Zinc Oxide Nanoparticles: Green Synthesis and Biomedical

REVIEW PAPER

Zinc Oxide Nanoparticles: Green Synthesis and BiomedicalApplications

Sahana Sadhasivam1• Megala Shanmugam1

• Pillai Divya Umamaheswaran1 • Anbazhagan Venkattappan2 •

Anusuya Shanmugam1

Received: 18 June 2020 / Accepted: 11 October 2020� Springer Science+Business Media, LLC, part of Springer Nature 2020

AbstractNanoparticles refer to ultrafine particles with the particle size at nanoscale. When metals and metal oxides were synthe-

sized at nanoscale, by their unique properties such as smaller particle size, high strength, reactivity, sensitivity, specificity

and stability, they have established a wide variety of applications, and thus have gained popularity in various industries

such as food, textile, cosmetic, automobile and pharmaceuticals. Silver, gold, copper, aluminium, nickel, iron, zinc oxide,

titanium dioxide and copper oxide nanoparticles are few among them. This article presents a review on zinc oxide

nanoparticles, its green synthesis methods and various applications in biomedical fields such as antibacterial, antifungal,

anticancer, anti-inflammatory and wound healing.

Keywords Zinc oxide nanoparticles � Green synthesis method � Antibacterial � Anticancer � Anti-inflammatory �Wound healing

Introduction

Nanotechnology arises from nature, which influences the

substance through physio-chemical processes finding

momentous application in science field [1]. In 1959,

Richard Feynman was the first person conveyed the con-

cept of nanotechnology [2]. Nanotechnology is a field of

science which deals with the materials production and

manipulation in nanometers [3]. Nanomaterials are

microscopic materials that have a structural dimension of

100 nm or less [4]. They have defined properties such as

large surface area, quantum size effects which are con-

sidered to be a significant state of matter. Metal and metal

oxide nanoparticles stated various advantageous

applications in the field of sensors, catalyst, electronics,

optical fibers, agriculture, bio-labelling and in biomedical

areas [5].

Conventionally metal nanoparticle synthetic methods

are classified as top-down and bottom-up methods [6]. The

top-down methods transform the bulk materials into

nanostructures using several techniques such as sonication,

laser ablation, mechanical milling, and physical vapor

deposition [7]. This method has number of drawbacks such

as elaborate, time consuming, high cost of production, and

lack the ability to produce particles of nano size [8]. In

bottom-up methods, the metal precursors are used either in

solid, liquid or gas phases to produce metal nanoparticles.

The bottom-up chemical methods can be done using sol–

gel process, chemical co-precipitation, and chemical vapor

deposition, which often lead to the formation of hazardous

byproducts [9]. In addition, the chemical reducing reagents

used in the nanoparticle synthesis such as sodium dodecyl

sulfate, hydrazine and sodium borohydride are also stated

as toxic. Hence, in contrast to chemical methods, in recent

decades, eco-friendly green synthesis methods, one of the

bottom-up approaches, have gained greater attention for

synthesizing nanoparticles. This method uses various nat-

ural resources such as plants, and microorganisms for

& Anusuya Shanmugam

[email protected]

1 Department of Pharmaceutical Engineering, Vinayaka

Mission’s Kirupananda Variyar Engineering College,

Vinayaka Mission’s Research Foundation (Deemed to be

University), Salem, Tamil Nadu 636308, India

2 Department of Chemistry, Vinayaka Mission’s Kirupananda

Variyar Arts and Science College, Vinayaka Mission’s

Research Foundation (Deemed to be University), Salem,

Tamil Nadu 636308, India

123

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synthesizing nanoparticles [10]. In green synthesis, active

enzymes work as the capping and reducing agents for the

massive production of small nanoparticles [11]. Apart from

enzymes, several phytochemicals present in the plant

extract also act as reducing, stabilizing and capping agent

in the process of nanoparticles synthesis [12]. Microor-

ganisms such as bacteria, algae, fungi, yeast also have the

ability to reduce metal ions and hence are also used for the

massive production of nanoparticles [13]. The green syn-

thesized nanoparticles are far superior to physiochemical

synthesized nanoparticles, because of its reduced environ-

mental impacts and also large scale production of

nanoparticles of well-defined size and morphology [14].

Figure 1 illustrates the various synthesis methods of

nanoparticles.

Zinc oxide (ZnO) is a distinctive inorganic material

exhibiting various properties like piezoelectric, pyroelec-

tric, semiconducting, optoelctronics and catalysis [15].

ZnO is an n-type semiconductor with band gap energy of

3.37 eV at room temperature and 60 meV excitation

binding energy [16]. ZnO is non-toxic, compatible with

skin, and also used as a UV blocker in sunscreen products

[17]. Various researches reported ZnO as the strongest

antimicrobial agent, recognized by release of reactive

oxygen species (ROS) on its surface [18]. Meanwhile, ZnO

is also documented as bio-safe, biocompatible with various

unique applications in biomedical and drug delivery sys-

tems. Since, past two decades, ZnO nanoparticles (ZnO

NPs) have drawn researcher’s interest because of its

extensive properties. These nanoparticles are commonly

employed in several areas such as ethanol gas sensors,

photo-catalyst, UV-light emitting devices and pharmaceu-

tical and cosmetic industries [19–22].

Even though ZnO NPs are synthesized by various

means, this review emphasizes green synthesis method,

where the ZnO NPs are synthesized using both plants and

microbes, which not only increase the synthesis efficacy

and also reduce the production cost. This review also

elaborates various biomedical applications of ZnO NPs

such as antibacterial, antifungal, anticancer, anti-inflam-

matory and wound healing.

Plant Mediated Synthesis of ZnO NPs

The green synthesis of nanoparticles shows an alternate

way for the physical and chemical method of nanoparticle

synthesis. The preponderance of researchers is intensive

towards the green synthesis of metal and metal oxide

nanoparticles using various biological sources [23]. Among

those, plant sources are found to be rapid, eco-friendly, low

cost and are also safe for the humankind [24].

Plant parts such as bark, stem, leaves, fruits and seeds

have been widely used for the ZnO NP synthesis [25]. The

natural plant extract mediated synthesis is a cheap process

and it also doesn’t include any intermediate base group

formation [26]. It is time efficient and with less facility, it

can produce a very pure and quality product which is free

of impurities. Plants are the highest chosen sources for the

nanoparticles synthesis because they results in large scale

production of stable, and varied sized nanoparticles for

specific applications [27]. The green synthesis process

involves biological reduction of metal ions or metal oxides

to metal nanoparticles with the aid of plant phytochemicals

such as alkaloids, terpenoids, aminoacids, polysaccharides,

and polyphenolic compounds [28]. Table 1 summarizes the

different plant sources that are utilized for the production

of ZnO NPs.

Universally, green synthesis of ZnO NPs using plant

sources starts with sterilization of plant parts using double

distilled water or Tween 20 [29–32]. Then, the plant part is

dried at room temperature followed by grinding into

powder using mortar and pestle. The plant extract is pre-

pared by adding distilled water to the weighed powder and

mixture is boiled with continuous mixing using a magnetic

stirrer. Then, the solution is filtered using whatsman filter

paper and is used as a plant extract for further process

[33–37]. The specific volume of plant extract is mixed with

Zinc precursors such as Zinc nitrate, zinc acetate, zinc

sulphate, zinc chloride solution [38–43]. Then, the mixture

is continuously stirred at higher temperature resulting in

formation of ZnO NPs. The formed ZnO NPs are visually

confirmed by color change [44]. The UV–Vis spectroscopy

was used to further confirm the nanoparticles synthesized

(Fig. 2).

Subsequently, morphology of the nanoparticles is mea-

sured using electron microscopes such as Scanning Elec-

tron Microscope (SEM), Transmission Electron

Microscope (TEM), and Atomic Force Microscopy (AFM)

[33, 45, 46]. Then the crystal structure and chemicalFig. 1 Nanoparticle synthesis methods

S. Sadhasivam et al.

123

Table 1 Synthesis of ZnO NPs using Plants

Plant source Description Precursor Size and shape References

Lantana aculeate Leaves Zinc nitrate 12 ± 3 nm and spherical shaped [48]

Terminalia chebula Fruit Zinc nitrate 12 nm and spherical shaped [49]

Parthenium hysterophorous Leaves Zinc nitrate 16 nm and spherical shaped [29]

Boswellia ovalifoliolata Stem Bark Zinc nitrate 20.3 nm and spherical shaped [50]

Corymbia citriodora Leaves Zinc nitrate 64 nm and polyhedron shaped [51]

Spathodea campanulata Leaves Zinc nitrate 20–50 nm and spherical shaped [44]

Aloe barbadensis miller Leaves Zinc nitrate 25–40 nm and spherical shaped [30]

Limonia acidissima Leaves Zinc nitrate 53 nm and spherical shaped [52]

Parthenium hysterophorus Leaves Zinc nitrate 27 ± 5 nm and spherical shaped [31]

Allium sativum, Allium cepa, Petroselinum crispum Leaves

Bulb

Zinc nitrate 14 and 70 nm and Hexagonal

shaped

[32]

Nephelium lappaceum Fruit Peel Zinc nitrate 50 nm and needle shaped [33]

Sedum alfredii Shoot 100 nm and column shaped [34]

Artabotrys hexapetalu Bambusa vulgaris Leaves Zinc nitrate 20–30 nm and spherical, rod

shaped

[35]

Cassia fistula Leaves Zinc nitrate 5–15 nm and crystalline shaped [36]

Pongamia pinnata Leaves Zinc nitrate 100 nm and spherical, hexagonal

shaped

[37]

Carica papaya Leaves Zinc nitrate 10.2 ± 0.6 nm and hexagonal

shaped

[53]

Physalis alkekengi Roots, Leaves,

Stems, and Fruits

Zinc nitrate 50 to 200 nm and spherical shaped [54]

Hibiscus rosa-sinensis Leaves Zinc nitrate 23.4–48.5 nm and spherical

shaped

[55]

Rosa canina Fruits Zinc nitrate 50 nm and spherical shaped [56]

Plectranthus amboinicus Leaves Zinc nitrate 88 nm and rod shaped [57]

Vitex trifolia Leaves Zinc nitrate 15–46 nm and spherical shaped [58]

Aspalathus linearis Flower Zinc nitrate 1–8 nm and spherical shaped [59]

Anisochilus carnosus Leaves Zinc nitrate 20–40 nm and Spherical shaped [60]

Mimosa pudica Leaves Zinc nitrate 2.71 nm and Wurtzite shaped [61]

Coffee extract Powder Zinc nitrate 4.6 nm and hexagonal shaped [61]

Ocimum basilicum L. var. purpurascens Benth. Leaves Zinc nitrate 50 nm and hexagonal shaped [62]

Citrus aurantifolia Peel Zinc nitrate 50 nm and pyramid shaped [63]

Azadirachta indica Leaves Zinc nitrate 10–30 nm and hexagonal shaped [64]

Phyllanthus niruri Leaves Zinc nitrate 25.61 nm and crystalline shaped [65]

Artocarpus gomezianus Fruit Zinc nitrate 12 nm and spherical shaped [66]

croton sparsiflorus morong Leaves Zinc nitrate 22–52 nm and spherical shaped [67]

Plectranthus amboinicus Leaves Zinc nitrate 20–50 nm and spherical,

hexagonal shaped

[68]

Solanum nigrum Leaves Zinc nitrate 29.79 nm and quasi-spherical

shaped

[69]

Carissa edulis Fruit Zinc nitrate 50–55 nm and Flower shaped [70]

Vitex negundo Leaves Zinc nitrate 75–80 nm and spherical shaped [71]

Polygala tenuifolia Root Zinc nitrate 33.03–73.48 nm and spherical

shaped

[72]

Carica papaya Milk Zinc nitrate 11–26 nm and Crystalline shaped [73]

Azadirachta indica Leaves Zinc nitrate 40 nm and spherical shaped [74]

Nephelium lappaceum Peel Zinc nitrate 25–40 nm and spherical shaped [75]

Eucalyptus globulus Leaves Zinc nitrate 11.6 nm and Spherical shaped [76]

Peganum harmala Seed Zinc nitrate 40 nm and non-uniform shaped [77]

Zinc Oxide Nanoparticles: Green Synthesis and Biomedical Applications

123

Table 1 (continued)


Lycopersicon esculentum, Citrus sinensis, Citrusparadisi, Citrus aurantifolia

Peel Zinc nitrate 9.7 nm and hexagonal shaped [78]

Camellia sinensis Leaves Zinc nitrate 8 ± .5 nm and Spherical shaped [79]

Limonia acidissima Leaves Zinc nitrate 12 nm–53 nm and Spherical

shaped

[52]

Solanum torvum Leaves Zinc nitrate 38.0 ± 2 nm and Spherical shaped [80]

Andrographis paniculata Leaves Zinc nitrate 57 ± 0.23 nm and spherical, oval,

hexagonal

[38]

Nigella Sativa Leaves Zinc nitrate 20 nm [81]

Scutellaria baicalensis Root Zinc nitrate 50 nm and sphere shaped [39]

Mangifera indica Leaves Zinc nitrate 45–60 nm and spherical,

hexagonal quartzite shaped

[82]

Rubus coreanus Fruit Zinc nitrate 23.16 nm and hexagonal wurtzite

shaped

[83]

Costus pictus D. Don Leaves Zinc nitrate 11–25 nm spherical, hexagonal

shaped

[84]

Albizia lebbeck Stem bark Zinc nitrate 66.25 nm and spherical shaped [85]

Mentha pulegium Leaves Zinc nitrate 38–49 nm and quasi spherical

shaped

[86]

Sesamum indicum Leaves, Stem and

Root

Zinc nitrate [87]

Lagenaria siceraria Pulp Zinc nitrate 25–55 nm and spherical shaped [88]

Populus ciliate Leaves Zinc nitrate 60–70 nm and spherical shaped [89]

Ceropegia candelabrum Leaves Zinc nitrate 12–35 nm and hexagonal wurtzite

shaped

[90]

Calotropis procera Latex Zinc acetate 5–40 nm and spherical shaped [46]

Black Tea Waste Zinc acetate 19.3 nm and rod shaped [91]

Lobelia leschenaultiana, Leaves Zinc acetate 20–65 nm and spherical,

hexagonal shaped

[92]

Passiflora caerulea Leaves Zinc acetate 70 nm and Spherical Shaped [93]

Ferulago angulata Boiss Zinc acetate 32 and 36 nm and spheroid shaped [94]

Couroupita guianensis Leaves Zinc acetate Hexagonal shaped [95]

Nyctanthes arbor-tristis Flower Zinc acetate 11–32 nm [96]

Ulva lactuca Seaweed Zinc acetate 10–50 nm and crystalline shaped [97]

Oak trees (Jaft) Fruit Zinc acetate 44 nm and hexagonal wurtzite

shaped

[98]

Juglans regia Leaves Zinc acetate 95–150 nm and spherical, flower

shaped

[99]

Cucurbita pepo Leaves Zinc acetate 8 nm [41]

Anchusa italic Flower Zinc acetate 8–14 nm and hexagonal shaped [100]

Abelmoschus esculentus okra crop Zinc acetate 29 nm and hexagonal wurtzite

shaped

[40]

Hyssops officinalis Whole plant Zinc acetate Pseudo spherical shaped [101]

Rehmanniae radix Root Zinc acetate 10–12 nm and hexagonal wurtzite

shaped

[102]

Catharanthus roseus Leaves Zinc acetate 50–90 nm and hexagonal wurtzite

shaped

[103]

Green tea Leaves Zinc acetate [104]

Bauhinia tomentosa Leaves Zinc sulphate 22–94 nm and hexagonal shaped [105]

Tecoma castanifolia Leaves Zinc sulphate 70–75 nm and spherical shaped [106]

Celosia argentea Leaves Zinc sulphate 25 nm and spherical shaped [107]

Trianthema portulacastrum Plant biomass Zinc sulphate 25–90 nm and spherical shaped [108]


123

composition of the nanoparticles are characterized using

X-Ray Diffraction Spectroscopy (XRD) and Energy Dis-

persive X-ray analysis (EDX) respectively [34]. The

functional groups on the nanoparticles surface are descri-

bed using Fourier transform infrared spectroscopy (FTIR)

technique. The size and dispersity of nanoparticles in the

liquid medium are determined using the Dynamic Light

Scattering (DLS) and Zeta potential techniques respec-

tively [47]. The various plant sources used in the synthesis

of ZnO NPs with its morphological characteristics are lis-

ted in Table 1.

Microbes Mediated Synthesis of ZnO NPs

The nanoparticle synthesis using microorganisms such as

bacteria, fungi remained unexplored by researchers. Green

synthesis of nanoparticles using microbes shows added

benefits than using plant sources because of the microbial

reproducibility. Nevertheless, it has lots of disadvantages

such as screening of microorganism, need of contamination

free environment for the entire process, lack of control on

nanoparticle size, and shape and high cost of nutrient

media for microbes [112]. The existence of various

enzymes, biomolecules and proteins in microorganisms are

recognized as capping agents in the formation of multiple

sized nanoparticles. Commonly, microbial cultures are

grown in culture medium and then to that metal precursor

were introduced in the form of soluble salts [113]. After the

reaction time of few hours, the synthesized nanoparticles

precipitate at the bottom with a visible color change [114].

Additionally, reaction parameters such as pH, temperature,

concentration of metal precursor and reaction time deter-

mine the size and yield of the synthesized nanoparticles.

The nanoparticles synthesized are characterized using UV–

VIS spectroscopy, SEM, XRD, FTIR to determine the

shape, size, functional group and surface charge [115].

Table 2 summarizes the microbial mediated ZnO NPs

synthesis.

Biomedical Applications

Antibacterial Activity of ZnO NPs

Bacterial diseases pose serious health threats among man-

kind. Increased antibiotic resistance against bacteria,

emergence of new strains intended the researchers to focus

on the metal and metal oxide nanoparticles as antibacterial

Table 1 (continued)


Aloe barbadensis Miller Leaves Zinc sulphate 8–18 nm and spherical, oval,

hexagonal shaped

[42]

Trifolium pretense Flower Zinc oxide 60–70 nm and Hexagonal shaped [109]

Tribulus terrestris Leaves Zinc oxide 6–10 nm and spherical shaped [44]

Lycopersicon esculentum Leaves Zinc oxide 10–50 nm and hexagonal wurtzite

shaped

[110]

Heritiera fomes, Sonneratia apetala Bark and leaves Zinc Chloride 20–50 nm [43]

Jacaranda mimosifolia Flower Zinc gluconate

hydrate

2–4 nm and spherical shaped [111]

Fig. 2 Schematic representation of green synthesis of zinc oxide

nanoparticles


123

agents. Due to the unique physiochemical properties and

increased surface area, ZnO NPs are extensively explored

as antibacterial agents. In addition, ZnO NPs are also found

to be safe and compatible with the human system

[128, 129].

Numerous literatures explain about the antibacterial

mechanism of ZnO nanoparticles, which includes (i) pro-

duction of reactive oxygen species (ROS) such as super-

oxide anions, hydrogen peroxides and hydroxyl radicals (ii)

triggering Zn2? release and (iii) the released Zn2? ions

interacts with the bacterial cell, especially the cell mem-

brane, cytoplasm and nucleic acid, and thus disintegrates

the cellular integrity which ultimately results in cell death

[130–132] which is illustrated in Fig. 3. The green syn-

thesized ZnO NPs are used as effective antibacterial agent

against both gram positive and gram negative bacteria such

as, Bacillus subtilis, Salmonella typhimurium, Staphylo-

coccus aureus, Streptococcus pyogenes, Mycobacterium

tuberculosis, Escherichia coli, Klebsiella pneumonia,

Mycobacterium luteus, Vibrio cholera, Aspergillus niger,

Aspergillus fumigatus, Fusarium culmorum, Fusarium

oxysporum, Pseudomonas aeruginosa, and Salmonella

paratyphi. Table 3 summarizes the antibacterial activity of

green synthesized ZnO NPs against various bacterial

pathogens. In addition with the antibacterial activity of

ZnO NPs, the ZnO nanocomposites are also proven for

their antibacterial activity. Bacterial cellose/ZnO

nanocomposites [133], chitin/chitosan-ZnO nanocompos-

ites [134, 135] and carboxymethyl chitosan-ZnO

nanocomposites [136, 137].

Antifungal Activity of ZnO NPs

In addition to antibacterial activity, ZnO NPs are also been

reported for their antifungal activities against many of the

harmful yeasts and fungi, due to which it is widely used as

antifungal additives in food industries. There is a very good

review article by Qi et al. on the antifungal activities of

ZnO NPs, its mechanism of action and a wide variety of

applications [140].

Rajiv et al. synthesized ZnO NPs using Parthenium

hysterophorus L and validated its antifungal activity.

Highest inhibition was observed against Aspergillus flavus

and Aspergillus niger at 25 lg/ml and also reported that the

activity is size-dependent [31]. Vijayakumar et al. also

synthesized ZnO NPs using Lycopersicon esculentum leaf-

extract and proved its antifungal activity against Candida

Table 2 Synthesis of ZnO NPs using microorganisms

Microorganism Description Precursor Size and shape References

Bacillus subtillis Bacteria Zinc acetate 10–15 nm [116]

Bacillus licheniformis Bacteria Zinc acetate 200 nm and nanoflower shaped [117]

Serratia ureilytica Bacteria Zinc acetate 170–250 nm and spherical, nanoflower shaped [113]

Staphylococcus aureus Bacteria Zinc acetate 10–50 nm and circular shaped [114]

Pseudomonas aeruginosa Bacteria Zinc nitrate 35–80 nm and spherical shaped [115]

Sphingobacterium thalpophilum Bacteria Zinc nitrate 37 nm and spherical shaped [118]

Rhodococcus pyridinivorans Bacteria Zinc sulphate 100–120 nm and spherical, hexagonal shaped [119]

Lactobacillus plantarum Bacteria Zinc sulphate 7–19 nm and spherical clusters shaped [120]

Lactobacillus sporogens Bacteria Zinc chloride 5–15 nm and tubule shaped [121]

Lactobacillus johnsonii Bacteria Zinc oxide 4–9 nm and irregular shaped [122]

Aeromonas hydrophila Bacteria Zinc oxide 57.72 nm and Spherical, oval shaped [123]

Candida albicans Fungus Zinc oxide 20 nm and quasi spherical shaped [124]

Aspergillus fumigatus Fungus Zinc nitrate 1.2–6.8 nm and oblate spherical, hexagonal shaped [125]

Alternaria alternate Fungus Zinc sulfate 75 ± 5 nm and Spherical, Triangular, Hexagonal shaped [126]

Aspergillus fumigatus Fungus Zinc sulfate 60–80 nm and spherical shaped [127]

Fig. 3 Schematic representation of antibacterial mechanism of zinc

oxide nanoparticles


123

Table 3 Antibacterial activity of green synthesized ZnO NPs

Plant source/

microorganism

Description Name of organism Antibacterial activity References

Cassia fistula Leaves Escherichia coli Antibacterial activity of ZnO NP

was 20 lg/mL

[36]

Pongamia pinnata Leaves Staphylococcus aureus, Escherichia coli [37]

Vitex trifolia Leaves Bacillus subtilis [58]

Phyllanthus niruri Leaves Staphylococcus saprophyticus. The Zone of inhibition of ZnO NP

was 2to 5 lm

[65]

Plectranthusamboinicus

Leaves Staphylococcus aureus Antibacterial activity of ZnO NP

was 8-10 lg/mL

[68]

Solanum nigrum Leaves Pseudomonas aeruginosa The Zone of inhibition of ZnO NP

was 2.7 to 4.9 lm

[69]

Vitex negunda Leaves Staphylococcus aureus, Staphylococcusparatyphi,

Escherichia coli

Antibacterial activity of ZnO NP

was 15-17 lg/mL

[71]

Costus pictus D. Don Leaves Staphylococcus aureus, Bacillus subtilis, Escherichiacoli, Salmonella paratyphi

The Zone of inhibition of ZnO NP

was 5 lm

[84]

Agro waste Solid

extract

Bacillus subtilis, Salmonella typhimurium [138]

Catharanthus roseus Leaves Staphylococcus aureus, Streptococcus pyogenes The Zone of inhibition of ZnO NP

was 2 to 7 lm

[103]

Trifolium pratense Flower

extract

Staphylococcus aureus, Pseudomonas aeruginosa,

Escherichia coliThe Zone of inhibition of ZnO NP

was 0.7 to 1.1 lm

[109]

Limonia acidissima Leaves Mycobacterium tuberculosis [52]

Ceropegiacandelabrum

Leaves Staphylococcus aureus,

Bacillus subtilis,

Escherichia coli,

Salmonella typhi


was 0.25 lg/mL

[90]

Celosia argentea Leaves Escherichia coli,

Salmonella, Acetobacter


was 3.1 lg/mL

[107]

Couroupitaguianensis

Leaves Bacillus cereus,

Klebsiella pneumonia,

Escherichia coli,

Mycobacterium luteus,

V. cholera


was 0.05-0.25 lg/mL

[95]

Parthenium

hysterophorus

Leaves Aspergillus flavus,

Aspergillus niger,

Aspergillus fumigatus,

Fusarium culmorum,

Fusarium oxysporum

[31]

Anisochilus carnosus Leaves Salmonella paratyphi,

Vibrio cholera,

Staphylococcus aureus, Escherichia coli

[60]

Jacarandamimosifolia

Flower Escherichia coli,

Enterococcus faecium

[111]

Green tea Leaves Staphylococcus aureus,

Escherichia coli


was 9.7 lg/mL

[104]

Caulerpa peltata,

Hypnea valencia,

Sargassummyriocystum

Leaves Staphylococcus aureus,

Streptococcus mutans,

Vibrio cholerae,

Neisseria gonorrhoeae,

Klebsiella pneumonia


was 0.10 lg/mL

[139]


123

albicans, a most prevalent fungal pathogen at concentra-

tions 100 lg/ml [110].

Suresh et al. synthesized ZnO NPs using Costus pictus

leaf extract which was also proven its antifungal activity

using disc diffusion method against two of the fungal

pathogen such as Aspergillus niger and Candida albicans

[84]. In a similar study by Irshad et al. where ZnO NPs

were synthesized using green tea leaves and was verified

for its biocidal activity against Aspergillus niger using well

diffusion method. Both the studies revealed that due to the

electrostatic attraction between the negatively charged cell

membrane and the positively charged NPs, the NPs get

attached with the cell membrane which ultimately results in

membrane disruption and cell death [104].

ZnO NPs synthesized by Jamdagni et al. using flower

extract of Nyctanthes arbor-tristis also showed an anti-

fungal activity against five of the fungal pathogens of

plants such as Alternaria alternata, Aspergillus niger,

Botrytis cinerea, Fusarium oxysporum and Penicillium

expansum. This study finds the lowest minimum inhibitory

concentration of 16 lg/ml against A. niger [96].

Jayaseelan et al., successfully synthesized ZnO NPs

using Aeromonas hydrophila microoraganism and evalu-

ated its activity against various fungal pathogens such as

Aspergillus flavus, Aspergillus niger, Candida albicans.

The antifungal activity of the Aeromonas hydrophila ZnO

NPs was performed using well diffusion method and it

shows minimum inhibition zone around 19 ± 1.0 mm

[123].

Anticancer Activity of ZnO NPs

Zinc is an essential mineral which maintains homeostasis

by regulating enzyme activities [141], whereas, its defi-

ciency initiates and promotes the formations of cancerous

cells. Zinc plays an important role in maintaining the

activity of p53, a tumor suppressor gene, which regulates

apoptosis by activating caspase-6 enzyme [142]. ZnO NPs

also possess a unique electrostatic characteristic which

helps in selective targeting of cancer cells. Cancer cells

contain anionic phospholipids in large concentration on

their surface which results in electrostatic attraction with

ZnO NPs. This promotes cellular uptake of ZnO NPs by the

cancer cells and finally leads to cytotoxicity [143],

whereas, the small size of ZnO NPs enhances the perme-

ation and retention of NPs inside the tumorous cells and

thus helps to act upon it [144]. The mechanism behind the

selective cytotoxicity of ZnO NPs towards cancer cells is

the intracellular release of dissolved zinc ions, followed by

ROS induction [145]. ZnO NP generates large amount of

ROS in cancer cells compared to the ROS in normal cells,

which results in generation of large amounts of oxidative

Table 3 (continued)

Plant source/

microorganism

Description Name of organism Antibacterial activity References

Serratia ureilytica Bacteria Escherichia coli,

Staphylococcus aureus

[113]

Staphylococcusaureus

Bacteria Escherichia coli,

Staphylococcus aureus,

Staphylococcus epidermidis,

Listeria monocytogenes,

Klebsiella pneumonia,

Enterococcus faecalis,

Pseudomonas aeruginosa,

Methicillin-resistant Staphylococcus aureus (MRSA)


was 10 lg/mL

[114]

Sphingobacteriumthalpophilum

Bacteria Pseudomonas aeruginosa,

Enterobacter aerogens

The Zone of inhibition of ZnO NP

was 14.3 mm, 11.1 mm

[118]

Aeromonashydrophila

Bacteria Aeromonas hydrophila,

Pseudomonas aeruginosa,

Escherichia coli,

Staphylococcus aureus,

Enterococcus faecalis,

Streptococcus pyogenes


was 1.2 lg/mL

[123]


123

stress in cancer cells. This leads to death of cancer cells

[146].

The anticancer activity of ZnO NPs prepared by green

synthesis method has been validated against a variety of

cell lines, such as Human Colon Adenocarcinoma (Caco-

2), Human Lung Adenocarcinoma (A549), Pancreatic

adenocarcinoma (PANC-1), Ovarian adenocarcinoma

(CaOV-3), Colonic adenocarcinoma (COLO205), Acute

promyelocytic leukemia (HL-60) cells, Breast adenocarci-

noma cell line(MDA-MB231) and are elaborated in

Table 4.

Anti-Inflammatory Activity of ZnO NPs

In the last few years, nanoparticles are broadly used as an

anti-inflammatory agent. The large surface area to volume

ratio converses the increased reactive properties of

nanoparticles, leading to the greater interaction with the

cell membrane and facilitating the transport inside the

membrane [153]. Because of ZnO NPs nanosize, Zn can be

effortlessly transferred through the cell membrane. The

earlier research article proposes the anti-inflammatory

activity of ZnO NP [154, 155]. ZnO NPs exert their anti-

inflammatory activity through various mechanisms namely,

inhibition of proinflammatory cytokines release [156],

inhibition of inducible nitric oxide synthase (iNOS)

enzyme expression [157], myeloperoxidase inhibition

[158], inhibition of the NF-jb pathway and inhibition of

mast cell degranulation [139]. The anti-inflammatory

activities of green synthesized ZnO NPs are summarized in

Table 5.

Wound Healing Activity of ZnO NPs

Skin is the largest organ of our body which protects us

from external invasion. Any damage happens to skin

results in wound. The wound will heal automatically, but

healing takes time. Often, wound healing may delay due to

microbial infection. Staphylococcus aureus and Pseu-

domonas aeruginosa are few such microorganisms which

cause severe wound infections. NPs are known for their

antibacterial activity and metal oxides NPs generate

hydrogen peroxide which can cause cell damage. Hence,

metal oxide NPs can be used to kill these pathogenic

organisms and thus can enhance the process of wound

healing. Several literatures evidenced the use of ZnO NPs

as successful wound healing agent [160–163]. However,

we summarize this wound healing property of ZnO NPs

prepared by green synthesis.

Khatami et al. prepared a cotton wound bandages by

impregnating them with ZnO NPs synthesized biologically

using coffee ground and experimented its antimicrobial

activities. Based on their minimum inhibitory

concentration (MIC), this study report the use of ZnO NPs

impregnated antibacterial bandages for treating wounds

and to cover infection sensitive wounds in diabetic patients

and wounds caused by burns [164].

Shao et al. synthesized ZnO NPs using Barleria gibsoni

leaf extract which exhibited excellent antibacterial activity

against pathogenic bacteria. In addition, they also devel-

oped a gel using this ZnO NPs which showed remarkable

wound healing property in rat and thus proved to be an

efficient topical antimicrobial formulation and wound

healing agent for general wounds and wounds due to burn

[165].

Ezealisiji et al. prepared ZnO NPs using Solanum tor-

vum (L) leaf extract, and made a ZnO nanoparticles–hy-

drogel composite and validated its toxicological profiles

using rats. This study predicted that there is a significant

increase in plasma concentration of zinc in dose and time

dependent manner. Due to this, there may be chances of

renal and hepatic failure upon its use for a prolonged

period. Hence, this study suggested the need to predict the

optimum dose of ZnO NPs which can be used as a wound

healing agent and also necessary to find the optimum time

it can be used in human [80].

ZnO NPs in Drug Delivery

The smaller particle size and the larger surface area of the

NPs facilitate its penetration via cell membrane and thus

get be absorbed into the cells, which leads to well distri-

bution. Hence, NPs are widely been used in drug delivery

where the drugs are loaded with NPs and thus are made to

reach their targets in sufficient quantity. In addition, when

the biodegradable materials are used for synthesizing NPs,

this prolongs the delivery of drugs in the target site [166].

By properly engineering the NPs, one can make the NPs

targeting specific cells. This property is applied to target

the cancerous cells and bacterial cells [107, 167].

Vaishnav et al. have synthesized ZnO NPs by green

synthesis method using the leaves of Celosia argentea and

have validated its drug delivery capacity using the drug

metronidazole benzoate. The results revealed that ZnO NPs

enhances the drug delivery of metronidazole [168]. Yuan

et al. synthesized a chitosan encapsulated ZnO NPs loaded

with doxorubicin and studied the effect of ZnO NPs in drug

delivery. The study showed that ZnO NPs helped in

releasing the drug at rapid rate initially which then grad-

ually become controlled release at the later period [169].


123

Table 4 Anticancer activity of green synthesized ZnO NPs by MTT assay

Plant source/

microorganism

Description Cell lines tested Activity values Results Reference

Deverra tortuosa Aerial

parts

Human Colon

Adenocarcinoma

‘‘Caco-2’’

1. IC50 value: 50.81 lg/mL Remarkable selective

cytotoxicity was shown

[147]

Human Lung

Adenocarcinoma

‘‘A549’’

83.47 lg/mL

2. Activity were compared

with human lung

fibroblast cell line (WI38)

434.6 lg/mL

Sargassummuticum Seaweed Pancreatic

adenocarcinoma

(PANC-1)

IC50 value 10.8 ± 0.3 lg/

mL

1.Nano composite is most

toxic to HL-60 cells.

2.HA/ZnO nanocomposite

treatment for 72 h did not

cause toxicity to the

normal human lung

fibroblast (MRC-5) cell

line

[148]

Ovarian adenocarcinoma

(CaOV-3)

15.4 ± 1.2 lg/mL

Colonic adenocarcinoma

(COLO205)

12.1 ± 0.9 lg/mL

Acute

promyelocyticleukemia

cells (HL-60)

6.25 ± 0.5 lg/mL

Hyssops officinalis Whole

plant

Breast adenocarcinoma

cell line(MDA-MB231)

Incubated with different

concentrations of ZnO

NPs& evaluated at time of

24 h, 48 h and 72 h

Showed inhibitory effects

on the growth of Breast

cancer cells.

[101]

Rehmanniae radix Root Osteosarcoma cancer cell

line(MG-63)

Cells were cultured for 24 h

under different

concentrations (5 lg/ml,

10 lg/ml, 20 lg/ml,

30 lg/ml, 40 lg/ml,

50 lg/ml, 60 lg/ml,

70 lg/ml and 80 lg/ml)

1. With the increase in

concentration of NPs, the

survival of cancer cell was

decreased. 2. Study

displayed that ZnO NPs

was more effective in

minimizing the cancer

cell growth and survival

rate of MG-63 cells

[102]

Laurusnobilis Leaves Lung cancer cells (A549) 1.Evaluated at different

concentrations (10 mg/

mL, 20 mg/mL, 40 mg/

mL and 80 mg/mL) 2.

The toxicity of ZnO NPs

was also evaluated on

normal murine

macrophage RAW264.7

cells

1. NPs were found to be

non-toxic to normal

murine macrophage

RAW264.7 cells. 2. At

higher concentrations of

80lgmL-1, NPs were

found to be effective in

inhibiting the viability of

human A549 lung cancer

cells.

[149]

Cucumis melo inodorus Rough

shell

Murine breast cancer cell

lines(TUBO)

IC50 values (lg/mL)

At 24 h:20 At 48 h:18 At

72 h :16

Activity depends on both

time duration of treatment

and dose. Longer

treatment with higher

doses exhibited the

reduced cancer cell lines

viability.

[150]

Human breast cancer cell

lines (MCF7)

IC50 values (lg/mL)

At 24 h:40 At 48 h:33 At

72 h:31

Ecliptaprostrata Leaves Human Liver Carcinoma

Cell line(Hep-G2)

Samples evaluated in

different concentrations of

1 lg/mL, 10 lg/mL,

100 lg/mL, 250 lg/mL,

and 500 lg/mL, which

showed the cell necrosis

of 14.5%, 51.5%, 67%,

84%, and 86.5%, for ZnO

NPs, respectively

Dose dependent cytopathic

effects was observed.

Significant cytotoxic

effects was observed at

100 mg/mL

concentration.

[151]


123

Table 4 (continued)

Plant source/

microorganism

Description Cell lines tested Activity values Results Reference

Ziziphusnummularia Leaves HeLa cancer cell line Evaluated at different

concentrations from 2 to

200 lg/ml

NPs showed dose-

dependent cytotoxic effect

pronounce cytotoxic

activity against HeLa

cancer cell lines.

[152]

Rhodococcuspyridinivorans Bacteria Colon cancer cell

(HT-29 cell line)

1.ZnO NPs loaded with

Anthraquinone were

prepared 2.Compared

with normal peripheral

blood mononuclear cells

(PBMCs).

Observed Concentration

dependent cytotoxicity of

anthraquinone loaded

ZnO NPs against

cancerous cells.

[119]

Table 5 Anti-Inflammatory activity of green ZnO NPs

Plant Source Description Model/Activity Result Reference

Hyssops officinalis Whole plant In-Vivo: carrageenan induced mouse model

of paw edema

Effects of ZnO-NPs on reduction of

inflammation were evaluated at defined

intervals of 1 h, 3 h & 6 h. NPs

significantly reduced the thickness of the

mouse paw edema

[101]

In vitro section: changes in the expression of

inflammatory genes (IL-1B and IL-10) were

investigated by real-time quantitative

polymerase chain reaction technique

Expression patterns of IL-10 and IL-1B genes

were evaluated which indicate that the

ZnO-NPs are capable of decreasing the IL-

10 and increasing the IL-1B gene-

expression levels. These changes show the

anti-inflammatory properties of the ZnO-

NPs

Andrographispaniculata

Leaves Model:Bovine serum albumin IC50(lg/ml):

1.ZnO NPs:66.78 2.AP leaf extract:75.42

3.ZnNO3:91.33

The anti-inflammatory activity of the

biosynthesized nanoparticles to inhibit

protein denaturation was studied through

in vitro assay.

Studies results proved that the synthesized

ZnO NPs can be used to reduce the

inflammations.

[38]

Heritierafomes,Sonneratiaapetala

Bark and

leaves

Bovine serum albumin Maximum inhibition

activity of 63.29 lg/ml IC50 value was

observed from the SA-ZnO NPs followed

by HF-ZnO NPs (72.35 lg/ml IC50 value).

The anti-inflammatory activity of the

biosynthesized nanoparticles, to inhibit

protein denaturation was studied through

in vitro assay ZnO NPs had a higher

potential for anti-inflammatory activity

(79%) as compared to silver nanoparticles

(69.1%)

[43]

Polygala tenuifolia Root LPS-stimulated RAW 264.7 macrophages ZnO NPs exhibited excellent anti-

inflammatory activity by dose-dependently

suppressing both mRNA and protein

expressions of iNOS, COX-2, IL-1b, IL-6

and TNF-a.

[72]

Oleaeuropeae Leaves In vivo: white albino rats Effect of ZnO-NPs on reduction of

inflammation were evaluated at defined

intervals of 30 min, 1 h, 2 h, 3 h & 24 h.

NPs significantly reduced the thickness of the

mouse paw edema after 1st and 2nd hr after

formalin injection

[159]


123

Conclusion

Nanoparticles have diverse properties in comparison with

the bulk material due to its small size and also it proposes

various new innovations in biomedical, biosensor, cosmetic

and food industry. The production of metallic nanoparticles

by green synthesis method is environmental friendly, in-

expensive, non-toxic and can be easily scaled up. Green

sources acts as both capping and reducing agent to produce

nanoparticles of controlled shape and size. In biomedical

field, nanoparticles are used as antimicrobial, anticancer

and anti-inflammatory agents and various other fields are

also emerging. ZnO NPs are one of the important nano-

materials used extensively in biomedical field. Whole-

somely, this review focuses on the green production of

ZnO NPs and its emerging application in the biomedical

fields such as antibacterial, antifungal, anticancer, anti-in-

flammatory, wound healing and drug delivery are

addressed.

Acknowledgement The authors acknowledge the financial support

from Vinayaka Mission’s Research Foundation (Deemed to be

University), Salem (Research Grant No: VMRF/SeedMoney/2020/

VMKVEC-Salem/6).

Author’s Contributions SS reviewed the literature, wrote sections

on introduction, plant mediated and microbial mediated synthesis of

ZnO NPs. MS reviewed the literature and wrote sections on

antibacterial activity of ZnO NPs. PDU reviewed the literature and

wrote sections on anti-inflammatory and anticancer activities of ZnO

NPs. AV reviewed the literature and wrote sections on wound healing

activity of ZnO NPs. AS reviewed the literature and wrote sections on

antifungal activity of ZnO NPs. SS and AS conceived the manuscript.

All the authors read and approved the manuscript.

Funding The authors acknowledge the financial support from

Vinayaka Mission’s Research Foundation (Deemed to be University),

Salem (Research Grant No: VMRF/SeedMoney/2020/VMKVEC-

Salem/6).

Availability of Data and Materials Not applicable.

Compliance with Ethical Standards

Ethics Approval Not applicable.

Consent to Participate Not applicable.

Conflicts of Interest The authors declare that they have no conflict of

interest.

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