Biological syntesis of nanoparticles from plants and microorganisms.pdf

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Review

Biological Synthesis of Nanoparticles from Plants andMicroorganismsPriyanka Singh,1 Y u-Jin Kim,1,2,* Dabing Zhang,2 and

Deok-Chun Yang1,*

Nanotechnology has become one of the most promising technologies applied in

all areas of science. Metal nanoparticles produced by nanotechnology have

received global attention due to their extensive applications in the biomedicaland physiochemical elds. Recently, synthesizing metal nanoparticles using

microorganisms and plants has been extensively studied and has been recog-

nized as a green and ef cient way for further exploiting microorganisms as

convenient nanofactories. Here, we explore and detail the potential uses of

various biological sources for nanoparticle synthesis and the application of

those nanoparticles. Furthermore, we highlight recent milestones achieved for

the biogenic synthesis of nanoparticles by controlling critical parameters,

including the choice of biological source, incubation period, pH, and

temperature.

Nanoparticles and their Applications

Nanotechnology (see Glossary ) has become one of the most important technologies in all

areas of science. It relies on the synthesis and modulation of nanoparticles, which requires

signicant modications of the properties of metals [1]. Nanomaterials have in fact been used

unknowingly for thousands of years; for example, gold nanoparticles that were used to stain

drinking glasses also cured certain diseases. Scientists have been progressively able to observe

the shape- and size-dependent physiochemical properties of nanoparticles by using advanced

techniques. Recently, the diverse applications of metal nanoparticles have been explored in

biomedical, agricultural, environmental, and physiochemical areas (Figure 1 ) [1–5]. For instance,

gold nanoparticles have been applied for the specic delivery of drugs, such as paclitaxel,

methotrexate, and doxorubicin [2]. Gold nanoparticles have been also used for tumor detection,

angiogenesis, genetic disease and genetic disorder diagnosis, photoimaging, and photother-

mal therapy. Iron oxide nanoparticles have been applied forcancer therapy, hyperthermia, drug

delivery, tissue repair, cell labeling, targeting and immunoassays, detoxication of biologicaluids, magnetic resonance imaging, and magnetically responsive drug delivery therapy [6–

8]. Silver nanoparticles have been used for many antimicrobial purposes, as well as in anticancer,

anti-inammatory, and wound treatment applications [9]. Due to their biocompatible, nontoxic,

self-cleansing, skin-compatible, antimicrobial, and dermatological behaviors, zinc and titanium

nanoparticles have been used in biomedical, cosmetic, ultraviolet (UV)-blocking agents, and

various cutting-edge processing applications [10,11]. Copper and palladium nanoparticles have

been applied in batteries, polymers, plastics plasmonic wave guides, and optical limiting devices

[12,13]. Moreover, they were found to be antimicrobial in nature against many pathogenic

microorganisms. Additionally, metal nanoparticles have been used in the spatial analysis of

various biomolecules, including several metabolites, peptides, nucleic acids, lipids, fatty acids,

Trends

The biological synthesis of nanoparti-

cles is increasingly regarded as a rapid,ecofriendly, and easily scaled-up

technology.

Metal nanoparticles produced using

microorganisms and plant extracts

are stable and can be monodispersed

by controlling synthetic parameters,

such as pH, temperature, incubation

period, and mixing ratio.

Recently, biological nanoparticles were

found to be more pharmacologically

active than physicochemically synthe-

sized nanoparticles.

Among the various biological nanopar-

ticles, those produced by medicinal

plants have been found to be the most

pharmacologically active, possibly due

to the attachment of several pharma-

cologically active residues.

1Department of Oriental Medicine

Biotechnology, College of Life

Science, Kyung Hee University,

Yongin 446-701, Korea2

Joint International ResearchLaboratory of Metabolic &

Developmental Sciences, Shanghai

Jiao Tong University–University of

Adelaide Joint Centre for Agriculture

and Health, State Key Laboratory of

Hybrid Rice, School of Life Sciences

and Biotechnology, Shanghai Jiao

Tong University, Shanghai, China

*Correspondence: [email protected]

(Y.-J. Kim) and [email protected]

(D.-C. Yang).

TIBTEC 1353 No. of Pages 12

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glycosphingolipids, and drug molecules, to visualize these molecules with higher sensitivity and

spatial resolution [14].

In addition, the unique properties of nanoparticles make them well suited for designing electro-chemical sensors and biosensors [15]. For example, nanosensors have been developed for the

detection of algal toxins, mycobacteria, and mercury present in drinking water [16]. Researchers

also developed nanosensors by utilizing nanomaterials for hormonal regulation and for detecting

crop pests, viruses, soil nutrient levels, and stress factors. For instance, nanosensors for sensing

auxin and oxygen distribution have been developed [17].

To date, due to the physiochemical properties and many applications of nanoparticles, the

scientic community has dedicated extensive efforts to develop suitable synthetic techniques for

producing nanoparticles. However, various physiochemical approaches for the synthesis of

metal nanoparticles are limited by the environmental pollution caused by heavy metals. Thus,

synthesizing nanoparticles by biological means, which has the advantages of nontoxicity,

reproducibility in production, easy scaling-up, and well-dened morphology, has become a

new trend in nanoparticle production. In particular, microorganisms and plants have beendemonstrated as new resources with considerable potential for synthesizing nanoparticles.

To date, several microorganisms, including bacteria, fungi, and yeast, as well as plants, have

been explored for the synthesis of metal nanoparticles. While the synthesis of nanoparticles has

been extensively reviewed elsewhere [5,18–20], here we provide an update on recent advances

in the synthesis of biological nanoparticles, and describe prospects for their future develop-

ment and applications.

Nanoparticle Synthesis Using Microorganisms

Microorganisms have been shown to be important nanofactories that hold immense potential as

ecofriendly and cost-effective tools, avoiding toxic, harsh chemicals and the high energy

demand required for physiochemical synthesis. Microorganisms have the ability to accumulate

and detoxify heavy metals due to various reductase enzymes, which are able to reduce metal

salts to metal nanoparticles with a narrow size distribution and, therefore, less polydispersity.

The mechanism and experimental methods of synthesizing nanoparticles in microorganisms is

described in Box 1. Over the past few years, microorganisms, including bacteria (such as

actinomycetes), fungi, and yeasts, have been studied extra- and intracellularly for the synthesis

of metal nanoparticles ( Table 1 ). An array of biological protocols for nanoparticle synthesis has

been reported using bacterial biomass, supernatant, and derived components. Among the

various methodologies, extracellular synthesis has received much attention because it eliminates

the downstream processing steps required for the recovery of nanoparticles in intracellular

methodologies, including sonication to break down the cell wall, several centrifugation and

washing steps required for nanoparticle purication, and others. Moreover, metal-resistant

genes, proteins, peptides, enzymes, reducing cofactors, and organic materials have signicant

roles by acting as reducing agents. Furthermore, these help in providing natural capping to

synthesize nanoparticles, thereby preventing the aggregation of nanoparticles and helping themto remain stable for a long time, thus providing additional stability.

In recent research, bacteria, including Pseudomonas deceptionensis [21], Weissella oryzae [22],

Bacillus methylotrophicus [23], Brevibacterium frigoritolerans [24], and Bhargavaea indica

[25,26], have been explored for silver and gold nanoparticle synthesis. Similar potential for

producing nanoparticles has been showedby using several Bacillus and other species, including

Bacillus licheniformis, Bacillus amyloliquefaciens, Rhodobacter sphaeroides [27–29], Listeria

monocytogenes, Bacillus subtilis, and Streptomyces anulatus [29,30]. Various genera of micro-

organisms have been reported for metal nanoparticle synthesis, including Bacillus, Pseudomo-

nas, Klebsiella, Escherichia, Enterobacter, Aeromonas, Corynebacterium, Lactobacillus,

Glossary

Biocompatibility: the compatibility

and noninjurious effects of metal

nanoparticles within the human body

or healthy living cells.

Biological nanofactories: biological

sources capable of synthesizing

metal nanoparticles, including

microorganisms and plants.

Biological nanoparticles:

nanoparticles obtaintend form

biological sources, such as

micoroganisms and plant extracts.

Biological synthesis: synthesis

using natural sources, avoiding any

toxic chemicals and hazardous by-

products, usually with lower energy

consumption.

Magnetically responsive drug

delivery: delivery of heavy drugs by

magnetic nanoparticles under the

inuence of an external magnetic

eld.

Mycosynthesis: biological synthesis

of metal nanoparticles from fungi.

Nanoparticles: small particles with

all three dimensions measuring


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Pseudomonas, Weissella, Rhodobacter, Rhodococcus, Brevibacterium, Streptomyces, Tricho-

derma, Desulfovibrio, Sargassum, Shewanella, Plectonemaboryanum, Rhodopseudomonas,

Pyrobaculum, and others[

[31]. These investigations suggest that the main mechanism of the

synthesis of nanoparticles using bacteria depends on enzymes [32]; for instance, the nitrate

reductase enzyme was found to be responsible for silver nanoparticle synthesis in B.

licheniformis.

Rather than using bacteria, mycosynthesis is a straightforward approach for achieving stable

and easy biological nanoparticle synthesis. Most fungi containing important metabolites with

higher bioaccumulation ability and simple downstream processing are easy to culture for the

ef cient, low-cost, production of nanoparticles [33]. Moreover, compared with bacteria, fungi

have higher tolerances to, and uptake competences for, metals, particularly in terms of the high

wall-binding capability of metal salts with fungal biomass for the high-yield production of

nanoparticles [33,34]. Three possible mechanisms have been proposed to explain the mycosyn-

thesis of metal nanoparticles: nitrate reductase action; electron shuttle quinones; or both [33].

Fungal enzymes, such as the reductase enzymes from Penicillium species and Fusarium

Acnomycetes

Microorganisms

Stem

Root

Fruit

Leaves

Peel

Applicaons under clinical trial

Most applicable area

Second most-applicable area

Flower

Plant ssues

Proteins,

amino acids,

vitamins,polysaccharides,

polyphenols,

terpenoids,

organic acid

Metal salts

Metal nanoparcles (NPs)

Magnecally

responsive

drug delivery

Photoimaging

NPs External

magnec field

Externalmagnec field

Gene

deliveryCell

labelling

Nanosensors detect

biomolecules,environmental factorsBrain

Skin

Lung

Colorectal

Prostate

Bladder

Breast

Various types of

human cancer

Cosmecs

and

medical

appliances

Applicaons

F u n g a l

c e l l

N I R

D e t e c t o r

Detector

C e l l s

N P sAnmicrobial,

anpathogen,

mosquitocidal uses

Tumor

cellNPs

Photothermal

therapy

Biological synthesis

of nanoparcles

Fungi

Enzymes

(e.g., nitrate reductase)

Enzymes

(e.g., naphthoquinones/

Anthraquinones)

Bacteria

Y e a s

t

Figure 1. Biological Synthesis and Applications of Metal Nanoparticles in Biomedical and Environmental Fields. Silvernanoparticles aremostlyused in the

medical eld due to their antimicrobial effect, and zinc and titanium nanoparticles are used in cosmetics. Silver, zinc, and other metal nanoparticles are also used in food

packaging, wound dressings, catheters for drug delivery, and so on, due to the broad range of antimicrobial effects. The second application area of biological

nanoparticles is the development of sensors for various biomolecules related to environmental factors and agriculture. Furthermore, nanoparticles are also used in gene

delivery and cell labeling in plants and in medicine. Some applications of metal nanoparticles are still in development, such as photoimaging, photothermal therapy, and

magnetically responsive drug delivery. The mechanisms of the antibacterial and anticancer activities are shown in Figure S1 in the supplemental information online.

Trends in Biotechnology, Month Year, Vol. xx, No. yy 3


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oxysporum, nitrate reductase, and /-NADPH-dependent reductases, were found to have a

signicant role in nanoparticle synthesis [35], similarly to the mechanism found in bacteria.

The synthesis of nanoparticles using actinomycetes has not been well explored, even though

actinomycetes-mediated nanoparticles have good monodispersity and stability and signicant

biocidal activities against various pathogens [36]. The synthesis of silver, copper, and zinc

nanoparticles using Streptomyces sp. has demonstrated that the reductase enzyme from

Streptomyces sp. has a vital role in the reduction of metal salts [37]. Similar to other micro-

organisms, yeasts have also been widely investigated for the extracellular synthesis of the

nanoparticles on a large scale, with straightforward downstream processing [38–41]. Further-

more, virus-mediated synthesis of nanoparticles is also possible. Viruses can be used to

synthesize nanowires with functional components that are assembled for various applications,

such as battery electrodes, photovoltaic devices, and supercapacitors [42]. However, most

microorganism-based syntheses for nanoparticles are slow with low productivity, and therecovery of nanoparticles requires downstream processing. Furthermore, problems related

to microorganism-based synthesis for nanoparticles also include the complex steps, such

as microbial sampling, isolation, culturing, and maintenance.

Nanoparticle Synthesis Using Plants

Recently, phytonanotechnology has provided new avenues for the synthesis of nanoparticles

and is an ecofriendly, simple, rapid, stable, and cost-effective method. Phytonanotechnology

has advantages, including biocompatibility, scalability, and the medical applicability of synthe-

sizing nanoparticles using the universal solvent, water, as a reducing medium [43]. Thus, plant-

derived nanoparticles produced by readily available plant materials and the nontoxic nature of

Box 1. Experimental and Mechanistic Steps for Producing Nanoparticles from Microorganisms and

Plants

Microorganisms are able to synthesize nanoparticles extracellularly or intracellularly. In extracellular synthesis, after

culturing the microorganisms for 1–2 days in a rotating shaker under optimum conditions (including pH, temperature,

medium components, etc.), the culture is centrifuged to remove the biomass. The obtained supernatant is used tosynthesizenanoparticles by adding a lter-sterilized metalsalt solution and is incubated again. The nanoparticle synthesis

canbe monitored by observinga changein thecolor of theculture medium; forinstance, forsilver nanoparticles, thecolor

changes to deep brown, whereas, for gold nanoparticles, it changes from ruby red to a deep purple color. After

incubation, the reaction mixture can be centrifuged at different speeds to remove any medium components or large

particles. Finally, the nanoparticles can be centrifuged at high speed or with a density gradient, washed thoroughly in

water/solvent (ethanol/methanol) and collected in the form of a bottom pellet.

In the intracellular synthesis of nanoparticles, after culturing the microorganism for a certain optimum growth period,

biomass is collected by centrifugation and washed thoroughly with sterile water, then dissolved in sterile water with a

lter-sterilized solution of metal salt. Similar to extracellular synthesis, the reaction mixture is monitored by visual

inspection for a color change. After the incubation period, the biomass is removed by repeated cycles of ultrasonication,

washing, and centrifugation. These steps help to break down the cell wall and enable the nanoparticles to be released.

The mixture is then centrifuged, washed, and collected.

For the synthesis of nanoparticles by plant extracts, the plant parts (root, leaf, bark, etc.) are washed thoroughly with

distilled water and then cut into small pieces and boiled to perform the extraction. Next, the extract can be puri ed by

ltration andcentrifugation.Different ratiosof plant extract, metal salt solution,and water (depending on theplantspecies

and parts) are used for nanoparticle synthesis. This reaction mixture is incubated further to reduce the metal salt and

monitored for a change in color. After synthesis, the nanoparticles are collected by similar methodologies as in

microorganism-mediated synthesis.

Inall ofthe synthesismethodologies, good monodispersity (i.e., a narrowsize distribution)can beachieved. bycontrolling

the relevant critical parameters (Figure 2, main text).

The mechanism underlying this biological synthesis is not yet fully elucidated, but is enzyme dependent for micro-

organisms. For plants, it depends on the species and different phytochemical components. The exact mechanism and

components should be resolved in the near future.

4 Trends in Biotechnology, Month Year, Vol. xx, No. yy


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plants are suitable for fullling the high demand for nanoparticles with applications in the

biomedical and environmental areas. Recently, successfully synthesized gold and silver nano-

particles using the leaf and root extract from the medicinal herbal plant Panax ginseng [44–46]

suggested the use of medicial plants as resources. Additionally, various plant parts, including

leaves, fruits, stems, roots, and their extracts, have been used for the synthesis of metal

nanoparticles ( Table 2 ) [47–61]. The exact mechanism and the components responsible for

plant-mediated synthetic nanoparticles remain to be elucidated. It has been proposed that

proteins, amino acids, organic acid, vitamins, as well as secondary metabolites, such as

avonoids, alkaloids, polyphenols, terpenoids, heterocyclic compounds, and polysaccharides,

Table 1. Synthesis and Applications of Biological Nanoparticles from Microorganisms

Microorganism Extracellular/

Intracellular

Types of

Nanoparticle

Shapes Size (nm) Applications Refs

Bacteria

Pseudomonas

deceptionensis

Extracellular Silver Spherical 10–30 Antimicrobial

and antibiolm

[21]

Weissella oryzae Intracellular Silver Spherical 10–30 Antimicrobial

and antibiolm

[22]

Bacillus

methylotrophicus

Extracellular Silver Spherical 10–30 Antimicrobial [23]

Brevibacterium

frigoritolerans

Extracellular Silver Spherical 10–30 Antimicrobial [24]

Bhargavaea indica Extracellular Silver and

gold

Silver anisotropic;

gold, ower

30–100 Anti microbial [25,26]

Bacillus

amyloliquefaciens

Extracellular Cadmium

sulde

Cubic/hexagonal 3–4 – [27]

Bacillus pumilus,

Bacillus persicus,

and Bacillus

licheniformis

E xtra ce llular Si lv er T riang ular,

hexagonal,

and spherical

77–92 Antiviral and

Antibacterial

[29]

Listeria

monocytogenes,

Bacillus subtilis,

and Streptomyces

anulatus

– Silver Anisotropic Varied

shape

and sizes

Antimicrobial and

mosquitocidal

[30]

Fungus

Neurospora crassa Intra- and

extracellular

Silver, gold,

bimetallic

silver and

gold

Quasi-spherical >100 – [34]

Actinomycetes

Streptomyces

sp. LK3

– Silver Spherical 5 Acaricidal [37]

Yeast

Yarrowia lipolytica

NCYC 789

Extracellular Silver Spherical 15 Antibiolm [38]

Rhodosporidium

diobovatum

Intracellular Lead – 2–5 – [39]

Extremophilic

yeast

Extracellular Silver and

gold

Irregular Silver, 20;

gold,30–100

– [40]

Candida utilis

NCIM 3469

Extracellular Silver Spherical 20–80 Antibacterial [41]



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have signicant roles in metal salt reduction and, furthermore, act as capping and stabilizing

agents for synthesized nanoparticles [62]. For instance, El-Kassas et al. showed that the

hydroxyl functional group from polyphenols and the carbonyl group from proteins of Corallina

of cinalis extract could assist in forming and stabilizing gold nanoparticles [63]. Philip et al.

showed the synthesis and stabilization of silver and gold nanoparticles by biomolecule attach-

ment in Murraya koenigii leaf extract [64]. Reports also suggest that different mechanisms for

synthesizing nanoparticles exist in different plant species [18]. For instance, specic

Table 2. Synthesis and Applications of Biological Nanoparticles from Plants

Plants Plant Tissues

for Extraction

Types of

Nanoparticle

Shapes Size (nm) Applications Refs

Euphorbia prostrata Leaves Silver and

titanium

dioxide (TiO2 )

Spher ical Si lver

10–15;

TiO2,

81.7–84.7

Leishmanicidal [11]

Sargassum algae Alga Palladium Octahedral 5 –1 0 Elec troc atalyt ic

activities towards

hydrogen peroxide

[12]

Ginkgo biloba Leaves Copper Spherical 15–20 Catalytic [13]

Panax ginseng Root Silver and

gold

Spher ical Si lver ,

10–30;

gold,

10–40

Antibacterial [44]

Red ginseng Root Silver Spherical 10–3 0 A nt ib ac te rial [46]

Cymbopogon citratus Leaves Gold Spherical,triangular,

hexagonal

and rod

20–

5 0 M os quitoc id al [47]

Azadirachta indica Leaves Silver – 41–6 0 B io la rv ic id al [48]

Nigella sativa Leaves Silver Spherical 15 Cytotoxicity [49]

Cocos nucifera Leaves Lead Spherical 47 Antibacterial and

photocatalytic

[50]

Catharanthus roseus Leaves Palladium Spherical 40 Catalytic activity in

dye degradation

[51]

Pistacia atlantica Seeds Silver Spherical 27 Antibacterial [52]

Banana Peel Cadmium

sulde

– 1.48 – [53]

Nyctanthes arbortristis Flower Silver – – Antibacterial

and cytotoxic

[54]

Anogeissus latifolia Gum powder Silver Spherical 5.5–5.9 Antibacterial [55]

Abutilon indicum Leaves Silver Spherical 5–25 Ant ibacterial [56]

Pinus densi ora Cones Silver Oval in shape,

few triangular

shaped

30–8 0 A nt im icrobial [57]

Artocarpus gomezianus Fruit Zinc Spherical > 20 Luminescence,

photocatalytic

and antioxidant

[58]

Citrus medica Fruit Copper – 20 Antimicrobial [59]

Orange and pineapple Fruits Silver Spherical 10–300 – [60]

Lawsonia inermis Leaves Iron Hexagonal 21 Antibacterial [61]

Gardenia jasminoides Leaves Iron Rock like

appearance

32 Antibacterial [61]



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components, such as emodin, a purgative resin with quinone compounds that is present in

xerophytes plants (plants adapted to survive in deserts or environments with little water) are

responsible for silver nanoparticle synthesis; cyperoquinone, dietchequinone, and remirin in

mesophytic plants (terrestrial plants adapted to neither a particularly dry nor particularly wetenvironment) are useful for metal nanoparticle synthesis. Eugenol, the main terpenoid of

Cinnamomum zeylanisum, was found to have a principal role in the synthesis of gold and silver

nanoparticles [19]. Notably, dicot plants contain many secondary metabolites that may be

suitable for nanoparticle synthesis ( Table 2 ).

Critical Parameters for the Biological Synthesis of Nanoparticles

Despite several advantages of a biological synthesis approach for nanoparticles, the poly-

dispersity of the nanoparticles formed remains a challenge. Therefore, many recent studies

have attempted to rationally establish a stable system for producing nanoparticles with

homogenous size and morphology ( Tables 1 and 2 ). Control of the shape and size of metal

nanoparticles has been shown by either constraining their environmental growth or altering

the functional molecules [26,65]. For instance, 20–nm monodispersed and biocompatible

gold nanoparticles were synthesized using Ganoderma spp. by improving the reactionconditions, including pH, temperature, incubation period, salt concentration, aeration, redox

conditions, mixing ratio, and irradiation [66]. Growing microorganisms at the maximum

possible temperature for optimal growth is recommended for the synthesis of nanoparticles

using microorganisms, because, at high temperatures, the enzyme responsible for nano-

particle synthesis is more active [67]. pH is also one of the most inuential factors and

different nanoparticles can be synthesized at different pH values. For instance, Gurunathan

et al. showed that most silver nanoparticles were synthesized at pH 10 in Escherichia coli

[67]. Among fungi, alkaline pH (for Isaria fumosorosea [68] ), p H 6.0 ( for Penicillium fellutanum

[67] ), and acidic pH (for Fusarium acuminatum ) were shown to be optimal for nanoparticle

synthesis. For plants, pH changes lead to changes in the charge of natural phytochemicals,

which further affects their binding ability and the reduction of metal ions during nanoparticle

synthesis. This in turn may affect the morphology and yield of nanoparticles. For instance, in

Avena sativa extract, at pH 3.0 and 4.0, numerous small-sized gold nanoparticles were

formed, whereas, at pH 2.0, nanoparticle aggregation was observed. Therefore, it has been

suggested that, at acidic pH values, nanoparticle aggregation is dominant over the process

of reduction.

This effect may be related to the fact that a larger number of functional groups that bind and

nucleate metal ions become accessible at pH 3.0 and 4.0 compared with pH 2.0. At pH 2.0, the

most accessible metal ions are involved in a smaller number of nucleation events, which leads to

the agglomeration of the metal [69]. By contrast, it was demonstrated using extracts from pears

that hexagonal and triangular gold nanoparticles are formed at alkaline pH values, whereas

nanoparticles do not form at acidic pHs [70]. In the case of silver nanoparticle synthesis from the

tuber powder of Curcuma longa, at alkaline pHs, extracts may contain more negatively charged

functional groups, which are capable of ef ciently binding and reducing silver ions and, thus,more nanoparticles were synthesized [69]. Another example of size- and shape-controlled

biological synthesis was shown by Kora et al., who demonstrated the size-controlled green

synthesis of silver nanoparticles of 5.7 0.2 nm by Anogeissus latifolia [55]. Triangular gold

nanoparticles were synthesized by Cymbopogon exuosus extract [71]. Similarly, other con-

ditions, such as duration time, salt concentrations, and localizations for nanoparticles synthesis

depend on species and extracts (Figure 2 ) [5].

Advantage of Biological Nanoparticles

The biocompatibility of nanoparticles, such as reduced metal cytotoxicity, is required for

nanoparticles with biomedical applications. Compared with physicochemically derived



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nanoparticles, nanoparticles obtained from biogenic routes are free from toxic contamination of

by-products that become attached to the nanoparticles during physiochemical synthesis, which

in turn limits the biomedical applications of the resulting nanoparticles [18]. The biological

synthesis of nanoparticles has several advantages, including rapid and ecofriendly production

methodologies and the cost-effective and biocompatible nature of synthesized nanoparticles.

Additionally, it does not require further stabilizing agents because plant and microorganism

constituents themselves act as capping and stabilizing agents [19]. Moreover, the surfaces of

biological nanoparticles progressively and selectively adsorb biomolecules when they contact

complex biological uids, forming a corona that interacts with biological systems. These corona

layers provide additional ef cacy over bare biological nanoparticles [72]. Thus, biological nano-

particles are more effective due to the attachment of biologically active components on the

surface of synthesized nanoparticles from the biological sources, such as plants and micro-

organisms. Especially in medicinal plants, there are abundant metabolites with pharmacological

activity that are hypothesized to attach to the synthesized nanoparticles, providing additional

benet by enhancing the ef cacies of the nanoparticles [19,73,74]. The additional advantage of

the biological synthesis of nanoparticles is that it can reduce the number of required steps,including the attachment of some functional groups to the nanoparticle surface to make them

biologically active, an additional step required in physiochemical synthesis [18].

In addition, the time required for biosynthesizing nanoparticles is shorter than that for physi-

ochemical approaches. Many researchers have developed rapid synthetic methodologies with

high yields by utilizing various plant sources. For instance, silver nanoparticles have been

synthesized using various plant extracts within 2 min [75], 5 min [76], 45 min [44], 1 h [46],

and 2 h [45]. Gold nanoparticles have also been demonstrated to be synthesized within 3 min

[44], 5 min [45], and 10 min [46], highlighting the simple and fast synthesis of nanoparticles using

plant extracts [75].

Biological synthesis

O p m i z a o n

Processing parameters:

1. Incubaon period2. Mixing rao

3. Temperature4. pH

5. Aeraon

Stable producon ofhomogenous andcapped NPs with

high yield

Metal salts

Metal nanoparcles (NPs)Modify processing parameters

Controlled shape and morphology of NPs

SphericalSquare HexagonalTriangular Rod

Microorganism orplant extract

Metal saltconcentraon

Producon ofheterogeneous NPswith low yield

Figure 2. Parameters for Producing Monodispersed, Stable, and High-Yield Biological Nanoparticles. It is

widely accepted that extracts of microorganisms and plants can be used to synthesize metal nanoparticles. However,

controlling parameters, such as salt concentration, mixing ratio of biological extract and metal salt, pH value, temperature,

incubation time, and aeration, still requires optimization for producing homogenous nanoparticles of a similar size and

shape. Biological synthesis can also provide an additional capping layer on synthesized nanoparticles with the attachment

of several biologically active groups, which can enhance the ef cacy of biological nanoparticles.



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Biological nanoparticles have been applied in many biomedical contexts, including anticancer

and antimicrobial applications because of the higher ef cacy of biological nanoparticles com-

pared with physiochemical nanoparticles for biomedical applications. For instance, Mukherjee

et al. showedthe better ef

cacy of biologicalsilvernanoparticles derived from Olax scandens leaf in terms of anticancer activity, biocompatibility for drug delivery, and imaging facilitator activity

compared with chemically synthesized silver nanoparticles [77]. Furthermore, biological nano-

particles showed high anticancer activity in the cancer cell lines A549 (human lung cancer), B16

(mouse melanoma), and MCF7 (human breast cancer) [77]. Additionally, biological nanoparticles

are more biocompatible with the rat cardiomyoblast normal cell line (H9C2), human umbilical vein

endothelial cells (HUVEC), and Chinese hamster ovary cells (CHO), than chemically synthesized

nanoparticles, which further supports the future applications of biological nanoparticles as drug

delivery carriers. Moreover, biological nanoparticles show bright-red uorescence inside cells,

which could be utilized to detect the localization of drug molecules inside cancer cells (a

diagnostic approach) [77].

El-Kassas et al. showed the cytotoxic activity of biological gold nanoparticles with an extract of

the red seaweed Corallina of cinalis on the MCF7 human breast cancer cell line [63]. Nethi et al.developed novel proangiogenic biosynthesized gold nanoconjugates to accelerate the growth of

new blood vessels through redox signaling [78]. Wang et al. showed the in vivo self-bioimaging

of tumors through uorescent gold nanoclusters that were spontaneously biosynthesized by

cancerous cells [i.e., HepG2 (a human hepatocarcinoma cell line) and K562 (a leukemia cell line)]

[79]. Mukherjee et al. demonstrated a biosynthetic approach for the fabrication of gold nano-

bioconjugates using Olax scandens leaf extract and applied to lung (A549), breast (MCF-7) and

colon (COLO 205) cancer cell lines. These results showed the signicant inhibition of cancer cell

proliferation and uorescence imaging in A549 cancer cells [80]. Patra et al. demonstrated the

better biocompatibility of biological gold and silver nanoparticles in the HUVEC and ECV-304 cell

lines compared with chemically synthesized nanoparticles. Furthermore, biological nanopar-

ticles combined with a drug, doxorubicin, were shown to have a higher anticancer effect in the

B16F10 cell line compared with the same drug combined with chemical nanoparticles [81].

Other examples includes gold and silver nanoparticles derived from the leaf extract of the

medicinal plant, Butea monosperma, which were found to be stable and biocompatible towards

normal endothelial cells (HUVEC, ECV-304) as well as cancer cell lines (B16F10, MCF-7,

HNGC2, and A549). In addition, by combining with doxorubicin, the gold and silver nano-

particles showed signicant inhibition of cancer cell proliferation (B16F10, MCF-7) compared

with that of chemically synthesized nanoparticles and isolated drug [64]. The possible anticancer

mechanism of nanoparticles is related to their size and shape, which are associated with the

generation of reactive oxygen species (ROS), causing damage to cellular components [82].

Additionally, nanoparticles may result in apoptosis via mitochondria-dependent and caspase-

dependent pathways [76] (Figure S1 in the supplemental information online).

For antimicrobial applications, investigations also showed the higher antimicrobial activity of

biologically synthesized nanoparticles compared with physicochemically mediated nanopar-ticles. Mukherjee et al. demonstrated that biological nanoparticles showed 96.67% antibacterial

activity at 30 mM, whereas the chemically synthesized nanoparticles did not show any signicant

ef cacy at the same concentration. Sudhasree et al. proposed that the biological nanoparticles

from Desmodium gangeticum are more monodispersed and have higher antioxidant, antibac-

terial, and biocompatible activities in LLC PK1 (epithelial cell lines) compared with chemically

synthesized nickel nanoparticles [83]. Mohammed et al. also described how biologically syn-

thesized zinc nanoparticles have more antimicrobial potential against Salmonella typhimurium

ATCC 14028, B. subtilis ATCC 6633, and Micrococcus luteus ATCC 9341 compared with

chemically synthesized zinc nanoparticles [84]. The exact antimicrobial mechanism is still under

debate, although there are various proposed mechanisms of action for nanoparticles, including



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disturbance of the cell membrane; alteration of cellular DNA and proteins, electron transport,

nutrient uptake, protein oxidation, or membrane potential; or the generation of ROS, which lead

to cell death (Figure S1 in the supplemental information online).

In addition to their anticancer and antimicrobial activities, biological nanoparticles have also been

proven to be more effective in designing sensors. For example, biogenic silver nanoparticles

were successfully used in the fabrication of an optical ber-based sensor for the detection of

H2O2 that is cost effective and portable and can be used in various industrial applications [85].

Furthermore, based on the higher ef cacy and biocompatable nature of biological metal nano-

particles, it has been hypothesized that biological nanoparticles may improve the action of a

typical anticancer drug by facilitating drug delivery to specic cells, which reduces the required

drug dosage and avoids the adverse effects of a high amount of drug. Moreover, biological

nanoparticles can replace physicochemically synthesized gold and iron nanoparticles in photo-

imaging and thermal therapies. Furthermore, biological nanoparticles could be used in cosmetic

and medical appliances (Figure 1 ).

Concluding Remarks and Prospects The potential of using metal nanoparticles in various elds increases the need to produce them

on an industrial scale and in stable formulations with environmentally friendly processes.

Therefore, much effort is being made [

towards exploiting natural resources and implementing

biological synthesis methods with proven advantages, such as being environmentally friendly,

easy to scale up, and cost-effective; thus, the green production of nanoparticles using biological

resources has great potential. The biological route of synthesizing nanoparticles has many

advantages, such as the stable production of nanoparticles with controlled sizes and shapes,

the lack of subsequent complex chemical synthesis, the lack of toxic contaminants, and the

ability for rapid synthesis using numerous medicinal plants and microorganisms.

Importantly, the yield of synthesized nanoparticles corresponding to the metal salt concentration

and the available biological resources remains to be elucidated, and the parameters that can

overcome the problems of polydispersity of biological nanoparticles still require optimization in

various biological systems. Furthermore, the lack of knowledge of the chemical components

responsible and the underlying mechanisms for the synthesis, action, and stabilization of

biological nanoparticles, remain open challenges in taking advantage of plants and micro-

organisms for nanoparticle synthesis. Especially in terms of biocompatibility, it is important

to understand how active groups from biological sources attach to the nanoparticle surface, and

which active groups are involved, to produce nanoparticles with higher ef cacy. Thus, the

plethora of microorganisms and plants that have been successfully used for the biological

synthesis of metal nanoparticles prompts the deeper exploration of biological nanofactories

to meet the need for nanoproducts in various elds (see Outstanding Questions). However,

issues relating to the biomedical applications of biological nanoparticles, including the distribu-

tion prole, excretion, and clearance of nanoparticles in in vivo trials, need to be addressed.

Additionally, investigations into the biocompatibility and bioavailability of nanoparticles are still atearly stages, and considerable research is needed in this direction.

Acknowledgments

This work was supported by funds from the Ministry of Science and Technology (MOST), The People's Republic of China

(2015DFG32560), and BasicScience Research Program through the National Research Foundation(NRF) from the Ministry

of Education (2013R1A1A2064430), Republic of Korea(Y-J.K.); and KoreaInstitute of Planning & Evaluationfor Technology

in Food, Agriculture, and Forestry & Fisheries (KIPET NO: 313038-03-2-SB020) (D-C.Y.).

Supplementary Information

Supplementary information associated with this article can be found[

online[

at [

http://dx.doi[

.org/10.1016/j.tibtech.2016.02.

006.

Outstanding Questions

Although many reports demonstrate

the advantages of producing nanopar-

ticles using biological sources, several

unresolved issues remain, with regardto optimization yield of biological syn-

thesis and their ef cacy.

The ef cient production of nanopar-

ticles using various microorganisms

and plants needs to be optimized, par-

ticularly for industrial production. Is

there any limitation to using biological

sources?

How does the nanoparticle yield differ

with different biological sources and

the same metal salt concentration?

Is there anystrategyby which theprob-

lem of polydispersed nanoparticles

during biological synthesis can be eas-

ily avoided?

Why does the ef cacy of biologically

active metal nanoparticles depend on

the size and shape of nanoparticles?

What is the exact mechanism behind

the biological ef cacy of nanoparticles,

particularly the higher ef cacy of bio-

logical nanoparticles?

Even though biological nanoparticles

are more biocompatible than physico-

chemically synthesized nanoparticles,

what are the future applications of bio-

logical nanoparticles in humans?

Although biological nanoparticles have

been found to be more pharmacologi-

cally active, which active groups from

biological sources attach to nanopar-

ticles and enhance their pharmacologi-

cal activity?

What determines the cytotoxicity, bio-

distribution, and excretion of nanopar-

ticles in vivo?


http://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006


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