materials

Review
Exploring the Journey of Zinc Oxide Nanoparticles (ZnO-NPs)
toward Biomedical Applications
Fahadul Islam 1,† , Sheikh Shohag 2,† , Md. Jalal Uddin 2 , Md. Rezaul Islam 1 , Mohamed H. Nafady 3 ,
Aklima Akter 1 , Saikat Mitra 4 , Arpita Roy 5 , Talha Bin Emran 1,6, * and Simona Cavalu 7, *

1 Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University,

Dhaka 1207, Bangladesh; [email protected] (F.I.); [email protected] (M.R.I.);
[email protected] (A.A.)
2 Department of Biochemistry and Molecular Biology, Faculty of Life Science, Bangabandhu Sheikh Mujibur
Rahman Science and Technology University, Gopalganj 8100, Bangladesh;
[email protected] (S.S.); [email protected] (M.J.U.)
3 Faculty of Applied Health Science Technology, Misr University for Science and Technology, Giza 12568, Egypt;
[email protected]
4 Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh;
[email protected]
5 Department of Biotechnology, School of Engineering & Technology, Sharda University,
Greater Noida 201310, India; [email protected]
6 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
7 Faculty of Medicine and Pharmacy, University of Oradea, 400087 Oradea, Romania
* Correspondence: [email protected] (T.B.E.); [email protected] (S.C.);
Tel.: +880-1819-942214 (T.B.E.)
† These authors contributed equally to this work.





 Abstract: The field of nanotechnology is concerned with the creation and application of materials
Citation: Islam, F.; Shohag, S.; Uddin, having a nanoscale spatial dimensioning. Having a considerable surface area to volume ratio,
M.J.; Islam, M.R.; Nafady, M.H.; nanoparticles have particularly unique properties. Several chemical and physical strategies have been
Akter, A.; Mitra, S.; Roy, A.; Emran,
used to prepare zinc oxide nanoparticles (ZnO-NPs). Still, biological methods using green or natural
T.B.; Cavalu, S. Exploring the Journey
routes in various underlying substances (e.g., plant extracts, enzymes, and microorganisms) can be
of Zinc Oxide Nanoparticles
more environmentally friendly and cost-effective than chemical and/or physical methods in the long
(ZnO-NPs) toward Biomedical
run. ZnO-NPs are now being studied as antibacterial agents in nanoscale and microscale formulations.
Applications. Materials 2022, 15, 2160.
https://doi.org/10.3390/
The purpose of this study is to analyze the prevalent traditional method of generating ZnO-NPs,
ma15062160 as well as its harmful side effects, and how it might be addressed utilizing an eco-friendly green
approach. The study’s primary focus is on the potential biomedical applications of green synthesized
Academic Editor: Gang Wei
ZnO-NPs. Biocompatibility and biomedical qualities have been improved in green-synthesized
Received: 2 February 2022 ZnO-NPs over their traditionally produced counterparts, making them excellent antibacterial and
Accepted: 3 March 2022 cancer-fighting drugs. Additionally, these ZnO-NPs are beneficial when combined with the healing
Published: 15 March 2022 processes of wounds and biosensing components to trace small portions of biomarkers linked with
Publisher’s Note: MDPI stays neutral
various disorders. It has also been discovered that ZnO-NPs can distribute and sense drugs. Green-
with regard to jurisdictional claims in synthesized ZnO-NPs are compared to traditionally synthesized ones in this review, which shows that
published maps and institutional affil- they have outstanding potential as a potent biological agent, as well as related hazardous properties.
iations.
Keywords: ZnO-NPs; traditional synthesis; green synthesis; biomedical applications; toxicity

Copyright: © 2022 by the authors.

Licensee MDPI, Basel, Switzerland. 1. Introduction
This article is an open access article
Nanotechnology is a rapidly developing discipline of science and technology con-
distributed under the terms and
cerned with producing and developing nanomaterials with particle sizes ranging from 1
conditions of the Creative Commons
Attribution (CC BY) license (https://
to 100 nanometers [1]. Recently, the scientific research community worldwide expressed
creativecommons.org/licenses/by/
interest in synthesizing metal and metal oxide nanoparticles (NPs) [2]. The ZnO-NPs are of
4.0/). huge importance due to their wide variety of applications in photocatalysis, antimicrobial

Materials 2022, 15, 2160. https://doi.org/10.3390/ma15062160 https://www.mdpi.com/journal/materials

Materials 2022, 15, 2160 2 of 31

defense, and water purification. ZnO-NPs display properties that are distinct from those
of typical NPs [3]. Additionally, these NPs are employed in the cosmetics industry to
produced sunblock creams, which guard the human body against ultraviolet radiations [4].
Due to ZnO-NPs’ characteristics, such as their biocompatibility and non-toxicity, they are
particularly well-suited for specialized biomedical applications [5–7]. Metal oxide NPs are
important components in a wide range of consumer goods, including electronic equipment
and cosmetics. ZnO-NPs are versatile materials with distinct chemical, optoelectronic, and
wettability properties. They are easily made and widely used in a variety of industries,
including wastewater treatment [8].
ZnO-NPs are manufactured using nanotechnology and are extensively used in various
nanotechnology disciplines involving gas sensors [9], biosensors [10,11], cosmetics [12],
ceramics [13], optical devices [14], display window materials for solar cells [15], and drug
delivery [16,17]. Solar cells may directly transform light energy into electricity with their
photovoltaic impact on ZnO-NPs [18].
ZnO-NPs absorb and scatter light very efficiently, making them excellent materials
for optoelectronics applications that operate in the ultraviolet and visible spectrum areas.
ZnO-NPs offer excellent photoluminescence properties, making them suitable for emission
display systems, such as televisions [14]. In terms of photocatalytic degradation, ZnO-NPs
seem to be the most promising choices [19]. The detection of gas leakage and the checking of
gaseous contaminants in the environment may both benefit from semiconductor nano ZnO
gas sensors [9]. ZnO-NPs are used to protect fabrics and wood from UV damage [20]. ZnO-
NPs are made in a way that does not harm the environment, and they can control harmful
microbes. Moreover, ZnO-NPs may be utilized as a treatment activator and a cross-linking
agent in rubber treating, and can promote the vulcanization procedure in rubbers used to
produce industrial and medical gloves, balloons, tires, and other rubber goods [21]. These
substances have excellent antimicrobial and UV absorption properties and are commonly
utilized in sunscreens, lotions, and ointments because of their versatility [12]. Antimicrobial
ZnO-NPs are used in food and in can linings to keep fish, pork, peas, and maize safe from
spoilage. ZnO-NPs have been proposed for next-generation biological applications, such as
the delivery of medication, use as antimicrobial agents, and use as bioimaging probes [22].
The two ways that can be used to synthesize NPs are the top-down approach and the
bottom-up approach (Figure 1). Electro-explosion, etching, sputtering, and mechanical
milling are examples of top-down approaches, whereas bottom-up approaches comprise
three basic methods for producing NPs: physical, chemical, and biological processes [23,24].
It is possible to produce pure, high-quality nanoparticles using conventional methods.
Still, the process is expensive and sometimes results in the development of hazardous
byproducts that may have detrimental consequences when employed for medical pur-
poses. Furthermore, additional capping and stabilizing chemicals are required for these
procedures [25]. This problem exists when NPs are produced using the green pathway, a
bottom-up strategy that results in an oxidation/reduction reaction [26].
Materials 2022, 15, 2160 3 of 31

Figure 1. Methods to synthesize NPs from the bottom up and the top down.

Green synthesis can be accomplished using plants, bacteria, fungi, and algae. They
enable the significant manufacturing of pure ZnO-NPs [27]. During green synthesis, a
mixture of different parts of medicinal plants is used to produce NPs. The phytochemicals
play a role as a biocatalyst, capping agent, and organic stabilizer for NPs [28]. The process
does not require high temperatures, pressures, expensive tools, or toxic chemicals [29]. The
green synthesis of NPs is more cost-efficient, toxic-free, and environmentally beneficial
than the expensive and hazardous procedures used before [30,31].
This review highlights the prevalent traditional method of generating ZnO-NPs, as
well as its harmful side effects, and discusses how it might utilize an eco-friendly green
approach. The study’s primary focus is on the potential biomedical applications of green-
synthesized ZnO-NPs.

2. Methodology
To identify the most relevant articles (available in the most well-known medical/biology/
chemical databases, such as Scopus, PubMed, and Web of Science) for this review as
precisely as possible, “zinc oxide nanoparticles,” “traditional techniques,” and “biomedical
applications” were used as primary keywords, and “plant extracts” and “green synthesis”
were used as secondary keywords. An algorithm shown by the flow chart displayed in
Figure 2 (according to the recommendations of Page et al. [32,33]) was used, which inserted
all of the steps/selections requisite for identifying the necessary material in the literature.
Materials 2022, 15, 2160 4 of 31

Figure 2. Stages involved in selecting published data for inclusion in the current study are depicted
in a flow chart; n = number of literature reports.

3. Traditional Synthesis of ZnO Nanomaterials

Traditional methods for producing metallic NPs, such as ZnO-NPs, include
mechanochemical and chemical processes. Sol-gel, hydrothermal, microemulsion pro-
cedures, and co-precipitation are all considered classic chemical synthesis approaches.
Mechanochemical synthesis includes high-energy ball milling and laser ablation tech-
niques [34–38]. The benefits and drawbacks of typical ZnO-NPs synthesis methods and
particular innovative and noteworthy examples are briefly explored in the following sec-
tions of this paper.

3.1. Sol-Gel Technique

The transformation of a sol (e.g., a solution comprising inorganic metallic salts) pro-
gressively into a solid “gel” phase over a succession of hydrolysis and polymerization
reactions is most commonly utilized to synthesize metal oxide NPs. Subsequently, the gel
is treated to vaporize the solvents and heated to produce the final product [39–41]. Figure 3
depicts the sol-gel process in a simplified form. Using the sol-gel technique, it is possible
to produce ZnO-NPs in a fine powder-like structure with a controlled chemical composi-
tion [42,43]. This process also has inherent drawbacks, including shrinkage, breaking while
drying, and an inability to manage porosity [41]. Since the protocol is easy to follow and
the critical material is generated quickly, it is frequently discussed in the relevant literature.
Despite its shortcomings, this technique remains one of the most regularly employed. Zinc
Materials 2022, 15, 2160 5 of 31

acetate dehydrates (Zn(CH3 COO)2 .2H2 O), and ethanol were utilized as solvents to create
rod-shaped ZnO-NPs in the range of 81.28–84.98 nanometers [23].

Figure 3. Diagrammatic representation of the stages required for the synthesis of metallic NPs (for
example ZnO-NPs) employing the sol-gel process.

ZnO-NPs that averaged 28 nm in diameter with a spherical structure was produced

by Jurablu et al. [44] using the sol-gel process. Zinc sulfate heptahydrate (ZnSO4 .7H2 O)
and diethylene glycol (C4 H10 O3 ) surfactants were utilized in this method. Additionally,
ZnO-NPs with a mean particle size between 12 and 30 nm were produced using a mixture
of ammonia and methanol, as well as Zn(CH3 COO)2 .2H2 O as the precursor in a sol-gel
process, which resulted in spherical ZnO-NPs in the range of 50–60 nm [43,45].

3.2. Hydrothermal Technique

An autoclave is a closed reaction vessel with high pressure and high temperature,
where hydrothermal activities are carried out. Under high temperature and high pressure,
the insoluble or challenging-to-dissolve materials are dissolved [46]. Various solvents can
be utilized in these reactions, such as water or organic solvents such as ethanol or polyols,
known as hydrothermal or solvothermal techniques, respectively [47,48]. An example
of a hydrothermal procedure is shown in Figure 4. In addition to high product purity
and crystallinity, hydrothermal methods control the final nanostructure size, shape, and
crystal phase with little pollution due to the closed system environment [37,48]. Since
the procedure is deemed environmentally beneficial, it is included in the green methods
for producing ZnO-NPs. This method has some negatives; for example, it requires an
extremely expensive autoclave and it has limitations for studies because the reactor cannot
be kept open. There are also potential safety hazards throughout the autoclave procedure,
which can be a concern [35,49,50]. Hydrothermal/solvothermal techniques, like the sol-gel
strategy, are simple to start up. Examples include a study by Bharti and Bharati [51], which
used a hydrothermal method to manufacture a length scale of 15.8–25 nm ZnO-NPs and
various morphologies. ZnO-NPs with cylinder-shaped pores ranging from 9 to 12 nm in
width were also manufactured by Reddy et al. [52], with the help of zinc nitrate hexahydrate
(Zn(NO3 )2 .6H2 O) and sodium hydroxide (NaOH). Similarly, by utilizing an autoclave unit,
Wirunmongkol et al. [52] produced ZnO-NPs in which NaOH and Zn(NO3 )2 .6H2 O were
used as the initial precursors. Shaped like tiny prisms and flowers, the NPs were between 30
and 80 nm wide and 0.5–0.1 µm long, depending on the type of material used to make them.
Materials 2022, 15, 2160 6 of 31

Figure 4. Diagrammatic representation of the stages required for metallic ZnO-NPs synthesis em-
ploying the hydrothermal technique.

3.3. Co-Precipitation Technique

The co-precipitation technique creates metallic NPs by simultaneous nucleation fol-
lowed by growing and then agglomerating tiny nuclei. The co-precipitation process is
depicted in Figure 5. This process has several advantages, including ease of use, minimal
need for high temperatures, and ease of overall energy management [35]. As a side note,
this approach has one significant drawback: it produces NPs with large quantities of water
molecules attached to them [53]. Additionally, batch-to-batch repeatability issues, a wide
range of particle sizes, and severe agglomeration are negatives [35,54,55]. However, re-
markable instances include zinc acetate solution in methanol, in which spherical ZnO-NPs
were synthesized by co-precipitation ranging between 2 and 10 nm in particle size. In
contrast, a co-precipitation method using zinc acetate dihydrate, hydrochloric acid, and
ammonia as reactants was used to manufacture ZnO-NPs. The ZnO-NPs was discovered to
have a pseudo-spherical form with an average particle size between 11 and 20 nm [56,57].
A similar co-precipitation approach was used by Adam et al. [58] to produce ZnO-NPs
with an average diameter of 140 nm.

Figure 5. Diagrammatic representation of the stages required for ZnO-NPs synthesis employing the
co-precipitation method.

3.4. Microemulsion Technique

Water droplets colliding with each other in a microemulsion environment resulted in
a precipitation reaction, which led to the formation of NPs with surfactant-stabilized nucle-
ation. The microemulsion process is depicted in Figure 6. The rewards of this approach
Materials 2022, 15, 2160 7 of 31

include its simplicity, thermodynamic stability, and low accumulation. Microemulsion tech-
niques have several drawbacks, including the impact of temperature and pH on the stability
of the microemulsion and the persistent demand for highly concentrated surfactants and/or
cosurfactants that may irritate [35]. ZnO-NPs have been manufactured in microchannel
reactor systems with an average diameter of 16 nanometers by Wang et al. [59]. Following a
drying period of 2 h at 130 ◦ C, the ZnO-NPs were then calcined at 550 ◦ C for 3 h. ZnO-NPs
were also produced by Li et al. [60] via a simple procedure of microemulsion, with diverse
morphologies including columnar and spherical.

Figure 6. Diagrammatic representation of the stages required for metallic ZnO-NPs synthesis em-
ploying the microemulsion method.

3.5. Laser Ablation Technique

A typical laser ablation technique can remove metallic ions from metal surfaces by
employing a laser beam and a small liquid quantity of methanol, ethanol, and purified
water. The surface is immersed in the liquid. A schematic representation of the laser
ablation approach is shown in Figure 7. Simplicity, and a quite safe procedure from an
environmental standpoint, are two of the approach’s advantages, resulting in a process
that is both efficient and simple to carry out [61]. Pyrolysis byproducts (the result of laser
ablation when organic substances are present) have yet to be fully clarified and need to be
addressed [62]. The works of Al-Dahash et al. [63] are exciting: with laser ablation in NaOH
aqueous solution, they could produce ZnO-NPs from 80.76 to 102.54 nm with a spherical
structure. In addition, Farahani et al. [64] used a zinc target in a solution of methanol and
distilled water to generate ZnO-NPs with a roughly spherical morphology ranging from 1
to 30 nm by laser ablation. In the same way, Mintcheva et al. [61] indicated that they made
ZnO-NPs that were rod-shaped, 30 nm in diameter, and 40–110 nm in size.
Materials 2022, 15, 2160 8 of 31

Figure 7. Diagrammatic representation of the stages required for metallic NPs synthesis (for example
ZnO-NPs) employing laser ablation.

3.6. High-Energy Ball Milling Techniques

The high-energy ball milling technique is a manufacturing process that produces fine
metal NPs in an elevated shaker mill [65]. This technology is depicted in Figure 8. Its key
advantage is the ability to generate vast quantities of material simultaneously. Its downsides
include contaminants from milling balls and/or from the environment and irregularly
shaped NPs that result from this process [66–68]. ZnO-NPs may still be synthesized using
commercially available ZnO powder with a mean of 0.8 m particle size, as demonstrated
by Prommalikit et al. [69], who used high-energy ball milling to manufacture ZnO-NPs.
Particles with a final size of 200–400 nm were obtained through milling. In a similar vein,
Mohammadi et al. [70] synthesized rod-shaped ZnO-NPs in the 20–90 nm range using a
high-energy ball milling technique. Salah et al. [70] employed the same high-intensity ball
milling procedure to make ZnO-NPs from ZnO microcrystalline powder. The samples
were ground into a ball mill for 2, 10, 20, and 50 h. The size of the particles changed over
time, according to the results. The smaller the particle size is, the longer the ball milling
process lasts. Spherical ZnO-NPs with approximately 30 nm particle sizes were found in
the milled sample.

Figure 8. Diagrammatic representation of the stages required for metallic NPs synthesis (for example
ZnO-NPs) employing high-energy ball milling procedures.
Materials 2022, 15, 2160 9 of 31

4. Green Synthesis of ZnO-NPs

4.1. Green Synthesis of ZnO-NPs Using Plant Extract
Because of the unique phytochemicals that they generate, plant components, for
instance, the root, stem, leaf, seed, and fruit, have been employed to fabricate ZnO-NPs.
The use of organic isolates of plant parts is a highly eco-friendly, cost-efficient method
that does not need intermediary base groups. It takes a fraction of the time, requires
no expensive equipment or precursors, and produces a highly natural and magnitude-
enriched product devoid of contaminants [71]. Plants are considered a popular source of
NP synthesis because they allow for the significant production of NPs with various shapes
and sizes [72].
Phytochemicals, such as polysaccharides, vitamins, alkaloids, polyphenolic com-
pounds, amino acids, and terpenoids released by plants, decrease metal oxides or metal
ions to around 0 valence metal NPs [71,72]. The plant portion’s manufacturing of ZnO-NPs
extracted from flowers or leaves is mainly processed via being bathed in running tap water
and sterilized double distilled water. The plant portion is then allowed to dry at room
temperature before being weighed and crushed with a mortar and pestle. The necessary
amount of Milli-Q H2 O is added to the plant component and boiled under vigorous agita-
tion using a magnetic stirrer [71–75]. The plant’s extractions are made by filtration through
Whatman filter paper (sample). To ensure efficient mixing, the mixture is heated to the
necessary temperature for the necessary time to integrate the extract into 0.5 mm of hydrous
zinc sulfate or zinc nitrate, or ZnO or solution [74,75]. At this point, some experiments
were done with extract concentration, temperature, duration, and pH to see what works
best. An incubation period causes the mixture to turn yellow as visual proof of the newly
produced NPs [74,75].
Next, the mixture is centrifuged and dried in a hot oven to obtain the crystal NPS
from the synthesized NPs, and confirmed by UV-Vis spectrometry [76]. To further charac-
terize the synthesized NPs, various techniques, such as Field Emission Scanning Electron
Microscopy (FE-SEM, JEOL IT800 series, New York, NY, USA), X-ray Photoelectron Mi-
croscopy (XPS, Phadke Instruments Private Limited, Maharashtra, India), Energy Disper-
sion Analysis of X-ray (EDAX, Nunes Instruments, Tamil Nadu, India),Scanning Electron
Microscopy (SEM, Analytical Technologies Limited, Gujarat, India), X-ray diffractometer
(XRD, Expert Vision Labs Pvt. Ltd., Maharashtra, India), UV-Visible Diffuse Reflectance
Spectroscopy (UV-DRS, Nunes Instruments, Tamil Nadu, India), Fourier Transform In-
frared Spectroscopy (FTIR, Alliance Enterprise, Mumbai, India), Transmission Electron
Microscopy (TEM, Expert Vision Labs Pvt. Ltd., Maharashtra, India), and Atomic Force
Microscopy (AFM, V Instek Analytical, Gujarat, India), are propagated [75–77]. Microwave
irradiation (MI, V Instek Analytical, Gujarat, India) takes less time than conventional
heating (CH), according to an experiment by Jafarirad et al. [78], and this is due to the
higher level of heating provided by MI and a consequently faster response rate. Anisochilus
carnosus [79], Plectranthus amboinicus [80], and Vitex negundo [81], members of the Lamiaceae
family, have been widely investigated; the size of produced NPs reduces as the content of a
plant extract increases [79–81].
Additionally, results comparing the size ranges recorded using other techniques, such
as FE-SEM, TEM, and XRD, revealed similar range values [80,81]. SEM and EDAX yielded
results that differed slightly from those of XRD. According to the Debye-Scherrer equation,
NPs synthesized from the leaves and flowers of Vitex negundo had the same diameter of
38.17 nm, validated by XRD analysis [81]. For the fabrication of ZnO-NPs, the leaves of the
Azadirachta indica of the Meliaceae family were the ones most typically employed [82,83].
XRD and TEM examination verified that the NPs in all trials were in the same size range,
with spherical and hexagonal disc-shaped NPs and Nano buds carboxylic acid, alkane,
amine alcohol, carbonate moieties, and amide were involved in the synthesis of NPs,
as evidenced by FTIR investigations. Aloe vera leaf extract and leaf peel belong to the
Liliaceae family [84,85]. The size of synthesized NPs differed (NPs synthesized from peel
were more extensive, as validated by SEM and TEM studies), but the forms were similar
Materials 2022, 15, 2160 10 of 31

(hexagonal and spherical). Agathosma betulina, Pongamia pinnata, Plectranthus amboinicus,

Nephelium lappaceum, and Calatropis gigantea were extracted for synthesized NPs, which
form aggregates [86]. Plants employed to synthesize ZnO-NPs up to these points are
included in Table 1.

Table 1. ZnO-NPs synthesized using a plant-mediated process.

Common Name Plant (Family) Extraction Part Functional Group Shape Size (nm) References
Primary and secondary
amine, aromatic,
Coptidis rhizoma Spherical,
Coptis Rhizome Dried Rhizome aliphatic amine, alcohol, 2.9–25.2 (TEM) [87]
(Ranunculaceae) rod-shaped
carboxylic acid, alkyl
halide, and alkynes.
Azadirachta indica Amine, alcohol, ketone,
Neem Fresh leaves Spherical 18 (XRD) [88]
(Meliaceae) carboxylic acid
O-H stretching, C=O 26 (XRD),
Pongamia pinnata spreading carboxylic Spherical, agglomeration of
Indian beech Fresh leaves [89]
(Legumes) acid or their ester, hexagonal, nanorod 100 (DLS, SEM,
C-O-H bending mode. TEM)
Ocimum basilicum Hexagonal 50 (TEM, EDS),
Red Rubin basil Leaf extract - [90]
(Lamiaceae) (wurtzite) 14.28 (XRD)
O-H, C-H, C-O
Bhuiamla, stone Phyllanthus niruri Hexagonal wurtzite, 25.61 (FE-SEM &
Leaf extract stretching, aromatic [91]
breaker (Phyllanthaceae) quasi-spherical XRD)
aldehyde.
Agathosma betulina O-H of hydroxyl group, Quasi-spherical 15.8 (TEM), 12–26
Buchu Dry leaves [92]
(Rutaceae) Zn-O stretching band agglomerates (HRTEM)
Trifolium pratense Hydroxyl, -C-O, -C-O-C,
Red clover Flower Spherical 60–70 (XRD) [93]
(Legumes) C=C stretching mode.
56.14 (30 mL of
O-H of water, alcohol, extract), 49.55
Anisochilus carnosus phenol C-H of alkane, Hexagonal wurtzite, (40 mL), 38.59
Kapurli Leaf extract [79]
(Lamiaceae) O-H of carboxylic acid, quasi-spherical (50 mL) [XRD],
C=O of the nitro group. 20–40 (FE-SEM),
30–40 (TEM)
E. crassipes Spherical without 32–36 (SEM &
Water hyacinth Leaf extract - [94]
(Pontederiaceae) aggregation TEM), 32 (XRD)
[13.3 (CH), 11.3
C-O and C=O of esters,
Rosa canina (MI)] (XRD),
Dog rose Fruit extract hydroxyl, C-H Spherical [7]
(Rosaceae) [25–204 (CH),
stretching.
21–243 (MI)] (DLS),
O-H, aldehydic C-H,
amide III bands of
Solanum nigrum Wurtzite hexagonal, 20–30(XRD and FE-
Black nightshade Leaf extract protein, carboxyl side [95]
(Solanaceae) quasi-spherical SEM),29.79(TEM)
group, C-N of amine, the
carbonyl group
Freeze-dried leaf Spherical,
Aloe vera Aloe vera (Liliaceae) - 25–65 (SEM & TEM) [84]
peel hexagonal
Amide II was stretching
band, C-N stretching
band of aliphatic,
aromatic amide, an
Azadirachta indica aliphatic amine, alcohol,
Neem Leaf Spherical 9.6–25.5 (TEM) [82]
(Meliaceae) phenol, secondary
amine, C-H of alkane
and aromatics, C=C-H of
alkynes, C=O, C-C of an
alkane.
Spherical and
O-H, C-H of alkane,
Moringa oleifera granular nano-sized 24 (XRD), 16–20
Drumstick tree Leaf C=O of alcohol, [96]
(Moringaceae) shape with a group (FE-SEM)
carboxylic acid
of aggregates
O-H of alcohol and a Spherical and
Cocus nucifera carboxylic acid, C=O of predominantly 20–80 (TEM), 21.2
Coconut Coconut water [97]
(Arecaceae) ketones, C-N of aromatic hexagonal without (XRD)
and aliphatic amines, any agglomeration
Gossypium O-H, [C=O, C-O, C-O-C] Wurtzite, spherical,
Cotton Cellulosic fiber 13 (XRD) [98]
(Malvaceae) (due to Zn precursor) nanorod
Materials 2022, 15, 2160 11 of 31

Table 1. Cont.

Common Name Plant (Family) Extraction Part Functional Group Shape Size (nm) References
N-H bending & N-H
stretching mode, a
Santa maria 22–35 (50% plant
Parthenium phosphorus compound,
feverfew, carrot Spherical, extract), 75–90 (25%
hysterophorus Leaf extract secondary sulfonamide, [99]
grass, congress hexagonal plant extract) (XRD,
(Asteraceae) monosubstituted alkyne,
weed TEM)
amine salt, vinyl cis-tri
substituted
Azadirachta indica O-H between H2 O and Hexagonal disk, 10–30 (TEM), 9–40
Neem Fresh leaves [83]
(Meliaceae) CO2 , carbonate moieties nanobuds (XRD)
Rod-shaped
Plectranthusamboinicus Zn-O, C-O of C-O-SO3 ,
Mexican mint Leaf extract nanoparticles with 50–180 (SEM) [100]
(Lamiaceae) phosphorus compound
agglomerates
Spherical-shaped
Calatropis gigantea
Crown flower Fresh leaves - forming 30–35 (SEM) [101]
(Apocynaceae)
agglomerates
Vitex negundo 38.17 (XRD), 10–130
Nochi Flowers - Hexagonal [30]
(Lamiaceae) (DLS)
N-H stretching of amide
S. album II, carboxylate group, 100 (DLS & SEM),
Sandalwood Leaves Nano rods [102]
(Santalaceae) carbonyl stretching, O-H 70–140 (TEM)
of alcohol
Vitex negundo OH, C-H, C=C 75–80 (SEM & EDX),
Nochi Leaf Spherical [103]
(Lamiaceae) stretching band. 38.17 (XRD)
Needle-shaped
Nephelium lappaceum O-H stretching, H-O-H
Rambutan Fruit peels forming 50.95 (XRD) [104]
(Sapindaceae) bending
agglomerate
O-H of phenol, amines,
O-H of alcohol, and C-H Spherical, oval,
Aloe Vera Aloe Vera (Liliaceae) Leaf extract 8–20 (XRD) [85]
of alkanes, the amide of hexagonal
protein and enzymes.
Sphathodea O-H stretching of
African tulip tree campanulata Leaf extract polyphenols, nitrile Spherical 30–50 (TEM) [105]
(Bignoniaceae) group, C-H, C=O group

4.2. ZnO-NPs Green Synthesis Using Bacteria

There are various drawbacks to employing bacteria to synthesize NPs, including the
time and effort necessary to screen microbes, the need for constant observing of culture
broth and the entire process, the NPs’ shape and size, and the expense of the media
used to grow bacteria. Using an eco-friendly technique, the photocatalytic activity and
degradation of nanoflowers ZnO were demonstrated by B. licheniformis. The photocatalytic
action for these nanoflowers was shown to be improved when compared to existing
photocatalytic materials. It has been speculated that the more considerable oxygen vacancy
in the produced NPs provides this property. It is possible to employ photocatalysis as a
bioremediation method because it generates active species by absorbing light. Synthesized
nanoflowers based on B. licheniformis were 40 nm wide by 400 nm long [106].
Rhodococcus can persist in unfavorable conditions and metabolize hydrophobic sub-
stances, which enables it to contribute to biodegradation [107]. Rhodococcus pyridinivorans
and zinc sulfate were used to manufacture spherical NPs with a 100–130 nm size range,
which XRD and FE-SEM assessment confirmed. In addition, FTIR examination indicated
the existence of mononuclear benzene band, secondary sulfornamide, lactone, amine salt,
monosubstituted alkyne, enol of 1-3-di ketone, hydroxy aryl ketone, amide I bending
band, alkane, amide II stretching band, and phosphorus compound [108]. NPs of ZnO
were created using Aeromonas hydrophilla as a substrate for ZnO synthesis. AFM and XRD
analyses showed that the NPs produced had a size range of 42–64 nm and diverse forms
including oval and spherical [109]. Because it is difficult for rhamnolipid to make micelle
aggregate on carboxymethyl cellulose, this helps keep ZnO-NPs from breaking apart into
micelle groups, making them more stable [110]. Because of its lengthy carbon chain, it
works as a better capping agent [111]. The TEM, XRD, and DLS analyses revealed the
synthesis of spherical NPs with a nano size range of 27–81 nm [111]. The properties of
ZnO-NPs produced utilizing bacterial strains are shown in Table 2.
Materials 2022, 15, 2160 12 of 31

Table 2. Synthesis of ZnO-NP using bacterial strain.

Family Bacterial Strain Functional Group Shape Size (nm) References

Bacillaceae Lactobacillus sporogens - Hexagonal unit cell 5–15 (TEM), 11 (XRD) [112]
O-H stretching vibration,
Pseudomonas -CH of aliphatic stretching 35–80 (TEM), 27
Pseudomonadaceae Spherical [113]
aeruginosa vibration, ester carbonyl (XRD), 81 (DLS)
group.
Phosphorus compound,
57.72 (AFM), 42–64
Pseudomonadaceae Aeromonas hydrophila vinyl cis-trisubstituted, Spherical, oval [114]
(XRD)
monosubstituted alkyne
0-H, N-H,-C-O (carbonyl
stretching in the amide I 200 with nanopetals
Bacillaceae B.licheniformis and amide II linkage of Nanoflowers 40 in width and 400 [108]
protein), C-N stretching in length (TEM)
bond.
Phosphorus compound,
secondary sulfornamide,
monosubstituted alkyne,
β-lactone, amine salt,
Rhodococcus amide II stretching band, Hexagonal phase, 100–120 (FE-SEM),
Nocardiaceae [110]
pyridinivorans enol of 1-3-di ketone, a roughly spherical 120–130 (XRD)
hydroxy aryl ketone, amide
I bending band, alkane,
mononuclear benzene
band.
170–250 (30 min),
Serratia ureilytica Spherical- to 300–600 (60 min),
Enterobacteriacea - [115]
(HM475278) nanoflower-shaped 185–365 (90 min)
[SEM]

4.3. ZnO-NPs Green Synthesis Using Microalgae and Macroalgae

Unicellular algae (chlorella) and multicellular algae (chlorophyll) are examples of
photosynthetic organisms (for instance, brown algae). Basic plant structures, such as leaves
and roots, are absent from algae. Marine algae are classified according to the pigments
they contain, such as Rhodophyta, Phaeophyta, and chlorophytes, which have red, brown,
and green pigments, respectively. For the formation of Au and Ag NPs, algae have been
extensively exploited. However, their utilization for ZnO-NPs synthesis has been limited
and documented in relatively few works [92]. The potential of microalgae to break down
hazardous metals and transform them into less harmful forms has drawn significant
attention [116]. S. muticum and S. myriocystum, both Sargassaceae plants, were employed
to synthesize ZnO-NPs. Sulfated polysaccharides were present in the NPs investigated
by XRD and FE SEM, revealing similar NP sizes and hexagonal wurtzite structure. For S.
myriocystum, DLS and AFM measurements demonstrated varied size ranges, with carbonyl
and hydroxol stretching in NPs that vary substantially in form [99]. The micro- and
macro-algae listed in Table 3 were used to synthesize ZnO-NPs.

Table 3. Synthesis of ZnO-NPs using algae.

Algal Strain Family Size (nm) Shape Functional Group Reference

C=O stretching, N-H bending
Chlamydomonas 55–80 (HR-SEM), 21 Nanorod, nanoflower, band of amide I and amide II,
Chlamydomonaceae [117]
reinhardtii (XRD) porous nanosheet C=O stretch of zinc acetate,
C-O-C of polysaccharide
Spherical, radial, O-H and C=O stretching band,
S. myriocystum Sargassaceae 46.6 (DLS), 20–36 (AFM) [118]
triangle, hexagonal, rod carboxylic acid
Asymmetric stretching band of
the sulfate group, an
30–57 (FE-SEM), 42 asymmetric C-O band
Sargassum muticum Sargassaceae Hexagonal wurtzite [119]
(XRD) associated with C-O-SO3 &
-OH group, sulfated
polysaccharides
Materials 2022, 15, 2160 13 of 31

4.4. ZnO-NPs Green Synthesis Using Fungus Theorem

Extensive production, easy downstream processing, and commercial feasibility make
extracellular NPs from fungi beneficial [120]. Because of their higher tolerance and their
ability to bioaccumulate metals, fungi are preferred over bacteria [121]. Mycelia of As-
pergillus fumigatus were used to produce ZnO-NPs. According to the DLS study, NPs
ranged from 1.2 to 6.8 in area size, with a 3.8 average size. AFM established the average
height of NPs to be 8.56 nm for 90 days, with a significant particle size of more than 100 nm.
After 90 days, they developed an agglomeration with an average particle size of 100 nm,
indicating that the produced NPs were stable for 90 days [122]. SEM confirmed a size
range between 54.8–82.6 nm for NPs produced from Aspergillus terreus that belong to the
Trichocomaceae family. XRD investigation results revealed a 29 nm average size, which
was determined using the Debye-Sherrer equation. FTIR analyses indicated the formation
of primary alcohol, aromatic nitro compounds, and amine in the produced NPs [123]. SEM,
TEM, and XRD analysis verified that NPs generated with Candida albicans had a comparable
size range of 15–25 nm [124]. In most cases, ZnO-NPs developed from Aspergillus species
were spherical. Table 4 lists the fungi most typically employed for ZnO-NPs production

Table 4. Synthesis of ZnO NPs using fungi.

Family Fungal Strain Functional Group Shape Size (nm) Reference

Spherical forming
Trichocomaceae Aspergillus strain - 50–120 (SEM) [125]
aggregates
C-N bond of primary
amine, C-O of a primary
alcohol, primary and
54.8–82.6 (SEM), 29
Trichocomaceae Aspergillus terreus secondary alcohol, N=O Spherical [126]
(XRD)
aromatic nitro compound,
alkyl C=C, amide,
open-chain amino group
Quasi-spherical,
25 (XRD), 15–25
Candida albicans - hexagonal phase [124]
(SEM), 20 (TEM)
(wurtzite structure)
Oblate spherical and
Aspergillus fumigatus 1.2–6.8 (DLS), 100
Trichocomaceae - hexagonal forming [106]
TFR-8 (agglomerate)
aggregates

4.5. ZnO-NPs Green Synthesis Using Other Green Sources

NPs can be synthesized using biocompatible chemicals and alternative green sources.
NP nucleation and synthesis reactions can be carried out within a short time and cost-
efficiently. They result in the production of NPs with a well-dispersed nature that may be
precisely regulated in shape and size [127]. Antibacterial capabilities improved in 99.9% of
NPs produced using a wet chemical method when layered on cotton fabric [128]. Table 5
summarizes a few more green resources used to synthesize ZnO-NPs.

Table 5. Synthesis of ZnO-NPs by proteins.

Others Size (nm) Shape Functional Group References

16 (XRD), 10–20 (TEM), Spherical, Hexagonal
Egg albumin Hydroxyl group [129]
8–22 (AFM) wurtzite
Hydroxyl group, C-O
L-alanine 50–110 (TEM, SEM) - [130]
vibration of Schiff- base.
Soluble starch 50 (SEM) - - [131]

5. Biomedical Applications of Green-Synthesized ZnO-NPs

There has been a sharp rise in attention to NP research in the past decade, particularly
in regard to biological applications [132]. Since nanotechnology has been integrated into
Materials 2022, 15, 2160 14 of 31

medical research, a more excellent grasp of molecular biology has been achieved. As a
result, innovative treatment strategies may be possible for illnesses that were previously
impossible to address due to size limits [133]. For biomedical applications, the formulation
of biofunctional NPs has attracted various research groups that are continually addressing
this subject [134]. Biomedical applications of ZnO-NPs are now under investigation using
a wide range of materials and chemical synthesis processes, as we have discussed in this
study. As an ecological element and part of nature’s intrinsic materials, zinc has a vital
role in human, animal, and plant metabolism. Zinc is required for all living species, which
must be exposed to environmentally appropriate amounts of zinc in the biosphere. ZnO
is extensively utilized in cosmetic, pharmaceutical, and medicinal applications, and as
a nutritional supplement. Even though ZnO dust and fumes are typically considered
harmless, breathing them should be avoided. Regulations have been put in place to limit
the risk of exposure [135]. Figure 9 depicts the green production and uses of ZnO-NPs.

Figure 9. An illustration of the green synthesis and use of ZnO-NPs.

5.1. ZnO-NPs Antibacterial Activity

Organic and inorganic materials are the most common divisions in pharmaceutical
medicinal agents. Organic medicinal drug substances have been found to be less stable
at high temperatures and high pressures, when compared with inorganic medicinal drug
substances [136]. ZnO-NPs are powerful pharmacological agents for therapeutic appli-
cations. ZnO-NPs seem to have a significant therapeutic drug activity when compared
with microparticles. It is noteworthy that the specific mechanisms of medicinal drug action
have not been wholly established [137]. Both gram-positive and gram-negative bacteria are
germicidal to ZnO-NPs [138], and the ZnO-NPs also include medical therapeutic actions
against high temperature and high pressure-resistant spores. Research shows that their
extent and concentration influence ZnO-NPs’ medicinal properties, but not their crystalline
structure or particle type. Therefore, the more NPs there are, the more potent the medical
medicine [139].
Synthesized ZnO-NPs, which have natural antibacterial effects and are photocatalytic
in the ultraviolet (UV-B) light range, can create potent hydroxyl (-OH) free radicals to
Materials 2022, 15, 2160 15 of 31

kill dangerous pathogens and germs at wound sites [140]. This observation led to the
development of a 3D printed customized wound-healing template made of ZnO-NPs that
were uniformly scattered within an alginate template, which can be easily created and
contour-printed to the exact size and depth of a wound. 3D printing consist of the adding
of material layer by layer, allowing for the fabrication of unique shapes and customizability,
which are crucial in biomedical areas such as tissue engineering and pharmaceuticals [141].
ZnO-NPs’ medical medication action mechanism is still a mystery. Hydrogen peroxide
emission may be the essential factor in the action of therapeutic drugs. It is also possible
that the mechanism is due to the binding of particles on the bacterial surface, owing
to static tensions [142]. According to the results, the antibacterial activity of ZnO-NPs
seems to be stronger than that of tiny particles. Particle dosage, treatment duration, and
the NP production process influence NPs’ efficacy. Furthermore, the surface area and
the size of particle variation, which are noteworthy in green-synthesized ZnO-NPs, are
responsible for enhanced antibacterial activity. Future medical difficulties might benefit
from green-synthesized ZnO-NPs applications in food safety and agriculture that have not
yet been confirmed [143]. Table 6 provides applications of green-synthesized ZnO-NPs for
antibacterial purposes.

Table 6. Green-synthesized ZnO-NPs applications for antibacterial purposes.

Platform Raw Material Size System Targeted Bacteria Reference

Bacillus megaterium 45–95 nm ZnO-NPs • H. pylori [144]

• P. aeruginosa
Bacillus • Proteus vulgaris
Bacteria-mediated 10–100 nm ZnO-NPs [145]
licheniformis • Bacillus subtilis
• Bacillus pumilus

• Klebsiella aerogenes
• E. coli
Cassia fistula 5–15 nm ZnO-NPs • Plasmodium [146]
desmolyticum

• P. aeruginosa
Trifolium pretense 60–70 nm ZnO-NPs • E. coli [93]
• S. aureus

Boerhavia diffusa 140 nm ZnO-NPs • MRSA [147]

Plant-mediated 39, 35, 31 nm

Artocarpus prepared with 5, • S. aureus
ZnO-NPs [148]
gomezianus 10 and 15 mL of
10% extract

• Bacillus subtilis
Sechium edule 30–70 nm ZnO-NPs [149]
• Klebsiella pneumonia

• Streptococcus pyogenes
Azadirachta indica 9.6–25.5 nm ZnO-NPs • E. coli [82]
• S. aureus

• Klebsiella aerogenes
Azadirachta indica 9–40 nm ZnO-NPs [83]
• S. aureus

• E. coli
Acalypha indica 20 nm ZnO-NPs [150]
• S. aureus
Materials 2022, 15, 2160 16 of 31

Table 6. Cont.

Platform Raw Material Size System Targeted Bacteria Reference

• E. coli
Tabernaemontana • S. aureus [151]
20–50 nm ZnO-NPs
divaricata • Salmonella paratyphi

• P. aeruginosa
Laurus nobilis 47.27 nm ZnO-NPs [152]
• S. aureus

• Klebsiella aerogenes
• P. aeruginosa
Ruta graveolens 28 nm ZnO-NPs [31]
• E. coli
• S. aureus

• Multi-drug resistant
organisms (MDROs)
Aristolochia indica 22.5 nm ZnONPs isolated from pus [153]
samples of DFU
patients

• S. aureus
• Bacillus subtilis
• L. monocytogenes
Allium sativum 14 and 27 nm ZnO-NPs [153]
• E. coli
• Salmonella typhimurium
• P. aeruginosa

• E. coli
Bauhinia tomentosa 22–94 nm ZnO-NPs [154]
• P. aeruginosa

• Bacillus licheniformis
• Bacillus pumilis
Ulva lactuca 10–50 nm ZnO-NPs • E. coli [155]
• Proteus vulgaris

243 nm Undoped and • E. coli

Amaranthus
undoped/197 nm Fe-doped • Bacillus safensis [156]
spinosus
1%-Fe-ZnO-NPs ZnO-NPs

Hibiscus Fe-doped • E. coli

15–170 nm [157]
rosa-sinensis ZnO-NPs
138 nm, 52 nm, Lanthanum-,
59 nm, and 63 cerium-, and • S. aureus
G. sylvestre nm for undoped, neodymium- • Streptococcus pneumonia [158]
La-, Ce-, and doped
Nd-doped ZnO-NPs

5.2. ZnO-NPs Antimicrobial Potential

ZnO is explored as a potential drug carrier in micro-and nanoscale formulations.
Even though the medicament-specific mechanisms are not fully understood, it has been
proposed that the ROS produced on the particle’s surface, membrane dysfunction, zinc
ion release, and the NPs’ acquisition area unit are the common causes of cell swelling.
Management of ZnO-NPs at elevated temperatures significantly affects their therapeutic
activity, whereas treatment at lower temperatures reduces activity. The mechanisms un-
derlying ZnO-NPs’ medicament activity are unknown. While it is hypothesized that oxide
generation contributes to such activity, it is indicated that the binding between particles
Materials 2022, 15, 2160 17 of 31

and microorganism surface, due to electrical forces, could be a mechanism for ZnO-NPs’
medicament behavior. This could be accomplished using oxygen electrode analysis and
chemiluminescence. Metal NPs are highly ionic and can be generated with exceptional
crystal and high surface, and morphologies with varying edge/corner and reactive sur-
face sites. The ZnO-NPs area unit is subject to current research concerning therapeutic
procedures with ablation regimens. Despite having a more significant thermal effect on
neoplasm ablation, NPs will provide an antineoplastic medical specialty with a synergetic
anticancer impact at the time of heat presence. They may even be imaged to achieve precise
medical assistance. Numerous experiments revealed that understanding the molecular
mechanism underlying tumor-mediated NP ablation will aid in the development of NPs
with appropriate composition and characteristics to induce the ablation property [159–161].

5.3. Proliferating Cells Selective Killers

ZnO cancerous cells are killed by ZnO-NPs, whereas healthy cells are
unaffected [162,163]. Before ZnO-NPs can be used medically, a slew of issues must be
addressed, including a lack of biocompatible dispersion procedures and a more profound
knowledge of the mechanism underlying their selective cytotoxicity [142]. To date, there
have only been a few investigations on the ZnO-NPs cytotoxicity mammal cells, and ex-
perts are divided about the importance of the results that have been published. A study
found that ZnO-NPs have no influence on T cells’ viability in both gram-negative and
gram-positive microorganism concentrations [164]. According to various publications,
these NPs are harmless with respect to the culture of human dermal fibroblasts; still, they
are harmful to metastatic tumor cells [165] and the cells of vascular endothelial [166],
triggering programmed cell death in neural stem cells. It has been stated that the NPs’
size can affect cell viability. Jones et al. [34] discovered that ZnO-NPs with a diameter
of eight nm were more hazardous than were larger zinc oxide particles (50–70 nm) in
Staphylococcus aureus. Hanley et al. [167] recently established a reverse relationship between
class cells’ toxicity and NP size, such as reactive oxygen species (ROS) production. In
contrast, Deng et al. [168] showed ZnO-NPs’ toxic influence on nervous stem cells in a
dose-dependent manner, regardless of particle size.

5.4. ZnO-NPs Anticancer Effects

ZnO cancer nanotechnology has vast implications for molecular identification, molec-
ular imaging, and tailored medical treatment, according to the nursing knowledge domain
area of analysis in engineering, science, and medications. To put it simply, nanometer-sized
particles, such as semiconductor quantum dots and iron chemical complex nanocrystals,
exhibit optical, magnetic, or structural features that are not found in molecules or bulk
materials. As soon as these NPs are attached to antigen-targeting ligands, such as anti-
bodies or peptides, they can target neoplasm antigens as biomarkers as well as neoplasm
vessels with significant similarity and specificity. Because of their large surface areas and
functional groups, many diagnostic and therapeutic substances can be conjugated to NPs
in the 5–100 nm diameter range. A junction rectifier to bio-affinity NPs for molecular and
cell imaging can provide customized medical treatment using NP medication. Researchers
have recently developed and incorporated nano-devices to detect and screen cancer in early
stages. Biomarkers for cancer diagnosis and treatment based on individualized molecular
profiles and tailored genetic and super molecular biomarkers are now possible because of
these breakthroughs in personalized medicine [169].
Several types of research have indicated that ZnO-NPs positively influence cancer
cell growth. It was found that the cell response to ZnO-NPs was dynamic. Hence, the
final composition was affected by multiple challenging or intersecting signals in the mi-
croenvironment, as revealed by Premanathan et al. [142]. ZnO-NPs were more hazardous
to HL60 cancer cells than to normal PBMCs with a therapeutic index, according to the
findings (i.e., hepatotoxic dose) [142]. The inability to distinguish between traditional and
changed tissues in malignant neoplasm medicine may be of essential clinical interest and
Materials 2022, 15, 2160 18 of 31

the biggest hurdle in treatment [170]. Even though various commonly prescribed drugs
can slow down the rate at which cells divide, many of these treatments have a low thera-
peutic index [171,172]. Table 7 summarizes the anticancer uses of ZnO-NPs synthesized
by the green synthesis technique, whereas Figure 10 illustrates the molecular mechanisms
underpinning green ZnO-NPs’ anticancer action.
Table 7. Anticancer applications of ZnO-NPs generated in the green synthesis process.

Platform Raw Material Size System Targeted Cell Line Reference

Pichia kudriavzevii yeast 10–61 nm ZnO-NPs MCF-7, breast [173]
MCF-7, breast HCT-116,
Penicillium chrysogenum fungus 29–37 nm ZnO-NPs [174]
colon
Fungi-mediated Aspergillus niger fungus 80–130 nm ZnO-NPs HepG2, liver [175]
Aspergillus niger fungus 11.8–17.6 nm ZnO-NPs A549, lung [176]
L-asparginase—ZnO-
Aspergillus terreus fungus 28–63 nm MCF-7, breast [177]
NPs
Sargassum muticum algae extract 30–57 nm ZnO-NPs HepG2, liver [178]
WEHI-3, murine
Sargassum muticum algae extract 50–100 nm ZnO-NPs [179]
leukemia
PANC-1, pancreas
Algae and CaOV-3, ovarian
Sargassum muticum algae extract 3–8 nm ZnO-NPs [180]
plant-mediated COLO205, colon HL-60,
leukemia
4.04 ± 1.81 nm;
Gracilaria edulis algae extract length 1.39 ± 0.6 nm; ZnO-NPs SiHa, cervical [181]
width
Rehmanniae radix plant extract 10–12 m ZnONPs MG-63 bone [182]
Myristica fragans plant extract 100–200 nm ZnONPs HeoG2, liver [183]
MCF-7, breast
Albizia lebbeck stem bark 66.25 nm ZnONPs [184]
MDAMB231, breast
Mangifera infica leaves 45–60 nm ZnO-NPs A549, lung [185]
Pongamia pinnata seeds 30.4–40.8 nm ZnO-NPs MCF-7, breast [186]
Eclipta prostrata leaves 20–1.3 nm ZnO-NPs HepG2, liver [187]
ZnO-NPs loaded with
Borassus flabellifer fruit extract 110 nm MDAMB231, breast [188]
DOX
Ziziphus nummalaria leaves 17.33 m ZnO-NPs HeLa, cervical [189]
Laurus nobilis leaves 47.27 nm ZnO-NPs A549, lung [152]
Nephelium lappaceum peel - ZnO-NPs HepG2, liver [190]
Tecoma castanifolia flower 70–75 nm ZnO-NPs A549, lung [191]
ZnO-NPs
Gymnema sylvestre, plant extract 38 nm 33/27/23 nm A498, kidney [158]
La/Nd/Ce—ZnO-NPs
DLA, Daltons
Costus pictus, leaves 20–80 nm ZnO-NPs [5]
lymphoma ascites
Collagen protein 20–50 nm ZnO-NPs HepG2, liver [192]
MCF-7, breast HeLa,
ZnO-NPs loaded with
Milk casein protein 9.3–13.7 nm cervical MDAMB231, [193]
Protein mediated curcumin
breast MG-63, bone
Chitosan coated
Tocopherol lipid 100 nm HeLa, cervical [194]
ZnO-NPs
Materials 2022, 15, 2160 19 of 31

Figure 10. The mechanisms underlying the anticancer activity of green ZnO-NPs. (A) Cytotoxic
action of La-doped ZnO-NPs causes cell death [195]. (B) The development of DOX-FA-ZnO NS
is a unique breast cancer treatment drug delivery system [195]. ZnO nanostructures (ZnO-NS),
doxorubicin (DOX), folic acid (FA), near-infrared (NIR), polyethylene glycol (PEG), and lanthanum
(La) are all components of ZnO-NS.

5.5. Treatment of Different Skin Conditions

ZnO is frequently used to treat skin diseases, including diaper rashes, and in shampoos,
anti-dandruff treatments, hemimorphite creams, and antibacterial ointments. Additionally,
it is a component of tape that athletes use as a bandage to prevent soft-tissue injuries
during workouts [196]. It is possible to use ZnO-NPs in the form of an ointment, cream,
or lotion to guard against UV-induced skin damage and the resulting sunburn. Only
this UVA/UVB reflector, which is entirely photo-stable, has been authorized for use as a
sunscreen [197]. As a sunscreen component, ZnO inhibits all UV-A (320–400 nm) and UV-B
wavelengths’ ultraviolet radiation. Additionally, ZnO-NPs are considered to be common
diverse conventional physical sun blocks, protecting pigments and area units that need to
be free from irritations, allergens, and acne-causing properties [198].

5.6. Drug Delivery

Among several nanotechnology implementations, drug delivery via ZnO-NPs has de-
veloped into a highly effective method for treating various disorders such as cancer [199,200].
Nanomaterials are one of the essential mechanisms in the delivery of drugs. ZnO-NPs
have been used for drug delivery for multiple diseases [199,200]. ZnO quantum dots were
employed in a study by Yuan et al. to administer doxorubicin to HeLa cells [201]. ZnO-NPs
were stabilized by encasing them in chitosan. According to the results of their study, this
Materials 2022, 15, 2160 20 of 31

drug delivery method could be utilized to target cancer cells with doxorubicin [201]. It
is also important to note that one of the primary uses of NPs is the transport of genetic
material to distinct cells, particularly tumor cells [200]. This technology for gene delivery
has several benefits. For instance, the appearance of a plasmid-encoded gene on NPs’
surfaces could assure reliable and effective gene delivery to the receiving tissues [199,200].
Consequently, NPs can be an effective instrument for directing genes to various cells,
including tumor cells. Nie et al. [202] reported that they had created ZnO tetrapod-like
nanostructures that might be employed as innovative gene-delivery vectors. They revealed
that ZnO-NSs, such as a silica-coated amino-modified tetra pod, could bind effectively to
DNA through electrostatic interactions, potentially increasing the efficacy of melanoma
cell transfection [202]. In another investigation, Zhang et al. [203] showed that polycation-
capped ZnO quantum dots might transmit DNA into COS-7 cells. Additionally, the
usage of this method allows for the instantaneous visualization of gene delivery [203].
Several investigations have employed metal oxide NPs for gene silencing and gene delivery.
However, it is vital that further knowledge be obtained [199,200]. ZnO-NPs-based drug
delivery methods are shown in Table 8.

Table 8. ZnO-NPs-based drug delivery methods.

Materials Cell Line Drug References

ZnO (Tetrapod) CHO-K1, HeLa, Vero, VK2/E6 - [204]
ZnO@PMAA-co-PDMAEMA-NPs COS-7 DNA [205]
ZnO/Carboxymethyl Cellulose (CMC) L929, MA104 Curcumin [206]
Curcumin/O-CMCS/n-ZnO nanocomposites MA 104 Curcumin [207]
Mesoporous ZnO - DOX [208]
ZnO@PNIPAM-NPs - DOX [209]
ZnO-NPs T47D PPDME [210]
ZnO-NPs HeLa DOX [211]
Gram-positive
ZnO/PEG-NPs DOX [212]
microorganisms
ZnO/Au-NPs Hela Camptothecin [213]
ZnO-QDs HepG2 - [214]
Chitosan/ZnO-NPs - DOX [201]
cancerous T, activated human
ZnO - [215]
T
ZnO@Polymer-NPs U251 DOX [216]

5.7. Bioimaging
ZnO is a common semiconductor material that can completely replace the typical Cd-
related species found in biological and optical environments [199,217]. At this point,
a variety of ZnO-NPs types have been identified. The bioimaging potential of ZnO-
NPs is intriguing to researchers [199,217]. A wide range of biological and medicinal
uses are possible for this feature. For instance, luminous ZnO-NPs may have excellent
photophysical qualities [199,217]. The surfaces of these NPs have been demonstrated to be
easily manipulated. For ZnO-NPs, it has been discovered that their quantum yield (QY)
may be increased to about 30% following careful tweaking [199,200,217]. According to the
common consensus, ZnO is a safe material. ZnO has been used in sunblock goods and
in diet packing as a food preservative. This means that many biological and medicinal
applications could use the luminous features of ZnO-NPs [199,200,217]. The bioimaging
uses of ZnO-NPs are shown in Table 9.
Materials 2022, 15, 2160 21 of 31

Table 9. Bioimaging Uses of ZnO-NPs.

Model Type of Material Size (nm) Reference

Skin tissue/cellular architecture ZnO-NPs 15–30 [218]
KB cells ZnO Nanocrystals <100 [219]
S. oneidensis CdSe(S)/ZnO-QDs 2–4 [220]
Human skin and rat liver cells ZnO-NPs 26–30 [221]
Plants tissues cell implosion ZnO-NPs 2–200 [222]
Blood cells of zebrafish; roots and shoots of Arabidopsis
ZnO-NPs 10–300 [223]
plants
Hela cells ZnO@silica-NPs 2–5 [224]
Skin ZnO-NPs 21 [225]
B16F10 cells ZnO/Au@PEG-NPs 45–98 [226]

6. Toxicity Associated with ZnO-NPs

ZnO is a nanomaterial that is widely employed in a variety of applications [227]. Using
a well-known photocatalyst, the degradation of environmental pollutants has garnered
considerable attention from researchers [19]. Zinc salts have been utilized as an active
ingredient in lubricants for a long time [228] and used by the pharmaceutical industry to
make emollients [229]. In wound care, anti-infection therapeutic goods, and disinfectants,
ZnO-NPs containing medicines are extensively employed. ZnO-NPs have many applica-
tions in cosmetics, hair and skincare formulations, protective sunblocks, food additives, and
vitamins, among others [230,231]. ZnO is used as an antibacterial compound commonly
used in lotions, ointments, body washes, and surface coatings to prevent the growth of
microorganisms [146,232]. As nutritional supplements, ZnO-NPs have also been utilized
by humans and livestock to stimulate the body’s reaction to inflammation and to enhance
the immune system [233]. The expanding use of ZnO-NPs in consumer goods and pharma-
ceuticals has prompted researchers to look into the potentially hazardous consequences of
ZnO-NPs for human health [230]. The advantages must be carefully balanced against the
potential disadvantages of other NPs.
According to the available research, the inhalation of ZnO-NPs has the most harmful
effects on human lungs [230,234]. The size and surface area of ZnO-NPs have been linked
to the severity of inflammatory illness caused by their exposure [235]. Previous research has
shown that ZnO-NPs elicit a more severe inflammatory response than liquid zinc ions [236].
In various investigations, ZnO-NPs’ cytotoxic characteristics have been tested on human red
and white blood cells. A cytotoxic effect has been seen at concentrations more than 50 ppm,
likely due to increased oxidative stress [237,238]. At more significant concentrations than
predicted in the environment, ZnO-NPs can produce acute impacts on fish [239]. Therefore,
a thorough evaluation of ZnO-NPs’ characteristics, routes of administration, target cells, and
related physiological processes is required to better understand the therapeutic advantages
and to minimize unwanted harmful consequences and negative clinical diagnostic potential.
Long-term effects must still be investigated for the better and safer use of these NPs.

7. Conclusions and Future Perspectives

Because of its environmentally friendly nature, the green synthesis of ZnO-NPs is
favored. The use of diverse plant components, bacteria, fungi, and algae to synthesize ZnO-
NPs is an efficient, simple, and environmentally friendly approach. Plant extracts contain
a variety of biomolecules that act as reducing, capping, and stabilizing agents, including
amino acids, proteins, and a variety of additional primary and secondary metabolites that
serve as reducing, capping, and stabilizing agents during the synthesis process.
The synthesis of these critical nanomaterials has some risks for the environment and
for civilization. As a result, the biological qualities of these materials are directly affected.
The use of biomolecules and living organisms as nanomaterials’ capping agents in green
nanotechnology is a powerful option as a potential solution to minimize the development of
toxic products and undesirable reactions with various biologic membranes. NPs biogenesis
Materials 2022, 15, 2160 22 of 31

with minimal impact on the environment has been the focus of research for the past
decade. These NPs can be precisely sized and shaped using green synthesis methods.
Medical practitioners are increasingly using antimicrobial NPs bandages. Medicine delivery
and clinical diagnostics have produced a growing demand for these technologies. A
rising number of people are interested in environmentally friendly nanomaterials such
as ZnO-NPs, which can be produced with minimal danger and expense. Green synthesis
technologies appear to be increasing in popularity in recent years. ZnO-NPs generated from
plants may be an essential research topic in the biomedical sectors. The green synthesis of
ZnO-NPs using plants and microbes has been highlighted in this review, as it is a rapid,
simple, environmentally friendly, and relatively low-cost process. Biosynthesized ZnO-NPs
for biomedical applications, especially against pathogenic germs, have also been addressed,
to overcome the limitations of conventional chemical and physical methods. The biological
source affects the size of ZnO-NPs and, consequently, their biological activities. However,
additional study is needed to standardize synthesis procedures, as a critical limitation
of green chemistry is the variability of the end products. Further in vitro and in vivo
experiments are expected to elucidate the mechanism of action involved at the cellular
level, with applications in various biomedical fields.

Author Contributions: Conceptualization, F.I. and S.S.; investigation and resources, F.I., M.J.U. and
S.C.; writing—original draft preparation, F.I., S.S., M.J.U., M.R.I. and M.H.N.; writing—review,
updating, and editing, A.A., S.M., A.R. and T.B.E.; visualization and supervision, A.A., S.C. and
T.B.E.; formal analysis, S.M., A.R. and A.A.; resources, F.I. and M.J.U.; project administration, A.A.
and T.B.E.; funding acquisition, S.C. 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: Available data are presented in the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

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