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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
Trends in Biotechnology, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.tibtech.2016.02.006 1© 2016 Elsevier Ltd. All rights reserved.
mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.tibtech.2016.02.006http://dx.doi.org/10.1016/j.tibtech.2016.02.006mailto:[email protected]:[email protected]
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TIBTEC 1353 No. of Pages 12
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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TIBTEC 1353 No. of Pages 12
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.
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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.
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TIBTEC 1353 No. of Pages 12
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
Trends in Biotechnology, Month Year, Vol. xx, No. yy 9
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TIBTEC 1353 No. of Pages 12
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?
10 Trends in Biotechnology, Month Year, Vol. xx, No. yy
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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