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Biological Synthesis of Nanoparticles from Plants and Microorganisms

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Review
Biological Synthesis of
Nanoparticles from Plants and
Microorganisms
Priyanka Singh,1 Yu-Jin Kim,1,2,* Dabing Zhang,2 and
Deok-Chun Yang1,*
Nanotechnology has become one of the most promising technologies applied in
Trends
all areas of science. Metal nanoparticles produced by nanotechnology have
The biological synthesis of nanoparti-
received global attention due to their extensive applications in the biomedical cles is increasingly regarded as a rapid,
and physiochemical fields. Recently, synthesizing metal nanoparticles using ecofriendly, and easily scaled-up
technology.
microorganisms and plants has been extensively studied and has been recog-
nized as a green and efficient way for further exploiting microorganisms as Metal nanoparticles produced using
convenient nanofactories. Here, we explore and detail the potential uses of microorganisms and plant extracts
are stable and can be monodispersed
various biological sources for nanoparticle synthesis and the application of by controlling synthetic parameters,
those nanoparticles. Furthermore, we highlight recent milestones achieved for such as pH, temperature, incubation
period, and mixing ratio.
the biogenic synthesis of nanoparticles by controlling critical parameters,
including the choice of biological source, incubation period, pH, and Recently, biological nanoparticles were
temperature. found to be more pharmacologically
active than physicochemically synthe-
sized nanoparticles.
Nanoparticles and their Applications
Among the various biological nanopar-
Nanotechnology (see Glossary) has become one of the most important technologies in all
ticles, those produced by medicinal
areas of science. It relies on the synthesis and modulation of nanoparticles, which requires plants have been found to be the most
significant modifications of the properties of metals [1]. Nanomaterials have in fact been used pharmacologically active, possibly due
unknowingly for thousands of years; for example, gold nanoparticles that were used to stain to the attachment of several pharma-
cologically active residues.
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 specific delivery of drugs, such as paclitaxel,
methotrexate, and doxorubicin [2]. Gold nanoparticles have been also used for tumor detection, 1
Department of Oriental Medicine
angiogenesis, genetic disease and genetic disorder diagnosis, photoimaging, and photother- Biotechnology, College of Life
Science, Kyung Hee University,
mal therapy. Iron oxide nanoparticles have been applied for cancer therapy, hyperthermia, drug Yongin 446-701, Korea
delivery, tissue repair, cell labeling, targeting and immunoassays, detoxification of biological 2
Joint International Research
fluids, magnetic resonance imaging, and magnetically responsive drug delivery therapy [6– Laboratory of Metabolic &
Developmental Sciences, Shanghai
8]. Silver nanoparticles have been used for many antimicrobial purposes, as well as in anticancer, Jiao Tong University–University of
anti-inflammatory, and wound treatment applications [9]. Due to their biocompatible, nontoxic, Adelaide Joint Centre for Agriculture
self-cleansing, skin-compatible, antimicrobial, and dermatological behaviors, zinc and titanium and Health, State Key Laboratory of
Hybrid Rice, School of Life Sciences
nanoparticles have been used in biomedical, cosmetic, ultraviolet (UV)-blocking agents, and and Biotechnology, Shanghai Jiao
various cutting-edge processing applications [10,11]. Copper and palladium nanoparticles have Tong University, Shanghai, China
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
*Correspondence: yujinkim@khu.ac.kr
microorganisms. Additionally, metal nanoparticles have been used in the spatial analysis of (Y.-J. Kim) and dcyang@khu.ac.kr
various biomolecules, including several metabolites, peptides, nucleic acids, lipids, fatty acids, (D.-C. Yang).

588 Trends in Biotechnology, July 2016, Vol. 34, No. 7 http://dx.doi.org/10.1016/j.tibtech.2016.02.006

© 2016 Elsevier Ltd. All rights reserved.
glycosphingolipids, and drug molecules, to visualize these molecules with higher sensitivity and Glossary
spatial resolution [14]. Biocompatibility: the compatibility
and noninjurious effects of metal
In addition, the unique properties of nanoparticles make them well suited for designing electro- nanoparticles within the human body
or healthy living cells.
chemical sensors and biosensors [15]. For example, nanosensors have been developed for the Biological nanofactories: biological
detection of algal toxins, mycobacteria, and mercury present in drinking water [16]. Researchers sources capable of synthesizing
also developed nanosensors by utilizing nanomaterials for hormonal regulation and for detecting metal nanoparticles, including
crop pests, viruses, soil nutrient levels, and stress factors. For instance, nanosensors for sensing microorganisms and plants.
Biological nanoparticles:
auxin and oxygen distribution have been developed [17]. nanoparticles obtaintend form
biological sources, such as
To date, due to the physiochemical properties and many applications of nanoparticles, the micoroganisms and plant extracts.
Biological synthesis: synthesis
scientific community has dedicated extensive efforts to develop suitable synthetic techniques for
using natural sources, avoiding any
producing nanoparticles. However, various physiochemical approaches for the synthesis of toxic chemicals and hazardous by-
metal nanoparticles are limited by the environmental pollution caused by heavy metals. Thus, products, usually with lower energy
synthesizing nanoparticles by biological means, which has the advantages of nontoxicity, consumption.
Magnetically responsive drug
reproducibility in production, easy scaling-up, and well-defined morphology, has become a
delivery: delivery of heavy drugs by
new trend in nanoparticle production. In particular, microorganisms and plants have been magnetic nanoparticles under the
demonstrated as new resources with considerable potential for synthesizing nanoparticles. influence of an external magnetic
To date, several microorganisms, including bacteria, fungi, and yeast, as well as plants, have field.
Mycosynthesis: biological synthesis
been explored for the synthesis of metal nanoparticles. While the synthesis of nanoparticles has
of metal nanoparticles from fungi.
been extensively reviewed elsewhere [5,18–20], here we provide an update on recent advances Nanoparticles: small particles with
in the synthesis of biological nanoparticles, and describe prospects for their future develop- all three dimensions measuring
ment and applications. <1000 nm.
Nanotechnology: technology
dealing with the development and
Nanoparticle Synthesis Using Microorganisms application of nanoparticles.
Microorganisms have been shown to be important nanofactories that hold immense potential as Photothermal therapy: therapy in
ecofriendly and cost-effective tools, avoiding toxic, harsh chemicals and the high energy specific cells, such as cancer cells,
by gold or iron nanoparticles under
demand required for physiochemical synthesis. Microorganisms have the ability to accumulate the influence of an external thermal
and detoxify heavy metals due to various reductase enzymes, which are able to reduce metal field.
salts to metal nanoparticles with a narrow size distribution and, therefore, less polydispersity. Phytonanotechnology: the
biological synthesis of metal
The mechanism and experimental methods of synthesizing nanoparticles in microorganisms is
nanoparticles from plant resources,
described in Box 1. Over the past few years, microorganisms, including bacteria (such as which further includes the
actinomycetes), fungi, and yeasts, have been studied extra- and intracellularly for the synthesis optimization and applications of
of metal nanoparticles (Table 1). An array of biological protocols for nanoparticle synthesis has synthesized nanoparticles.
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 purification, and others. Moreover, metal-resistant
genes, proteins, peptides, enzymes, reducing cofactors, and organic materials have significant
roles by acting as reducing agents. Furthermore, these help in providing natural capping to
synthesize nanoparticles, thereby preventing the aggregation of nanoparticles and helping them
to 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 showed by 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,

Trends in Biotechnology, July 2016, Vol. 34, No. 7 589

 Fungi Bacteria
t
as Proteins, Leaves
Ye
amino acids, Fruit
Enzymes
vitamins, Stem Peel
(e.g., nitrate reductase)
polysaccharides,
Enzymes polyphenols,
(e.g., naphthoquinones/ terpenoids, Flower
Acnomycetes Anthraquinones) Biological synthesis organic acid Root
Microorganisms of nanoparcles Plant ssues
Metal salts
Metal nanoparcles (NPs)
Applicaons
Detector
ell
al c
ng
Fu

Nanosensors detect
biomolecules,
External Brain environmental factors
Anmicrobial, lls
Detector

magnec field Ce s
Skin NP
anpathogen, Cosmecs Lung
mosquitocidal uses and
Breast
medical Gene
appliances Photoimaging Prostate
Cell delivery
labelling
Colorectal
NI

Bladder
R

NPs External
Tumor magnec field
Most applicable area cell
Second most-applicable area NPs Magnecally Various types of
Applicaons under clinical trial Photothermal responsive human cancer
therapy drug delivery

Figure 1. Biological Synthesis and Applications of Metal Nanoparticles in Biomedical and Environmental Fields. Silver nanoparticles are mostly used in the
medical field 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.

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
efficient, 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

590 Trends in Biotechnology, July 2016, Vol. 34, No. 7

 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 to
synthesize nanoparticles by adding a filter-sterilized metal salt solution and is incubated again. The nanoparticle synthesis
can be monitored by observing a change in the color of the culture medium; for instance, for silver nanoparticles, the color
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
filter-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 purified by
filtration and centrifugation. Different ratios of plant extract, metal salt solution, and water (depending on the plant species
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.

In all of the synthesis methodologies, good monodispersity (i.e., a narrow size distribution) can be achieved. by controlling
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.

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

significant 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 significant
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 the
recovery 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

Trends in Biotechnology, July 2016, Vol. 34, No. 7 591

Table 1. Synthesis and Applications of Biological Nanoparticles from Microorganisms
Microorganism Extracellular/ Types of Shapes Size (nm) Applications Refs
Intracellular Nanoparticle

Bacteria

Pseudomonas Extracellular Silver Spherical 10–30 Antimicrobial [21]

deceptionensis and antibiofilm

Weissella oryzae Intracellular Silver Spherical 10–30 Antimicrobial [22]

and antibiofilm

Bacillus Extracellular Silver Spherical 10–30 Antimicrobial [23]

methylotrophicus

Brevibacterium Extracellular Silver Spherical 10–30 Antimicrobial [24]

frigoritolerans

Bhargavaea indica Extracellular Silver and Silver anisotropic; 30–100 Antimicrobial [25,26]
gold gold, flower

Bacillus Extracellular Cadmium Cubic/hexagonal 3–4 – [27]

amyloliquefaciens sulfide

Bacillus pumilus, Extracellular Silver Triangular, 77–92 Antiviral and [29]

Bacillus persicus, hexagonal, Antibacterial
and Bacillus and spherical
licheniformis

Listeria – Silver Anisotropic Varied Antimicrobial and [30]

monocytogenes, shape mosquitocidal
Bacillus subtilis, and sizes
and Streptomyces
anulatus

Fungus

Neurospora crassa Intra- and Silver, gold, Quasi-spherical >100 – [34]

extracellular bimetallic
silver and
gold

Actinomycetes

Streptomyces – Silver Spherical 5 Acaricidal [37]

sp. LK3

Yeast

Yarrowia lipolytica Extracellular Silver Spherical 15 Antibiofilm [38]

NCYC 789

Rhodosporidium Intracellular Lead – 2–5 – [39]

diobovatum

Extremophilic Extracellular Silver and Irregular Silver, 20; – [40]

yeast gold gold,30–100

Candida utilis Extracellular Silver Spherical 20–80 Antibacterial [41]

NCIM 3469

plants are suitable for fulfilling 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
flavonoids, alkaloids, polyphenols, terpenoids, heterocyclic compounds, and polysaccharides,

592 Trends in Biotechnology, July 2016, Vol. 34, No. 7

Table 2. Synthesis and Applications of Biological Nanoparticles from Plants
Plants Plant Tissues Types of Shapes Size (nm) Applications Refs
for Extraction Nanoparticle

Euphorbia prostrata Leaves Silver and Spherical Silver Leishmanicidal [11]

titanium 10–15;
dioxide (TiO2) TiO2,
81.7–84.7

Sargassum algae Alga Palladium Octahedral 5 –10 Electrocatalytic [12]

activities towards
hydrogen peroxide

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

Panax ginseng Root Silver and Spherical Silver, Antibacterial [44]

gold 10–30;
gold,
10–40

Red ginseng Root Silver Spherical 10–30 Antibacterial [46]

Cymbopogon citratus Leaves Gold Spherical, 20–50 Mosquitocidal [47]

triangular,
hexagonal
and rod

Azadirachta indica Leaves Silver – 41–60 Biolarvicidal [48]

Nigella sativa Leaves Silver Spherical 15 Cytotoxicity [49]

Cocos nucifera Leaves Lead Spherical 47 Antibacterial and [50]

photocatalytic

Catharanthus roseus Leaves Palladium Spherical 40 Catalytic activity in [51]

dye degradation

Pistacia atlantica Seeds Silver Spherical 27 Antibacterial [52]

Banana Peel Cadmium – 1.48 – [53]

sulfide

Nyctanthes arbortristis Flower Silver – – Antibacterial [54]

and cytotoxic

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

Abutilon indicum Leaves Silver Spherical 5–25 Antibacterial [56]

Pinus densiflora Cones Silver Oval in shape, 30–80 Antimicrobial [57]

few triangular
shaped

Artocarpus gomezianus Fruit Zinc Spherical > 20 Luminescence, [58]

photocatalytic
and antioxidant

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 32 Antibacterial [61]

appearance

have significant 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
officinalis 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, specific

Trends in Biotechnology, July 2016, Vol. 34, No. 7 593

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 wet
environment) 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 reaction
conditions, 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 influential 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]), pH 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 efficiently 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 flexuosus 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

594 Trends in Biotechnology, July 2016, Vol. 34, No. 7

 Biological synthesis
Metal salt Microorganism or
concentraon plant extract

Producon of
heterogeneous NPs
with low yield

Processing parameters:

Opmizaon
1. Incubaon period
2. Mixing rao
3. Temperature
4. pH
5. Aeraon

Stable producon of
homogenous and
capped NPs with
high yield

Metal salts
Modify processing parameters Metal nanoparcles (NPs)

Square Spherical Triangular Hexagonal Rod

Controlled shape and morphology of NPs

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 efficacy of biological nanoparticles.

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 fluids, forming a corona that interacts with biological systems. These corona
layers provide additional efficacy 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
benefit by enhancing the efficacies 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].

Trends in Biotechnology, July 2016, Vol. 34, No. 7 595

Biological nanoparticles have been applied in many biomedical contexts, including anticancer
and antimicrobial applications because of the higher efficacy of biological nanoparticles com-
pared with physiochemical nanoparticles for biomedical applications. For instance, Mukherjee
et al. showed the better efficacy of biological silver nanoparticles 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 fluorescence 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 officinalis 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 fluorescent 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 significant inhibition of cancer cell
proliferation and fluorescence 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 significant 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 significant
efficacy 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

596 Trends in Biotechnology, July 2016, Vol. 34, No. 7

disturbance of the cell membrane; alteration of cellular DNA and proteins, electron transport, Outstanding Questions
nutrient uptake, protein oxidation, or membrane potential; or the generation of ROS, which lead Although many reports demonstrate
to cell death (Figure S1 in the supplemental information online). the advantages of producing nanopar-
ticles using biological sources, several
unresolved issues remain, with regard
In addition to their anticancer and antimicrobial activities, biological nanoparticles have also been to optimization yield of biological syn-
proven to be more effective in designing sensors. For example, biogenic silver nanoparticles thesis and their efficacy.
were successfully used in the fabrication of an optical fiber-based sensor for the detection of
The efficient production of nanopar-
H2O2 that is cost effective and portable and can be used in various industrial applications [85]. ticles using various microorganisms
Furthermore, based on the higher efficacy and biocompatable nature of biological metal nano- and plants needs to be optimized, par-
particles, it has been hypothesized that biological nanoparticles may improve the action of a ticularly for industrial production. Is
there any limitation to using biological
typical anticancer drug by facilitating drug delivery to specific cells, which reduces the required
sources?
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- How does the nanoparticle yield differ
imaging and thermal therapies. Furthermore, biological nanoparticles could be used in cosmetic with different biological sources and
the same metal salt concentration?
and medical appliances (Figure 1).
Is there any strategy by which the prob-
Concluding Remarks and Prospects lem of polydispersed nanoparticles
The potential of using metal nanoparticles in various fields increases the need to produce them during biological synthesis can be eas-
ily avoided?
on an industrial scale and in stable formulations with environmentally friendly processes.
Therefore, much effort is being made towards exploiting natural resources and implementing Why does the efficacy of biologically
biological synthesis methods with proven advantages, such as being environmentally friendly, active metal nanoparticles depend on
easy to scale up, and cost-effective; thus, the green production of nanoparticles using biological the size and shape of nanoparticles?

resources has great potential. The biological route of synthesizing nanoparticles has many What is the exact mechanism behind
advantages, such as the stable production of nanoparticles with controlled sizes and shapes, the biological efficacy of nanoparticles,
the lack of subsequent complex chemical synthesis, the lack of toxic contaminants, and the particularly the higher efficacy of bio-
logical nanoparticles?
ability for rapid synthesis using numerous medicinal plants and microorganisms.
Even though biological nanoparticles
Importantly, the yield of synthesized nanoparticles corresponding to the metal salt concentration are more biocompatible than physico-
and the available biological resources remains to be elucidated, and the parameters that can chemically synthesized nanoparticles,
what are the future applications of bio-
overcome the problems of polydispersity of biological nanoparticles still require optimization in
logical nanoparticles in humans?
various biological systems. Furthermore, the lack of knowledge of the chemical components
responsible and the underlying mechanisms for the synthesis, action, and stabilization of Although biological nanoparticles have
biological nanoparticles, remain open challenges in taking advantage of plants and micro- been found to be more pharmacologi-
cally active, which active groups from
organisms for nanoparticle synthesis. Especially in terms of biocompatibility, it is important
biological sources attach to nanopar-
to understand how active groups from biological sources attach to the nanoparticle surface, and ticles and enhance their pharmacologi-
which active groups are involved, to produce nanoparticles with higher efficacy. Thus, the cal activity?
plethora of microorganisms and plants that have been successfully used for the biological
What determines the cytotoxicity, bio-
synthesis of metal nanoparticles prompts the deeper exploration of biological nanofactories distribution, and excretion of nanopar-
to meet the need for nanoproducts in various fields (see Outstanding Questions). However, ticles in vivo?
issues relating to the biomedical applications of biological nanoparticles, including the distribu-
tion profile, excretion, and clearance of nanoparticles in in vivo trials, need to be addressed.
Additionally, investigations into the biocompatibility and bioavailability of nanoparticles are still at
early 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 Basic Science Research Program through the National Research Foundation (NRF) from the Ministry
of Education (2013R1A1A2064430), Republic of Korea (Y-J.K.); and Korea Institute of Planning & Evaluation for 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.

Trends in Biotechnology, July 2016, Vol. 34, No. 7 597

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