide
nano-particle OR zinc-oxide nano-particle OR zinc oxide
nanoparticle OR ZnO nano-particle OR ZnO NP OR ZnONp
OR zincoxide NP OR zinc oxide NP OR zincoxide OR zinc
oxide AND viruses OR virus OR viral infection OR antiviral Fig. (1). Selection procedure of articles.
OR anti viral OR anti-viral. The search was first limited to
English articles, and because no study has been performed 3.2. Study Results
on humans so far, we selected all available in vitro studies.
Afterwards, irrelevant documents in addition to review arti- Nanoparticles are considered safe, cost-effective biologi-
cles were excluded from further evaluation. The search was cal agents that have been recently evaluated as potent anti-
independently performed by two authors, and every possible bacterial and antiviral drugs (Table 1). In this regard, many
disagreement was resolved in each step. The study concept, studies have reported the antiviral potential and efficiency of
design, and search method followed the PRISMA checklist nanomaterials comparable to some conventional antiviral
2009, which is a recommended protocol for reporting sys- drugs. The results of a study included in this literature re-
tematic reviews [20]. view showed that ZnONPs at a concentration of 0.2 mg/ml
significantly reduced the viral titer and viral RNA of the
Chikungunya virus [21]. The results of an animal study on
2.2. Data Extraction
BALB/c mice also showed that ZnO tetrapod nanoparticle
All the informative data, including the author’s name, was an effective suppressor of herpes simplex virus-2 (HSV-
publication date, types of virus, size, and dose of the NPs 2) that can reduce the clinical signs of vaginal infection in
were extracted. All the data are summarized in Table 1. In animals [22]. In addition, it blocks HSV-1 entry into the cells
addition, the measured variables in each study were col- as well as interaction with glycoprotein D (gD) receptor,
lected. The most important variables include viral titer, cyto- leading to deactivation of the virus through virostatic poten-
kines levels including interleukin-1 beta (IL-1b) and tumor tial [23]. At a concentration of 200 μg/ml, ZnONPs led to
inhibition of approximately 92% in the copy number of
Zinc Oxide Nanoparticles as a Potential Agent for Antiviral Drug Delivery
HSV-1 genomic DNA [24]. Other surface-modified zinc
nanoparticles, such as hydroxyl group, oleic acid, or chito-
san-rich ZnONPs could also reduce the viral infectivity of
HSV-1 at 0.01 mg/ml [25]. PEGylated ZnONPs at 200 μg/ml
led to a 2.8 log reduction in virus titer of the H1N1 influenza
virus [26]. ZnONPs could also effectively inactivate bacte-
riophages, including MS2, ΦX174, and PR772 with an aver-
age 4 log reduction at 50 mg/l [27]. Recent findings on the
antibiofilm activity of metal oxide nanoparticles have shown
that Exopolysaccharide (EPS)-coated ZnONPs have high
larvicidal toxicity against malaria and Zika virus vectors,
which may help in controlling malaria [28]. ZnONPs at con-
centrations ranging from 24 to 50 μg/ml can protect cell cul-
ture and animals against bovine herpesvirus-1 (BoHV-1)
viral infections [29].
4. DISCUSSION
It has been previously shown that zinc acts as an antiviral
agent against many viruses, including Rotavirus, Rhinovirus,
Picornavirus, HSV, hepatitis E virus (HEV), hepatitis C vi-
rus (HCV), and human immunodeficiency virus (HIV) as
well as severe acute respiratory syndrome coronavirus [35].
Since zinc-containing therapeutics have been shown to boost
immune response, research on the formulation of ZnONPs
for the prevention and treatment of viral infection has gained
a lot of attention in recent years. In the present study, the
efficiency of ZnONPs on viral infection is reviewed.
It has been shown that zinc can act through various
mechanisms, such as modulation of immune response in the
host since it enhances natural killer (NK) cell-mediated de-
fense mechanisms against pathogens [36]. On the other side,
zinc strengthens the antiviral action by inducing the produc-
tion of interferon-alpha (IFN-α) and gamma (IFN-γ) [37, 38].
It is known that IFN-γ stimulates the major histocompatibil-
ity complex (MHC) II-dependent presentation of antigens
that is an important process in inducing immune responses.
Zinc also activates the nuclear factor kappa B (NF-kB) and
its target genes, including TNF-a, IL1b, and IL-6 [39]. NF-
kB is a transcription factor that is known to be activated in
the infected cells [40]. Also, zinc is a cofactor of many cellu-
lar proteins, transcription factors, and enzymes; therefore, it
can control viral infection by interfering with cellular proc-
esses including transcription of genes that are necessary for
innate immunity [41]. In this respect, it has been shown that
ZnO can induce various immunity-related genes, macro-
phage maturation, leucocyte migration, and inflammatory
response through up-regulation of TNF and IL-1beta [33].
On the other hand, inoculating the viruses with ZnONPs has
been reported to be more effective in reducing viral infectiv-
ity than cellular pretreatment of ZnONPs, indicating that
neutralizing the virus infectivity is the most probable mecha-
nistic pathway of ZnONPs rather than interfering with tar-
gets inside the cells [35]. ZnO tetrapods as virus trapping
agents were found to decrease the viral internalization of
HSV-2 and block viral spread [34]. Findings have shown
that ZnO NPs significantly lower virus colonization by in-
creasing the phytohormone levels and also through directly
deactivating the Tobacco mosaic virus (TMV) in Nicotiana
benthamiana [42].On the other hand, zinc ions have been
Current Nanoscience, 2022, Vol. 18, No. 2 149
reported to be involved in viral mRNA degradation, and pro-
tein hydrolysis of HIV-1[43]. Recent studies have reported
that photo-activation and particularly UV irradiation of metal
oxide nanoparticles may enhance antiviral properties of
ZnONPs through metal-based photosensitization and modu-
lation of electrostatic properties of ZnONPs, which is an
efficient method of viral disinfection system [44].
NPs-based antiviral vaccines are a new generation of
vaccines that overcome the major limitations of conventional
methods including the risk of reversion to a pathogenic form,
or weak immune response https://doi.org/10.3389/fimmu.
2019.00022 [45, 46]. It seems that recombinant NPs that are
typically loaded with the desired viral antigen can efficiently
activate the immune system in the body to fight against the
virus. The main advantages of using recombinant NPs
against respiratory viruses, such as Coronavirus infection,
include mimicking the size, shape, and surface properties of
respiratory viruses by the nano vaccines [45, 47]. Most of the
metal NPs are in the same size of 20–200 nm as most respi-
ratory viruses https://doi.org/10.3389/fimmu.2019.00022
[45]. Also, positively charged metal oxide-based NPs can
strongly induce immune responses compared to other nega-
tively charged NPshttps://www.ncbi.nlm.nih.gov/pubmed/
29071191 [47]. On the other hand, a combination of metal
nanoparticles with peptides can increase the efficiency of
treatment; hence, peptide ZnO NPs may also be considered
as potential antiviral agents in clinical practice [48, 49]. An-
other promising approach is photosensitization and photody-
namic therapy, which involves the use of non-toxic light
sensors that are excited in the presence of visible light and
produce ROS in the presence of oxygen [50, 51]. ROS can
therefore interact and destroy the virus envelope. According
to the aforementioned and the suggested mechanism of ac-
tion for ZnO NPs, ZnO NPs are expected to act on a variety
of RNA viruses, including HIV and Coronavirus infection.
The main reason for this claim is the virostatic, electrostatic,
and other physiochemical properties of ZnO NPs, such as
size, modifiable shape and surface properties. However,
without further evaluation, this hypothesis cannot be veri-
fied. Although many studies have shown that zinc salts may
be beneficial in improving immune responses against viral
infection, possible imbalance of zinc homeostasis in serum
and plasma, which may increase the risk of Alzheimer's dis-
ease (AD), aging, and other neurodegenerative disorders may
limit their use [52, 53]. Recently, many studies have been
conducted to improve the technology of nanofluids, which
can improve their stability and hydrodynamic properties and
provide easier and safer use of nanomaterials as a medicine
[54-57]. Therefore, a comprehensive study is suggested to be
performed on human to evaluate such benefits and possible
risks.
CONCLUSION
The results of the present systematic review showed that
ZnO NPs are powerful antiviral agents, which can be used in
drug development against various viral and bacterial infec-
tions. They are safe, biocompatible, and non-toxic NPs that
due to owning the positive charge, the same size as many
150 Current Nanoscience, 2022, Vol. 18, No. 2 Nasrollahzadeh et al.

Table 1. Data of included literature.

No Reference Country Animal / Virus type Nano Size Dose Variable Outcomes Synthesis
cell type [nm] method

1 Rabiee N, Iran Mammalian H1N1 ZnO NPs - 20 μg/ml inhibition rate ZnO NPs could inactivate Green synthesis

2020 [30] cell influenza the H1N1 influenza virus.

2 Choudhary S, India Vero cells Alphaviruses ZnO NPs 12 0.2 mg/ml viral titer, viral RNA ZnO NPs act as good Green synthesis
2020 [21] level antiviral agents.

3 Zeedan GSG, Egypt New Zealand BoHV-1 ZnO NPs 10- 50 24-50 plaque forming ZnO NPs are able to inhibit Green synthesis
2020 [29] White rabbits μg/ml BoHV-1.

4 Agelidis A, USA Balb/c mice HSV-2 ZOTEN 20000 0.1 mg/ml plaques, antibodies, ZOTEN-neutralized virions Flame transport
2019 [31] cytokine elicit a local immune synthesis
response.

5 Ghaffari H, 2019 Iran Madin-Darby H1N1 ZnO NPs, 16- 50 75-200 viral antigens ZnO-PEG-NPs are effective Mechanical
[26] canine kidney influenza ZnO-PEG- μg/ml antiviral agents against method
SIAT1 cells NPs H1N1 influenza virus
infection.

6 Abinaya M, India, Saudi Mosquito Zika Virus ZnO NPs 10-100 <100 μg/ml - ZnO NPs showed anti- Co-precipitation
2018 [28] Arabia, Italy larvae biofilm and larvicidal
activity against malaria and
Zika virus vectors.

7 Tavakoli A, Iran Vero cells HSV-1 ZnO NPs, 20- 40 200 μg/ml HSV-1 antigens ZnO-PEG-NPs could be an Mechanical
2018 [24] ZnO-PEG- efficient agent for HSV-1 method
NPs inhibition.

8 Farouk F, 2018 Egypt Vero cells HSV-1 H-ZNPs, 7 0.01 mg/ml virus titer H-ZNP and C-ZNP were Co-precipitation
[25] OA-ZNPs, able to neutralize the HSV-1
C-ZNPs and reduce its infection in
host cells.

9 Duggal N, USA Human HSV-1 ZOTEN 200 1 mg/ml plaques, cytokine ZOTEN inhibited HSV Flame transport

2017 [32] corneal profile infection. synthesis

epithelial
cells

10 Poon WL, 2017 Finland THP-1 cells - ZnO NPs 20 10 µg/ml IL-1b, TNF, lym- ZnO NPs induce the expres- Commercial
[33] phocyte activation sion of genes involved in
immunity against viruses.

11 Mac Mahon J, Ireland - * MS2, ZnO NPs 25 50 mg/l phage plaques, ZnO NPs inactivated PR772 Chemical
2017 [27] ΦX174 and colonies and ΦX174 completely method
PR772 removed MS2.

12 Antoine TE, Germany, Female HSV-2 ZOTEN 200 - clinical signs, ZOTEN is protective against Flame transport
2016 [22] USA BALB/c mice antibody responses primary and secondary synthesis
female genital herpes
infections.

13 Antoine TE, USA Human HSV-2 ZOTEN 200 0.1 mg/ml expression of β- ZOTEN acts as anti-HSV-2 Flame transport
2012 [34] vaginal galactosidase, agents. synthesis
epithelial and antibody responses
HeLa cells

14 Mishra YK, Germany Human HSV-1 ZnO MNSs 100-500 100 μg/ml expression of β- ZnO MNSs are the potent Flame transport
2011 [23] corneal galactosidase and HSV-1 inhibitor. synthesis
fibroblasts receptor nectin-1

* Bacteriophages
ZnO NPs: Zinc oxide nanoparticles, ZOTEN: Zinc oxide tetrapod nanoparticles, ZnO MNSs: Zinc oxide micro-nano structures, ZnO-PEG-NPs: PEGylated zinc oxide nanoparticles.
BoHV-1: Bovine herpesvirus-1, HSV: Herpes simplex virus.
Zinc Oxide Nanoparticles as a Potential Agent for Antiviral Drug Delivery
viruses, and strong virostatic potential may be promising
candidates in developing NPs-based vaccines against viral,
especially RNA viruses. Although recent reports have shown
hopeful results of the ZnO NPs in vitro drug delivery for
antiviral purposes, efforts for introducing the formulations in
the clinical trial of viral infections remain fruitless due to the
probable risks mentioned above. However, further human
studies are recommended to confirm their effectiveness in
clinical practice and assess their risk.
CONSENT FOR PUBLICATION
Not applicable.
STANDARDS OF REPORTING
PRISMA guidelines were followed for the study.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher's
website along with the published article.
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