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Cite this: Chem. Soc. Rev., 2012, 41, 68746887
Colloidal nanoparticle clusters: functional materials by design
Zhenda Lu and Yadong Yin*
Received 1st June 2012
DOI: 10.1039/c2cs35197h
Signicant advances in colloidal synthesis made in the past two decades have enabled the
preparation of high quality nanoparticles with well-controlled sizes, shapes, and compositions.
It has recently been realized that such nanoparticles can be utilized as articial atoms for
building new materials which not only combine the size- and shape-dependent properties of
individual nanoparticles but also create new collective properties by taking advantage of their
electromagnetic interactions. The controlled clustering of nanoparticle building blocks into
dened geometric arrangements opens a new research area in materials science and as a result
much interest has been paid to the creation of secondary structures of nanoparticles, either by
direct solution growth or self-assembly methods. In this tutorial review, we introduce recently
developed strategies for the creation and surface modication of colloidal nanoparticle clusters,
demonstrate the new collective properties resulting from their secondary structures, and highlight
several of their many important technological applications ranging from photonics, separation,
and detection, to multimodal imaging, energy storage and transformation, and catalysis.
1. Introduction
Colloidal nanoparticles are of great interest for researchers
from a wide range of disciplines, including materials science,
chemistry, physics, and engineering, because of their unique
magnetic, electronic and optical properties, as compared to
their bulk counterparts. Signicant progress has been made in
the development of robust synthesis protocols which allow
precise control over composition, size, shape, surface proper-
ties, and uniformity of colloidal inorganic nanoparticles.1,2
Recently, the focus of synthetic eorts has been directed
towards the creation of secondary structures of colloidal
nanoparticles, which holds great promise for the development
of advanced materials with novel integrated functions.3
Clustering nanoparticles into secondary structures to form
so-called colloidal nanoparticle clusters (CNCs) not only
allows the combination of properties of individual nano-
particles but also takes advantage of the interactions between
neighboring nanoparticles which can result in new propertiesDepartment of Chemistry, University of California, Riverside CA92521, USA. E-mail: [email protected]
Zhenda Lu
Zhenda Lu received his BSand MS in Chemistry fromNanjing University in Chinain 2004 and 2007, respectively.He then came to the UnitedStates and is currently pursu-ing his PhD under the super-vision of Prof. Yadong Yin atUniversity of California,Riverside. His researchfocuses on the synthesis, sur-face modication and self-assembly of nanoparticles,and their bioanalytical andcatalytic applications. Yadong Yin
Yadong Yin received his BSand MS in Chemistry fromthe University of Science andTechnology of China in 1996and 1998, respectively, andthen PhD in Materials Scienceand Engineering from theUniversity of Washington in2002. He then worked as apostdoctoral fellow at theUniversity of California,Berkeley, and the LawrenceBerkeley National Labora-tory. In 2006 he joined theDepartment of Chemistry atUniversity of California,
Riverside. His research interests include colloidal chemistry,self-assembly, surface functionalization, and synthesis of nano-structured materials and their applications.
Chem Soc Rev Dynamic Article Links
www.rsc.org/csr TUTORIAL REVIEW
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not present in the original constituents.4 A well-known example
is the assembly of noble metal nanoparticles into secondary
structures, which induces near eld coupling of surface plasmon
between adjacent particles. As a result, new optical properties
can be obtained, inducing shifts of plasmonic peaks and the
generation of hot spots that are very useful for enhancing
Raman scattering.57
Considering the fact that syntheses for a large variety of
nanoparticles have been developed in the past two decades and
the large number of dierent combinations that can be made
from these nanoparticles, one can easily see the great potential
of clustering approaches for the creation of novel nanoparticle-
based functional materials. Moreover, the forces involved in
nanoparticle clustering, including both covalent and non-covalent
interactions (e.g. hydrogen bonding, electrostatics and van der
Waals interactions) can be tailored by changing solvents,
surfactants, and reaction temperatures, providing exciting
opportunities for controlling specic geometric congurations
and consequently desired functions. Furthermore, the formation
of secondary structures may be able to eectively address many
challenges that are currently limiting the direct use of colloidal
nanoparticles in practical applications. For example, owing to
their high surface-to-volume ratio, small nanoparticles are widely
believed to possess signicantly enhanced catalytic activity. In
reality, however, the catalytic activity may quickly decay due to
the growth of nanoparticles as the result of interparticle sintering
during reactions. In addition, the capping ligands, which are
generally required to stabilize the nanoparticles during their
initial synthesis, may block access of the target molecules to
the catalyst surface and therefore severely reduce the catalytic
activity. We have recently shown that by organizing nanoparticle
catalysts into clusters we can circumvent these diculties by
allowing additional post-treatment to remove the capping
ligands, for example, by calcination at an appropriately high
temperature, while at the same time maintaining the high
surface area needed for high catalytic activity.8,9 Although
more eorts are still required to develop eective bottom-up
assembly approaches for colloidal nanoparticle clusters, this
strategy now opens up a nearly unlimited platform for designing
and manufacturing functional materials with new physical and
chemical properties.
This review will focus on the liquid-phase synthesis and
surface modication of various colloidal nanoparticle clusters,
which are typically composed of primary nanocrystallites of
approximately several to tens of nanometers in size. We also
highlight a number of representative examples of their many
potential technological applications, which may include catalysis,
energy storage and conversion, magnetic separation, multimode
imaging, chemical detection, and drug loading and release.
2. Synthesis of colloidal nanoparticle clusters
Colloidal nanoparticles are nanometer-scale inorganic nano-
particles, typically crystallites, stabilized by a layer of organic
capping ligands and dispersed in a solution. Pioneering work
on the synthesis of CdX (X = S, Se, Te) nanoparticles with
narrow size distributions in molten trioctylphosphine oxide
(TOPO) laid the foundation for the classic thermolytic routes,
which involve the reactions of inorganic precursors in organic
solvents at high temperatures.2 Many technologically important
high quality nanoparticles, such as semiconductor and metal oxide
nanocrystals, can now be routinely prepared through various
modied versions of the thermolytic method. Upon heating the
reaction solution to a suciently high temperature (typically
150320 1C), the precursors will be chemically transformed intoactive atomic or molecular species, which then condense to form
nanoparticles, the growth of which is strongly inuenced by the
presence of capping ligands. The size of nanoparticles can be
controlled by stopping the reaction at dierent growth stages or
changing the ligand concentrations. Shaped nanoparticles such as
nanodisks, nanorods, and nanoscale polyhedral structures can
also be synthesized by taking advantage of the selective adhesion
of certain ligands to particular crystalline facets to kinetically
control the relative growth rates along dierent crystalline
directions.1
The formation of secondary nanoparticle structures typically
involves more complex procedures or reaction pathways. As
shown in Fig. 1, there are basically two strategies for the
preparation of CNCs: (i) one-step processes which integrate the
synthesis of nanoparticles and their aggregation into clusters in a
single step; and (ii) multi-step processes which rst produce
nanoparticles with desired size, shape and surface functionality,
and then assemble them into clusters of designed congurations
in separate steps via methods such as solvent evaporation,
electrostatic attraction, or interfacial tension. While the one-step
processes are more ecient at producing CNC structures, the
multi-step processes have the advantage of being more exible
and universal for organizing nanoparticles of a large variety of
materials into CNCs with highly congurable structures.
2.1. Direct synthesis of nanoparticle clusters
Nanoparticle clusters can be produced through a number of
dierent one-step techniques, including thermolysis, solvothermal,
and microwave methods. Table 1 summarizes the various CNC
syntheses reported in the recent literature. Although the details in
these methods are dierent, every synthesis involves two growth
Fig. 1 Schematic illustration of the preparation strategies for colloidal
nanoparticle clusters (CNCs).
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stages in which primary nanoparticles rst nucleate and grow
in a supersaturated solution and then aggregate into larger
secondary particles.
2.1.1. Thermolysis method. A typical thermolysis process
entails reacting precursors in a solvent in the presence of a
surfactant at high temperatures. The reaction typically consists
of three critical components: precursors, organic capping
ligands, and solvents. The capping ligands bind to the nano-
particle surfaces, limit their growth, and prevent interparticle
agglomeration through steric interactions. With sucient
ligand protection, uniform nanoparticles, typically with dot
shapes, are obtained. However, by reducing the degree of ligand
protection to the domain of so-called limited ligand protec-
tion (LLP), complex three-dimensional (3D) nanostructures
can be produced through the oriented attachment of primary
nanoparticles. Peng et al. produced 3D nanoower-like struc-
tures for metal oxides such as In2O3, CoO, MnO and ZnO by
reducing the amount of stabilizing organic ligands to the point
that the primary nanoparticles were insuciently protected.10,11
Similar to the mainstream thermolytic syntheses, metal oxide
nanoparticles nucleate upon the thermolysis of precursors.
With increasing reaction temperature, the dot-shaped nano-
particles grow further at 250 1C and eventually agglomerateinto the ower-like clusters due to lack of sucient protection
from ligands. The key to CNC formation is to maintain an
appropriate concentration of capping ligands, which is not
enough to protect the primary nanoparticles against aggrega-
tion but sucient to stabilize the resulting 3D nanostructures.
The formation of relatively large crystalline clusters proceeds
through the 3D oriented attachment of primary nanoparticles.12
By changing the reaction conditions such as the specic concen-
tration of ligands and reaction time, the size of the clusters
can be adjusted within a reasonably wide range, for example,
1560 nm in the case of In2O3.10 The LLP approach is a
powerful strategy for the design of complex 3D CNCs, which
can be applied to metal oxides with dierent compositions. It is
also believed that the principle of LLP may be applicable to a
broad spectrum of colloidal nanoparticles, without involving
drastic alternations to the synthetic chemistry established for
simple 0D and 1D nanoparticles in the past decades.
Recently, our group has developed a one-pot high-tempera-
ture polyol process for the synthesis of polyelectrolyte-capped
superparamagnetic CNCs of magnetite (Fe3O4).13 Briey,
Fe3O4 CNCs were prepared by hydrolyzing FeCl3 with NaOH
atB220 1C in a diethylene glycol (DEG) solution with short-chain polyacrylic acid (PAA) as a surfactant. DEG was chosen
as the polar solvent because of its high boiling point as well as
its high permittivity, which enables high solubility for a variety
of polar inorganic and many organic compounds. Under the
reductive environment provided by DEG at a high tempera-
ture, Fe3+ partially transforms into Fe2+ and nally forms
Fe3O4 particles. The particle size can be tuned from 30 to
180 nm with a relatively narrow distribution by changing the
concentration of NaOH. The growth of CNCs follows the
well-documented two-stage growth model in which primary
nanoparticles nucleate rst in a supersaturated solution and
then aggregate into larger secondary particles. As shown in the
transmission electron microscopy (TEM) images in Fig. 2,
these magnetite CNCs have a well-developed cluster-like
structure: each cluster is composed of many interconnected
primary nanoparticles with a size of B10 nm. The crystallo-graphic alignment of the primary crystals relative to one another
has been observed in high resolution imaging and electron
diraction studies, suggesting that the possible formation
mechanism of CNCs involves oriented attachment and subsequent
high-temperature sintering during synthesis. This method has
been extended to the synthesis of CNCs of other materials,
such as PbS14 and ZnS.15
Recently, Kotovs group reported a one-step method for the
synthesis and self-assembly of monodispersed CdSe CNCs.16
Cadmium and selenium precursors were mixed at 80 1C in anaqueous solution with short and highly charged ligands such
as citrate anions, leading to the formation of nanoparticle
clusters with sizes tunable from 20 to 50 nm by changing
the reaction time. Similar to the two-stage growth model
for Fe3O4 CNCs discussed above, the assembly of CdSe
nanoparticle clusters occurs when primary nanoparticles are
present in the reaction media. It is important to note that the
polydispersity of the clusters (810%) was signicantly smaller
when compared with that of the primary nanoparticles of
which they are comprised (2530%). This self-limiting growth
Table 1 Summary of one-step approaches for CNC synthesis
Cluster Precursors Solvent and Surfactant Method T/1C Size range/nm Ref.
In2O3, ZnO, CoO, MnO2 Metal carboxylate(Ac, Mt or St)
ODE, OA or DA Thermolysis 250280 11
In2O3 Indium carboxylate(Ac, Mt or St)
ODE, DA Thermolysis 250290 1560 10
Fe3O4 FeCl3, NaOH DEG, PAA Thermolysis 220 30180 13PbS Pb(Ac)2, thiourea DEG, PAA Thermolysis 215 155240 14ZnO Zn(Ac)2, NaOH DEG, PAA Thermolysis 210 60180 15MFe2O4 (MQFe, Co, Mn, Zn) FeCl3, MCl2, NaAc EG, PEG Solvothermal 200 200800 23Fe3O4 Fe(acac)3 EG, PVP Solvothermal 140145 50100 18Fe3O4 FeCl3, NaAc EG, DEG, Sodium acrylate Solvothermal 200 6170 20MFe2O4 (MQFe, Mn, Zn, Co, Ni) FeCl3, MCl2, NaAc EG, DEG, PVP Solvothermal 200 20300 19Fe3O4 FeCl3, NaAc EG, Na3Cit Solvothermal 200 170300 21a-Fe2O3 FeCl3, urea THF, ethanol, PVP Solvothermal 180 22ZnO Zn(Ac)2 DEG Thermolysis (microwave) 57274 17
Abbreviations: Ac: acetate; Mt: myristate; St: stearate; ODE: 1-octadecene; OA: octadecyl alcohol; DA: decyl alcohol; EG: ethylene glycol; DEG:
diethylene glycol; PEG: polyethylene glycol; Cit: citrate; PAA: polyacyl acid; PVP: polyvinyl pyrrolidone.
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is enabled by a balance between electrostatic repulsion force
and van der Waals attraction force. This method has been
extended to the synthesis of CNCs of other materials, such as
CdS, ZnSe and PdS.
Thermolysis using microwave irradiation for heating represents
another method for producing colloidal inorganic nanomaterials,
which is very ecient and features unique advantages for
synthesis. It is believed that microwave dielectric heating can
address problematic issues such as heating inhomogeneity and
slow reaction kinetics present in conventional thermolysis
reactions, which rely on thermal conduction to drive chemical
reactions. As a result, it is becoming an increasingly popular
heating method for nanomaterial synthesis. Hu et al. have
employed a rapid microwave process to produce narrowly
distributed ZnO CNCs in relatively large quantities by heating
a zinc acetate solution in DEG using microwave irradiation.17
The high polarizability of DEGmakes this solvent an excellent
microwave absorbing agent, thus leading to a high heating rate
and short reaction time compared to existing solution-based
synthetic routes using conventional heating techniques. The size
of the clusters, which comprise small primary nanoparticles, can
be tuned continuously and precisely from about 57 to 274 nm
by simply varying the amount of zinc precursor.
2.1.2. Solvothermal synthesis. Solvothermal synthesis refers
to chemical reactions that are performed in a closed reaction
vessel (autoclave) at temperatures higher than the boiling point
of the solvent. This approach has become one of the most
widely used tools for nanoparticle synthesis due to the relatively
easy steps involved, simple setups, and reduced energy require-
ments, although it suers from several drawbacks such as
limited scalability and the lack of opportunities for direct
monitoring of the reaction process. A number of examples of
3D CNCs composed of primary nanoparticles have been
demonstrated through solvothermal methods.1823 In a typical
process for the synthesis of Fe3O4 CNCs, a solution containing
Fe(acac)3 (precursor), polyvinylpyrrolidone (PVP, surfactant),
and ethylene glycol (EG, solvent) was sealed in a Teon-lined
autoclave and heated to 140145 1C for 36 h.18 The products
were Fe3O4 CNCs containing disordered nanoscale pores
formed during assembly of the corresponding primary nano-
particles. Although the exact formation mechanism is unclear
due to the diculty of sampling under high temperature and
high pressure, it is convenient to control the size of the Fe3O4CNCs by changing the amount of precursor Fe(acac)3. To
further tune the sizes of the primary nanoparticles and secondary
Fe3O4 CNCs, Xuan et al. modied the solvothermal process
by utilizing sodium acrylate as surfactant to synthesize a series
of clusters.20 The average primary nanoparticle size could
be continuously tuned from B5.9 to B21.5 nm by simplychanging the weight ratio of sodium acrylate/NaAc, while the
overall size of the secondary structures could also be precisely
controlled in a wide range (up to B280 nm) by regulatingthe ratio of the two solvents (EG/DEG). Although this
solvothermal method is believed to be general for constructing
cluster structures from many other inorganic materials, the
success has been mainly limited to iron related materials, such
as Fe3O4, ferrite, and a-Fe2O3 (Table 1).
2.2. Clustering pre-synthesized nanoparticles
The utilization of pre-prepared nanoparticles as building
blocks for new materials such as 3D CNCs provides unique
opportunities to combine the inherent functionality of the
nanoparticles with potential collective properties resulting
from their interaction. Thanks to rapid progress in colloidal
nanostructure synthesis, a great number of materials can now
be routinely produced in the form of nanoparticles with excellent
control over size, shape and surface properties.1 It can easily be
appreciated that modular assembly approaches are highly attractive
for the preparation of secondary structured nanomaterials
with various congurations and programmable properties.
Many nanoparticle assembly methods have been developed
in the last decade. In this review, we focus on liquid-phase
strategies, which are very exible for controlling the structure,
composition and morphology of the nal CNC structures.
2.2.1. Evaporation-induced self-assembly (EISA). Self-assembly
of pre-synthesized nanoparticles through evaporation of solvents
in the presence of block-copolymers as structure directing
templates was initially designed for preparing mesoporous
metal oxide structures with high surface areas, high thermal
stability, and fully crystalline networks.24,25 Although meso-
porous materials have been extensively reported, the prepara-
tion of fully crystalline frameworks has remained a major
challenge due to the fact that many mesoporous oxide struc-
tures collapse during the crystallization process. Compared to
the well-known surfactant-templating method for mesoporous
silica structures, EISA utilizes crystalline nanoparticles instead
of molecular precursors as building blocks. In a typical
EISA process, monodisperse tin oxide nanoparticles of several
nanometers were prepared rst, and then dispersed in tetra-
hydrofuran (THF), forming a transparent and stable dispersion
with the addition of polybutadiene-block-poly(ethylene oxide)
(PB-PEO) block copolymer.26 The subsequent evaporation of
the THF solvent induced the assembly of nanoparticles and
PB-PEO block-copolymer micelles, nally leading to the formation
of mesoporous structures with ordered 1820 nm mesoscale pores.
The samples were further treated under air at high temperatures
Fig. 2 Representative TEM images of Fe3O4 CNCs with average
diameters of (a) 53, (b) 93, and (c) 141 nm. (d) High magnication
TEM images of 93 nm CNCs. Adapted with permission from ref. 13.
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to completely remove the polymer templates, producing high
quality mesoporous structures.
EISA is a general method for the preparation of meso-
porous structures containing dierent nanoscale components.
When applied to nanoparticle dispersions conned in dened
volumes, such as droplets in an emulsion, it becomes a powerful
method to produce various mesoporous nanoparticle clusters
with desired overall dimensions. However, great eort is still
required to make these structures into a colloidal form with small
sizes and homogenous morphology in order to satisfy the needs
of specic applications, such as photonics and bioanalysis.
The oil-in-water emulsion evaporation method can be divided
into two steps as shown in Fig. 3a: (i) A nonpolar dispersion of
pre-synthesized nanoparticles is emulsied into an aqueous
solution containing emulsier (i.e., sodium dodecyl sulfate (SDS)
and cetyltrimethylammonium bromide (CTAB)), producing an
oil-in-water emulsion with oil droplets of a few micrometers.
(ii) The nanoparticles are concentrated and condensed into CNC
structures by evaporating the oil phase in the emulsion droplets.
The assembly is driven by the hydrophobic van der Waals
interactions of the capping ligands on the nanoparticle surface.
The hydrophobic nature of the nanoparticles also keeps the
clusters aggregated and prevents them from breaking up in the
aqueous environment. The emulsier is adsorbed onto the cluster
surface through the hydrophobichydrophobic interaction with
the capping ligands on the nanoparticles, which also helps to
disperse the clusters in water. Bai et al. demonstrated this facile
and universal bottom-up assembly strategy for preparing CNCs
from various nanoscale building blocks with dierent sizes and
shapes, such as BaCrO4, Ag2Se, CdS, PbS, Fe3O4, ZrO2, NaYF4nanodots, Bi2S3 and LaF3 nanoplates, and PbSeO3 nanorods.
27
The TEM images of BaCrO4 CNCs shown in Fig. 3b and c clearly
illustrate that the constituent nanoparticles retain their individual
character and do not sinter into larger units. The size of the CNCs
can be controlled by the parameters of the emulsication process
such as the concentration of nanoparticles in the oil phase and
the oil-to-water ratio. Specically, smaller clusters were
obtained by emulsication under sonication instead of stirring;
a higher nanoparticle concentration and oil-to-water ratio led
to larger clusters. More experimental details of this emulsion-
based nanoparticle assembly were studied by Simard and
co-workers.28 They concluded that: (1) the size and size
distribution of the clusters are dened by the droplets made
during emulsication and, as a result, are determined by the
emulsication conditions and emulsion composition; (2) the
size of the clusters is most conveniently controlled by varying
the concentration of nanoparticles in the oil phase; (3) the size
distribution can be narrowed by using a high volume fraction
of the droplet phase. This emulsion-based assembly process
also brings the convenience of incorporation of multiple compo-
nents into clusters to enable multifunctionality. Composite nano-
particle clusters can be fabricated by simply starting with amixture
of dierent types of nanoparticles, such as gFe2O3/TiO2,29
NaYF4-Yb,Er/NaYF4:Eu30 and CeO2/Pd.
31 The nanoparticle
packing characteristics in clusters can be determined by the
reaction temperature, which determines the rate of solvent
evaporation.32 Well-ordered nanoparticle superlattices with a
body-centered cubic (bcc) structure form with slow evapora-
tion at room temperature, while at a higher evaporation
temperature, multi-domain polycrystalline structures and
eventually completely amorphous structures will be produced.
To achieve more ordered packing of nanoparticles in clusters,
Cao and co-workers developed a modied assembly approach as
illustrated in Fig. 3c. Pre-synthesized uniform nanoparticles were
rst transferred from nonpolar solvent to aqueous solution by
using surfactants such as dodecyltrimethylammonium bromide
(DTAB). Then, ethylene glycol (EG) was added to the nano-
particle dispersion, leading to the formation of CNC structures
due to the weakened protection of DTAB in the EG solution.
Finally, the clusters were protected by adding PVP and annealed at
80 1C for 6 h.3,33,34 The annealing treatment is important forincreasing the order of the nanoparticle packing in the CNCs.
TEM images in Fig. 3d clearly show superlattice fringes, suggesting
that the nanoparticles were rearranged into a nearly perfect face-
centered cubic (fcc) packing after annealing.
Several modications to the emulsion evaporation method
were reported for fabricating CNC structures. Silica precursor
tetraethylorthosilicate (TEOS) was mixed with hydrophobic
nanoparticles in a nonpolar solvent and then emulsied in DEG
using a surfactant, as shown in Fig. 4a.35 This oil-in-DEG
technique oers the following advantages: (1) TEOS is constrained
Fig. 3 (a) Schematic illustration of oil-in-water emulsion solvent
evaporation for CNC preparation. (b) TEM images of BaCrO4 CNCs.
Adapted with permission from ref. 27. (c) Schematic illustration of CNC
preparation. (d) TEM images of CNCs 190 nm in diameter made of
Fe3O4 nanoparticles (5.8 0.2 nm in diameter) viewed along dierentzone axes. Scale bars: 20 nm. Adapted with permission from ref. 3.
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in the oil droplets together with the nanoparticles, ensuring
that the hydrolysis and condensation of TEOS only occurs in
the oil droplets, avoiding the formation of free silica spheres.
Silica was directly coated onto the CNCs after assembly.
(2) The use of DEG eectively limits the hydrolysis and
condensation of TEOS within the oil droplets, resulting in
better control of the particle size and avoidance of agglomeration.
In another case, biodegradable polymer (poly(D,L-lactic-co-glycolic
acid), PLGA) was introduced into the nanoparticle-containing oil
droplet to form an oil-in-water emulsion (Fig. 4b).36 After oil
evaporation, the nanoparticles were successfully embedded into
the PLGA matrix to form CNC structures. With the same
approach, QDs can be embedded in the matrix of polystyrene-
co-methacrylic acid (poly-St-co-MAA) copolymer.37 In these
assemblies, the polymers acted as glue for clustering nano-
particles and provided a matrix for loading drugs or other
functional species, such as uorescent probes. In addition to
serving as matrices, polymers can also be used as templates for
nanoparticle clustering.32 When polymers that were incompatible
with the nanoparticles were included in the emulsion formulation,
monolayer- and multilayer-nanoparticle coated polymer beads
and partially coated Janus beads were prepared. The nanoparticles
were expelled by the polymer as its concentration increased
upon evaporation of the solvent and accumulated on the
surfaces of the polymer beads (Fig. 4c). The number of
nanoparticle layers depended on the polymer/nanoparticle
ratio in the oil droplet phase.
2.2.2. Layer-by-layer (LBL) assembly. The layer-by-layer
(LBL) assembly technique was originally used for producing
thin polyelectrolyte lms on solid surfaces. The assembly
process involves sequential incubation of a charged solid
support in an oppositely charged polyelectrolyte solution.
After its invention, the LBL process was quickly adopted as
a versatile route for the creation of various nanoparticle shells
by sequential adsorption of nanoparticles and polyelectrolyte
onto the surface of submicrometer beads.3841 In a typical
process, submicrometer beads (e.g. silica or polystyrene) are rst
primed with several layers of polyelectrolyte lm to provide a
uniform charged surface that assists in the subsequent uniform
deposition of nanoparticles. Following nanoparticle adsorption, the
beads are centrifuged and washed for several cycles to remove
unadsorbed species, and then used for the next cycle of adsorption
of polyelectrolytes. The process is repeated until the desired number
of layers is obtained. An apparent limitation of the LBL assembly
method is that it typically only works with hydrophilic nano-
particles because it relies heavily on electrostatic interactions.
Many technologically important high quality nanoparticles,
Fig. 4 Schematic illustration of three emulsion evaporation based preparation methods for CNC structures and the corresponding TEM images
of the products: (a) TEOS assisted clustering, adapted with permission from ref. 35; (b) polymer assisted clustering, adapted with permission from
ref. 36; (c) polymer assisted clustering followed by phase segregation, adapted with permission from ref. 32.Dow
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especially semiconductors and metal oxides, cannot be directly
assembled using the LBL method because they are predominantly
prepared and dispersed in organic solvents.
We recently developed a general LBL process that allows
convenient production of multifunctional composite particles by
direct self-assembly of hydrophobic nanoparticles on mercapto-
silica hosts containing high-density surface thiol groups.4 As
shown in Fig. 5a, hydrophobic nanoparticles can be directly
assembled onto the host surface through the strong coordination
interactions between soft metal cations and thiol groups. By
alternating mercapto-silica coatings and the nanoparticle
immobilization processes, multilayer structures composed of
various nanoparticles can be achieved. As a demonstration, we
started with 300 nm MPS spheres (mercapto-silica beads,
produced by hydrolysis and condensation of (3-mercaptopropyl)-
trimethoxysilane), immobilized g-Fe2O3 nanoparticles onthe surface, overcoated with a thin SiO2/MPS layer, and the
immobilized QDs on the surface. Fig. 5b and c show the electron
dispersive X-ray (EDX) elemental mapping and a typical TEM
image of a multilayer MPS@g-Fe2O3@SiO2&MPS@QD struc-ture. As indicated by the two dotted lines in Fig. 5c, the dierent
locations of Fe and Cd clearly suggest that the g-Fe2O3 nano-particles and QDs are distributed within dierent layers of the
composite. The gap between these two nanoparticle layers is 50 nm,
which corresponds to the thickness of the SiO2&MPS layer.
Yoon et al. recently developed a novel LBL method for
nanoparticle assembly based on the nucleophilic substitution reac-
tion between bromo and amine groups in organic media.42 They
rst prepared 2-bromo-2-methylpropionic acid (BMPA) stabilized
nanoparticles and amine-functionalized poly(amidoamine)
(PAMA) dendrimers, which were then sequentially coated
on colloidal silica beads. Analogous to the assembly induced
by the metalthiol interaction, the direct adsorption of the
nanoparticles in organic nonpolar solvent signicantly increases
their packing density in the lateral dimensions because electro-
static repulsion between neighboring nanoparticles is absent.
Moreover, the capping ligands on the nanoparticles are not
disturbed so that they retain their original properties such as
highly ecient luminescence.
2.2.3. Liquidliquid interface assembly. The assembly of
nanoparticles at a liquidliquid interface, analogous to the case
of Pickering emulsions, generates a resistant lm at the interface
between two immiscible phases, inhibiting the coalescence of
emulsion drops, as shown in Fig. 6a. A typical example is CdSe
nanoparticle assembly at the watertoluene interface to form a
kinetically stabilized water-in-oil emulsion (Fig. 6b and c).43 This
interfacial assembly is driven by the reduction in interfacial
energy, which depends on the nanoparticle size, particleparticle
interaction, particlewater and particleoil interactions. Larger
nanoparticles have a stronger stabilization eect for the assembly.
For example, 4.6 nm CdSe nanoparticles can be assembled on the
surface of an already stabilized droplet, displacing smaller 2.8 nm
particles.44 To fabricate mechanically stable capsules and
membranes from spherical nanoparticle assemblies, the nano-
particles need to be crosslinked at the interface, which requires
pre-modication of the nanoparticle surface with reactive
organic molecules.45 Compared with layer-by-layer polyelectro-
lyte deposition, assembly at the liquidliquid interface requires
fewer steps, aords ultrathin nanoparticle shells, and may reduce
structural defects due to the mobility of nanoparticles at the uid
interface. However, the emulsion droplets produced by liquid
liquid interface assembly are generally larger than several micro-
meters, which may limit their potential applications.
2.3. Comparison of one-step and multi-step methods
One-step syntheses of CNC structures are more convenient
and time-saving than those involving multiple steps. More-
over, clusters obtained through this method typically have
Fig. 5 (a) Schematic illustration showing the procedure of layer-by-
layer assembly of hydrophobic nanoparticles on MPS spheres.
(b and c) TEM and EDX mapping of the elemental distribution of
MPS@g-Fe2O3@SiO2&MPS@CdSe multilayer composites. Adaptedwith permission from ref. 4.
Fig. 6 (a) Schematic of the self-assembly of solid nanoparticles at the
oilwater interface. (b) Fluorescence confocal microscope image of
water droplets dispersed in toluene, covered with CdSe nanoparticles.
(c) Dierential interference contrast optical microscopy image of dried
droplets on a silicon substrate. Inset: AFM height section analysis.
Adapted with permission from ref. 43.
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narrower size distribution, which is very important for applica-
tions that require high uniformity, for example, in the construc-
tion of photonic crystals. However, the literature only contains a
limited number of examples for successful preparation of CNC
structures because controlling the clustering of the nanoparticles
during synthesis is usually even more challenging than that of
simple isolated nanoparticles. The key issue is to identify the
critical point of ligand protection for cluster formation. Above
the critical point, isolated and non-agglomerated nanoparticles
will form, whereas below the critical point, care has to be
taken to avoid the formation of uncontrolled aggregations
with random morphologies. Nanoparticle assembly through
two or more consecutive steps represents a more general class of
strategies for the preparation of CNC structures. Considering
the variety of nanoparticles that has been prepared in the last
decade, and the many possibilities to arrange them, such
modular approaches are advantageous for preparing materials
with tailored properties. Among various assembly approaches,
EISA in combination with emulsions represents a general
method which is very exible in organizing various nano-
particles into cluster structures, although it remains a challenge
to improve the uniformity of the resulting clusters. Assembly of
nanoparticles at a liquidliquid interface is unique in that it
produces hollow shells which can be further stabilized by
crosslinking the surface ligands. The challenge is in controlling
the size as well as the thickness of the shells. LBL assembly also
provides a universal strategy to arrange nanoparticles into
clusters with uniform size and morphology, but the loading
density of the nanoparticles is relatively low due to single layer
adsorption.
3. Surface modication of CNCs
Directly synthesized CNC structures are usually mechanically
stable and can be processed in the same manner as typical
colloidal nanoparticles, including multiple cleaning steps,
surface modication, and further assembly into more complex
structures. On the other hand, CNCs produced through
assembly approaches are generally protected by a layer of
surfactants that renders the particles highly dispersible in
solvents. The van der Waals interactions between the ligands
capping the nanoparticles and the hydrophobic tails of the
surfactant are generally weak and can be easily disturbed by
changes in the chemical environment, sometimes leading to
aggregation of the clusters in solution. The cluster structure
may be destroyed when subjected to strong mechanical forces
or when exposed to good solvents which can solvate individual
nanoparticles. In addition, it is often necessary to link func-
tional molecules to the surface of the CNCs, which is dicult
due to the weakly adsorbed surfactants. To address these
issues, a more robust protecting layer is often required. For
some applications, in particular, catalysis, a clean surface is
essential. Although calcination at high temperatures allows the
removal of the surfactants/capping ligands, it can lead to the
production of big aggregates. In this case, it may become
necessary to introduce a sacricial coating onto the surface of
the clusters which can prevent the formation of large aggrega-
tions. Here we summarize the three main surface treatment
methods reported for nanoparticle cluster structures: direct
calcination, silica coating, and polymer coating, as schemati-
cally illustrated in Fig. 7a.
3.1. Direct calcination
The application of nanostructured materials in bio-separation
or catalysis generally requires a clean surface to ensure sucient
active surface sites. However, high quality nanoparticles, as well
as CNCs assembled from them, are typically covered with a
layer of capping ligands, which prevents them from eectively
accepting target molecules. Direct calcination is the most
straightforward treatment to remove these organic ligands
and completely clean the material surface. Han et al. calcined
iron oxide clusters at 550 1C in air for 3 h to yield mesoporousmicrospheres with clean surfaces. The calcination removes
ligands occupying the materials surface and enhances the
mechanical stability of the clusters by bridging neighboring
nanoparticles through thermal fusion. On the other hand,
the primary nanoparticles still can be distinguished by TEM
imaging, suggesting that the interparticle fusion is modest.46
However, as expected, the calcination can cause severe aggrega-
tion of the clusters, and their spherical morphology may not be
well maintained during calcination.29
3.2. Silica coating
The usefulness of silica as a coating material mainly lies in its
high stability, easy control during the coating process,
chemical inertness, controllable porosity, processability and
optical transparency. In addition, a silica coating can endow a
composite with biocompatibility and the possibility of subsequent
functionalization. We have demonstrated a silica coating on
hydrophilic Fe3O4 CNCs by hydrolyzing tetraethoxysilane
(TEOS) in a mixture containing ethanol, CNCs, and ammonia
(NH3H2O) aqueous solution (Fig. 7b). The thickness of the silicashell can be tuned from ten to several hundred nanometers by
simply controlling the concentration of the precursor, TEOS.47,48
After silica coating, the CNCs can be well-dispersed in polar
solvents such as water and alcohol.
As an additional advantage, a silica shell provides more possibi-
lities for further surface modication through well-developed silane
chemistry. For example, we have demonstrated that a monolayer
of hydrophobic alkyl chains of n-octadecyltrimethoxysilane
Fig. 7 (a) Schematic illustration of surface treatment methods for
CNC structures. (b) TEM image of silica coated Fe3O4 CNCs.
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(ODTMS) can be grafted onto the silica surface through
covalent SiOSi bonds, making the Fe3O4 CNC@SiO2colloids dispersible in most nonpolar solvents such as
1,2-dichlorobenzene, toluene, chloroform, and hexane.49 In
another demonstration, we have functionalized the Fe3O4CNC@SiO2 colloids with [3-(methacryloyloxy)propyl] trimethoxy-
silane (MPTMS) through siloxane linkage. An aqueous phase
precipitation polymerization process was then used to form a robust
thermoresponsive polymer coating on the core surface by
copolymerizing the surface MPTMS with N-isopropylacryl-
amide (NIPAM, monomer).50,51
A mesoporous silica shell can also be coated onto the CNCs
through a well-known surfactant-templating approach with
CTAB as the templating surfactant.52 An ordered mesoporous
silica phase with cylindrical channels is formed in the outer
layer, as conrmed by TEM imaging. These unique meso-
porous channels, which are perpendicular to the CNC core
surface, oer high surface area for the derivatization of
various functional groups, provide a large pore volume
for the adsorption and encapsulation of biomacromolecules
and even functional nanoparticles, and also enhance the
accessibility of the CNC cores.
For CNCs assembled from preformed nanoparticles, a silica
layer is critically important for maintaining their morphology
during calcination. We have recently developed a protected
calcination method to obtain readily dispersible colloidal
clusters by using hydrophobic TiO2 CNCs as a model system.8
In a typical process, TiO2 CNCs are prepared by evaporation
of the nonpolar solvent from an oil-in-water emulsion, and
then coated with a silica layer, calcined at 500 1C for 2 h in air,followed by removal of the SiO2 layer through chemical
etching in a dilute aqueous solution of NaOH. The silica
coating and removal steps are essential for the successful
fabrication of well-dispersible clusters. First, the silica layer
protects the clusters from aggregation during calcination at
high temperatures. Even though slight inter-cluster aggregation
occurs due to silica fusion during calcination, the subsequent
etching by NaOH removes the silica layer and releases the
clusters from aggregation. Second, the etching process after
calcination introduces a relatively high density of hydroxyl
groups so that the cluster surface becomes negatively charged,
making the clusters dispersible in water. This silica coating
calcination-silica removal method can be easily extended to
other clusters with dierent components or prepared by dierent
methods.
3.3. Polymer coating
Polymer coating is an alternative method to render clusters
more mechanically robust. In addition, polymer coating has a
number of other advantages: (1) the surface properties of
clusters can be easily tuned by coating with dierent polymer
layers. For example, polyethylene glycol (PEG) will greatly
enhance the water dispersity and biocompatibility of clusters.
(2) The large family of functional polymers oers many
opportunities for building up multifunctional clusters. (3) A
new functionality may also be incorporated into a polymer
shell by copolymerizing a functional monomer or through
post-modication methods. (4) The thickness of a polymer
shell can easily be adjusted down to several nanometers, which
is particularly important when only a thin shell is required. A
polymer coating can be achieved either by polymer adsorption
or monomer polymerization on the CNC surface. For example,
the positively charged poly(L-lysine)-poly(ethylene glycol)-folate
(PLL-PEG-FOL) can be adsorbed on negatively charged cluster
surfaces through the electrostatic interaction.36 An amphiphilic
hydrolyzed polymer, poly(maleic anhydride-alt-1-octadecene)
(PMAO), can be utilized to partially replace SDS coated
onto clusters through the coordination interaction between
carboxylic acid and metal oxide surfaces.53 Paquet et al.
reported a direct polymer coating for clusters using seed-
emulsion polymerization.28 In this method, CNCs were rst
prepared by the oil-in-water emulsion evaporation method
with SDS adsorbed on the surface. As the polymerization
reaction was thermally initiated, monomers such as methyl
methacrylate, styrene, and/or acrylic acid started to grow on
the cluster surface. To achieve polymerization at the surface of the
clusters and prevent nucleation and polymerization in micelles
formed by SDS, the concentration of the SDS in the dispersion of
clusters was maintained below the critical micelle concentration,
but high enough to maintain stability of the clusters.
When nanoparticles are originally covered with ligands
containing polymerizable groups, such as diynes and enediynes,
in situ photo-polymerization may be used to crosslink these
ligands after nanoparticle assembly.54,55 For example, Au
nanoparticles with protecting ligand 46-mercapto-22,43-
dioxo-3,6,9,12,15,18-hexaoxa-21,44-diazahexatetraconta-31,33-
diyn-1-oic acid (DA-PEG) were rst assembled into chain
structures by manipulating the electric dipoledipole inter-
actions, and then exposed to UV irradiation to crosslink the
surface ligands, thereby xing the cluster structure through the
polymerized DA-PEG thin layer and signicantly enhancing
their stabilities.54
4. Applications of CNCs
CNCs represent a new class of materials that have broad
applications in photonics, catalysis and bioanalysis due to
their unique properties compared to their primary nanoparticle
building blocks.
(1) CNCs can enhance the properties of the primary nano-
particles. For example, quantum dots (QDs) are attractive
uorescent materials for biological imaging due to their
spectral tunability in the visible and infrared regions. Individual
QDs, although possessing high quantum yields, sometimes are
insuciently bright due to their small sizes. However, CNC
structures assembled from primary QDs can provide much
stronger signals in biological imaging.56 Another important
case is superparamagnetic iron oxide nanoparticles, which have
primarily received attention for potential biomedical applica-
tions, as they are not subject to strong magnetic interactions in
dispersion. Several robust approaches have been developed for
synthesizing magnetic iron oxide (e.g., g-Fe2O3 or Fe3O4)nanoparticles with sizes ranging from several to B20 nm.However, these as-synthesized nanoparticles have a low
magnetization per particle, which limits their usage in many
important applications such as separation, targeted delivery or
magnetic resonance imaging (MRI). Increasing the nanoparticle
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size increases the saturation magnetization, but also induces
the superparamagneticferromagnetic transition.13 Assembling
these nanoparticles into CNCs produces a material that possesses
a much higher saturated magnetization, but retains the original
superparamagnetic behavior of its building blocks even though
the overall cluster size exceeds 30 nm. By taking advantage of this
unique feature, many groups have successfully demonstrated the
use of these superparamagnetic iron oxide CNCs with various
sizes for magnetic separation.57,58 In addition, iron oxide CNCs
have shown improved contrast in MRI due to the high concen-
tration of nanoparticles in the cluster structures.59
(2) Clustering may enable multifunctionality by combining
various building blocks. For example, clusters composed of
magnetic iron oxide nanoparticles and uorescent quantum
dots have been widely studied as multiple-mode imaging
contrast agents for combining MRI and optical imaging.36
Replacing QDs with noble metal nanoparticles in such compo-
sites creates multifunctional structures that are capable of MRI
enhancement and photothermal therapy.60 Superparamagnetic
iron oxide nanoparticles were added to TiO2 clusters to facilitate
separation by an external magnetic eld for phosphopeptide
enrichment.29 Besides the building blocks of the clusters, capping
ligands on nanoparticles and the protection layer of the clusters
such as silica and polymer can also act as functional materials.
Clusters composed of oleic acid capped iron oxide nanoparticles
were employed for enrichment of peptides and proteins based
on the use of hydrophobichydrophobic interactions between
the oleic acid and the analytes.61 Aligned mesoporous silica
shells coated on paramagnetic clusters can be used for the
removal of microcystins.52
(3) CNCs may exhibit collective properties not present in
individual nanoparticles. A classic example is the clustering of
noble metal nanoparticles for generation of hot spots for
enhancing Raman scattering. The assembly of plasmonic
nanoparticles into secondary structures may induce near eld
electromagnetic coupling of surface plasmons between adjacent
particles, thus creating hot spots that can signicantly enhance
the Raman signals from analytes.62,63
(4) CNCs represent novel mesoporous structures with crystal-
line frameworks. Mesopores can be formed by packing primary
nanoparticles into clusters. For primary nanoparticles containing
capping ligands, they are typically calcined to remove the organic
ligands to allow full access by the target molecule. Calcination at
high temperatures may also enhance the mechanical stability of
the clusters by bridging neighboring nanoparticles together
through thermal fusion. Due to the crystalline nature of the
primary particles, they do not grow signicantly during calcina-
tion, preserving the high surface area and spherical morphology
of the clusters. The pore sizes of CNCs can be conveniently
controlled by changing the size and shape of the building blocks
during assembly. The submicrometer size of the clusters and the
three-dimensional pores enable fast diusion and adsorption of
target molecules. As a result of these great properties, clusters can
be employed for drug loading and delivery,64 bioseparation,8
sensing17 and catalysis.9 Furthermore, clustering methods can be
easily extended to the production of multicomponent structures
such as QD/TiO2 and QD/Au/TiO2 hybrid mesoporous
CNCs, which have been found to be highly ecient in photo-
electrochemical (PEC) cell applications.65,66
(5) Clusters facilitate surface modication. Ligand exchange
for individual nanoparticles usually involves several complex
steps and in many cases is detrimental to the physical proper-
ties of the nanoparticles because the new ligands may not be
able to eectively insulate the inorganic cores from chemical
disturbance from their environment. On the other hand,
surface modication of nanoparticle clusters can be considerably
easier as many approaches including ligand attachment, silica
encapsulation, and polymer coating have been well developed for
submicrometer objects.
These features have enabled a number of interesting appli-
cations for CNC structures in the last few years. Since it is
dicult to give a complete overview in this tutorial review,
here we use three typical applications to highlight their unique
advantages in designing structural and surface properties.
4.1. Magnetic responsive photonic crystal structures
The unique cluster structure allows Fe3O4 CNCs to retain
their superparamagnetism at room temperature even though
their overall size exceeds the critical size (30 nm) distinguishing
ferromagnetic and superparamagnetic magnetite. As shown in
Fig. 8a and b, the magnetization hysteresis loops of CNCs
with various sizes display typical superparamagnetic charac-
teristics with immeasurable remanence or coercivity at 300 K.
The cluster structure gives the Fe3O4 CNCs a much higher
saturated magnetization and thereby a stronger magnetic
response to external elds than the constituent nanoparticles.
The inset shows that the magnetic moment per cluster increases
with its overall size.
With the successful synthesis of Fe3O4 CNCs featuring the
superparamagnetic property, large and uniform sizes, and
highly charged surfaces, we have demonstrated their assembly
in aqueous solution into photonic crystal structures whose
optical signals can be instantly tuned by using external magnetic
elds.67,68 Under white light illumination, the colloidal photonic
crystals in the solution show brilliant colors from red to blue
when the strength of the applied magnetic eld is increased
(Fig. 8c). This visual eect, observable when viewed parallel to
the magnetic eld, results from the Bragg diraction of
incident light by the periodically ordered structures assembled
from Fe3O4 CNCs. A strong magnetic dipoledipole inter-
particle attraction is induced instantly in the superpara-
magnetic particle dispersion in response to the application of
external magnetic elds, which creates one-dimensional chains
each containing a string of particles (Fig. 8d). The interparticle
separation is dened by the balance between the magnetic
attraction and the interparticle repulsion of the electrostatic
force. By employing uniform superparamagnetic CNCs of appro-
priate sizes and surface charges, one-dimensional periodicity may
be created, which leads to strong diraction in the visible regime.
Magnetic forces, acting remotely over a large distance, not
only drive the rapid formation of colloidal photonic arrays
with a wide range of interparticle spacing, but also allow
instant tuning of the photonic properties by changing the
orientation of the colloidal assemblies or their periodicity
through the manipulation of the interparticle force balance.
Fig. 8e shows the reection spectra of 120 nm Fe3O4 CNC
aqueous solution in response to an external magnetic eld with
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varying strength achieved by changing the magnet-sample distance.
This optical response to the external magnetic eld is instantaneous
and fully reversible, and the required eld strength for realizing the
ordering of CNCs and color tuning is merely 50500 G. By
modifying the CNC surface property, we have been able to extend
this assembly process to solvents of various polarities,49 making it
possible to fabricate photonic crystal microspheres whose orienta-
tion and consequently photonic property can be easily controlled by
using external magnetic elds.69
4.2. Catalysis
Metal nanoparticles have been extensively studied as eective
catalysts in many reactions. In catalysis, it is important to ensure
that the dispersed metal nanoparticles retain their original struc-
ture, in particular their size and shape, throughout their pretreat-
ment, activation, and catalytic use. However, metal nanoparticles
tend to reconstruct, diuse, coalesce, and sinter during the reaction
process, which leads to signicant reduction in catalytic activity. It
is therefore highly desirable to develop ways to overcome
this limitation. Nanoparticle clusters are ideal support materials
because of their intrinsic porous structure, high surface area, rigid
framework, short diusion length for surrounding solutes, and
easy inclusion of catalyst nanoparticles. For example, metal
nanoparticles can be conveniently embedded in metal oxide
CNCs and display high and stable catalytic activity, as shown
in Fig. 9. The metal particles are eectively separated from
each other and trapped in the metal oxide matrix. Even after
heat treatment, the metal nanoparticles are still well separated.
In addition, the target molecules can easily access the metal
nanoparticle surface through the mesopores of the CNC
structures.31 The hydrogenation of cyclohexene to cyclohex-
ane and its dehydrogenation to benzene were used as probe
reactions to study the catalytic performance of the prepared
PdCeO2 composite CNCs. The results in Fig. 9 show excellent
selectivity of the CNC catalyst, with products being exclusively
cyclohexane at low reaction temperature (o185 1C) and benzeneat high temperature (B350 1C). Conducting the hydroconversionreactions for three cycles shows no signicant loss in catalytic
activity, indicating good thermal stability and robust performance
of the composite catalyst.
4.3. Bioseparation
Metal oxide anity chromatography (MOAC), built upon a
variety of metal oxide materials such as TiO2, has been
Fig. 8 (a) Schematic illustration showing that larger Fe3O4 CNCs have higher saturated magnetization. (b) Mass magnetization (M) as a function
of applied external eld (H) measured for 53 nm, 93 nm, 174 nm CNCs and a reference sample of 8 nm single crystalline nanoparticles of Fe3O4.
Inset shows the magnetic moment (m) per cluster (or particle) plotted in a logarithmic graph. Adapted with permission from ref. 13 (c).Photographs of aqueous solution of Fe3O4 CNCs in response to an increasing magnetic eld. The sample-magnet distance increases gradually from
left to right. (d) Schematic illustration showing the magnetic assembly of Fe3O4 CNCs into chains of periodically arranged particles which can
diract visible light. (e) Reection spectra of 120 nm Fe3O4 CNC aqueous solution in response to an external magnetic eld with varying strength
achieved by changing the magnet-sample distance. Adapted with permission from ref. 67.
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intensively studied because of its high selectivity for phospho-
peptide trapping. In addition, nanoparticles have many super-
ior characteristics for bioseparation compared to those of the
conventional micrometer-sized resins or beads, including high
capacity, fast and eective binding, and short diusion length
for biomolecules. However, there are several intrinsic dicul-
ties in the application of nanoparticles for bio-separation.
First, they cannot be conveniently separated from the solution
mixture by conventional methods such as centrifugation be-
cause of their extremely small sizes. Second, high quality
nanoparticles are typically synthesized in nonpolar solvents
so that they are covered with a layer of hydrophobic ligands,
which makes the particles non-water-soluble and greatly limits
their direct use in aqueous environments. Third, the surfaces
covered with hydrophobic ligands cannot eectively trap
biomolecules. Mesoporous CNCs with clean surfaces after
calcination can address these challenges. Using TiO2 CNCs
as an example, the high specicity and capacity of these
mesoporous TiO2 clusters have been demonstrated by eec-
tively enriching phosphopeptides from digests of phosphopro-
tein (a-casein), nonfat milk and human serum sample. Asshown in Fig. 10, after enrichment using the mesoporous TiO2clusters, phosphopeptides can be observed without any
obvious peaks from non-phosphopeptides, clearly showing
the eectiveness of the phosphopeptide enrichment.29 These
results conrm the excellent enrichment power of the nano-
particle clusters compared to solid TiO2 spheres, which can be
attributed to their high specic surface area and the clean TiO2surface. The outer surface of each cluster is made highly
hydrophilic to enhance the accessibility of the nanoparticle
clusters to phosphopeptides. The excellent performance of the
CNCs is also attributed to the submicron size of the clusters
and the three-dimensional pores which enable fast diusion
and adsorption of target molecules. By introducing a silica
coating/removal step, we were able to enhance the mechanical
stability of the clusters through calcination, and also make
their surface considerably charged to enable high water dis-
persibility. The calcination at high temperatures in air removes
the organic surfactants and makes the TiO2 surface fully
accessible to phosphopeptides. As a result, the porous TiO2clusters show attractive performance for selective enrichment
of phosphopeptides, with advantages including high adsorp-
tion capacity, high detection sensitivity, high selectivity, great
water dispersibility, high chemical/mechanical stability, and
easy separation from solution.
An inherent advantage of the self-assembly process is the
convenient incorporation of multiple components into the
clusters to further facilitate separation and detection. We have
also shown that the addition of superparamagnetic iron
oxide nanoparticles to the clusters allows not only selective
phosphopeptide enrichment but also their ecient removal
from the analyte solution by using an external magnetic eld.
Moreover, the pore sizes of the TiO2 clusters can be conve-
niently controlled by changing the size and shape of the
building blocks during assembly, and thus making it possible
to isolate the biomolecules such as intact phosphorylated
proteins with dierent sizes based on the size-exclusion
strategy.8
5. Conclusions and perspectives
We have reviewed the most recent strategies developed for the
preparation, surface modication, and application of colloidal
nanoparticle clusters. A number of liquid-phase synthesis
methods have been discussed, each of which has its own
advantages and drawbacks. While the one-step method is
straightforward and can produce uniform clusters, it is only
limited to a small group of materials. As a matter of fact,
the growth from nanoparticles to clusters is often more
challenging to control than that of the growth of individual
nanoparticles. In the multiple-step assembly strategy, the
synthesis and assembly of nanoparticles are carried out in
two or more consecutive steps. This exible preparation
strategy provides nearly limitless opportunities for producing
nanoparticle clusters from a large variety of materials and
their composites.
There are still many challenges that must be addressed
before CNCs reach their full potential in practical applica-
tions. The most critical problem is how to position specic
nanoparticles in desired locations within clusters, which is a
key for new collective properties resulting from nanoparticle
interactions. The second challenge is the development of
general methods that can produce uniform colloidal clusters
with controllable sizes and shapes. Some recent works have
clearly demonstrated the feasibility of assembling nanocrystals
into superstructures with dened shapes such as micron-sized
cubes, tetragonal structures,70,71 and dodecahedrons and
bipyramids.72 At the current stage, there is still room for
signicant improvement in controlling the size and uniformity
of CNCs. Similar to the development of synthesis methods
for individual colloidal nanoparticles, it is believed that
future research eorts may be directed to the production of
CNCs with particular shapes. Many interesting opportunities
may exist for shape-controlled CNCs, for example, for
constructing highly complex three-dimensional hierarchical
porous structures.
Fig. 9 Selectivity of the cyclohexene hydrogenation to cyclohexane
(lled symbols) and dehydrogenation to benzene (empty symbols) with
PdCeO2 CNCs as catalysts. Inset is a typical TEM image of hybrid
CNC structures. Adapted with permission from ref. 31.
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6886 Chem. Soc. Rev., 2012, 41, 68746887 This journal is c The Royal Society of Chemistry 2012
For clusters made using self-assembly approaches, another
challenge is the realization of ordering nanoparticles within
each cluster. The use of uniform primary nanoparticles is
apparently necessary, which however may not guarantee
perfect long range ordering. Many other parameters such as
solvents, temperature, and ligands may inuence the assembly
processes. Although very nice studies have been initiated on
this interesting concept,3,73 more eorts are still needed to
reveal the interactions involved during the assembly and how
they can be used to manipulate the superstructures built from
primary nanoparticles, which are often seen as articial
atoms in analogy to molecular building blocks. The structural
complexity may increase signicantly when nonspherical nano-
particles are used as building blocks for assembly. In addition, it
is expected that inclusion of impurity nanoparticles with
dierent sizes, shapes, compositions and surface properties
may induce the development of dierent polymorphic forms.
Eventually, it would be interesting to study the change in
physical properties associated with the crystal structural variation
in the formed clusters.
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