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TUTORIAL REVIEW

Colloidal nanoparticle clusters: functional materials by design

Zhenda Lu and Yadong Yin*
Received 1st June 2012 DOI: 10.1039/c2cs35197h
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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
Department of Chemistry, University of California, Riverside CA 92521, USA. E-mail: yadong.yin@ucr.edu

precise control over composition, size, shape, surface properties, 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 nanoparticles but also takes advantage of the interactions between neighboring nanoparticles which can result in new properties

Zhenda Lu

Zhenda Lu received his BS and MS in Chemistry from Nanjing University in China in 2004 and 2007, respectively. He then came to the United States and is currently pursuing his PhD under the supervision of Prof. Yadong Yin at University of California, Riverside. His research focuses on the synthesis, surface modication and selfassembly of nanoparticles, and their bioanalytical and catalytic applications.

Yadong Yin received his BS and MS in Chemistry from the University of Science and Technology of China in 1996 and 1998, respectively, and then PhD in Materials Science and Engineering from the University of Washington in 2002. He then worked as a postdoctoral fellow at the University of California, Berkeley, and the Lawrence Berkeley National Laboratory. In 2006 he joined the Department of Chemistry at Yadong Yin University of California, Riverside. His research interests include colloidal chemistry, self-assembly, surface functionalization, and synthesis of nanostructured materials and their applications.
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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 nanoparticlebased 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.

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Fig. 1 Schematic illustration of the preparation strategies for colloidal nanoparticle clusters (CNCs).

2. Synthesis of colloidal nanoparticle clusters

Colloidal nanoparticles are nanometer-scale inorganic nanoparticles, 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
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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 into active 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
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Summary of one-step approaches for CNC synthesis Precursors Solvent and Surfactant ODE, OA or DA ODE, DA DEG, PAA DEG, PAA DEG, PAA EG, PEG EG, PVP EG, DEG, Sodium acrylate EG, DEG, PVP EG, Na3Cit THF, ethanol, PVP DEG Method Thermolysis Thermolysis Thermolysis Thermolysis Thermolysis Solvothermal Solvothermal Solvothermal Solvothermal Solvothermal Solvothermal Thermolysis (microwave) T/1C 250280 250290 1560 220 215 210 200 140145 200 200 200 180 30180 155240 60180 200800 50100 6170 20300 170300 57274 Size range/nm Ref. 11 10 13 14 15 23 18 20 19 21 22 17

Table 1 Cluster

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Metal carboxylate (Ac, Mt or St) Indium carboxylate In2O3 (Ac, Mt or St) FeCl3, NaOH Fe3O4 PbS Pb(Ac)2, thiourea ZnO Zn(Ac)2, NaOH FeCl3, MCl2, NaAc MFe2O4 (MQFe, Co, Mn, Zn) Fe(acac)3 Fe3O4 FeCl3, NaAc Fe3O4 MFe2O4 (MQFe, Mn, Zn, Co, Ni) FeCl3, MCl2, NaAc FeCl3, NaAc Fe3O4 FeCl3, urea a-Fe2O3 ZnO Zn(Ac)2

In2O3, ZnO, CoO, MnO2

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.

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 nanoparticle 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 protection (LLP), complex three-dimensional (3D) nanostructures can be produced through the oriented attachment of primary nanoparticles. Peng et al. produced 3D nanoower-like structures 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 nanoparticles grow further at 250 1C and eventually agglomerate into 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 aggregation 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 concentration 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.
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Recently, our group has developed a one-pot high-temperature polyol process for the synthesis of polyelectrolyte-capped superparamagnetic CNCs of magnetite (Fe3O4).13 Briey, Fe3O4 CNCs were prepared by hydrolyzing FeCl3 with NaOH at B220 1C in a diethylene glycol (DEG) solution with shortchain 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 temperature, 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 crystallographic 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 an aqueous 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
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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.

were Fe3O4 CNCs containing disordered nanoscale pores formed during assembly of the corresponding primary nanoparticles. 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 Fe3O4 CNCs 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 simply changing 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 regulating the 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

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 DEG makes 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 requirements, 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
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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 mesoporous materials have been extensively reported, the preparation of fully crystalline frameworks has remained a major challenge due to the fact that many mesoporous oxide structures 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 tetrahydrofuran (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
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to completely remove the polymer templates, producing high quality mesoporous structures. EISA is a general method for the preparation of mesoporous 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, NaYF4 nanodots, 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 emulsionbased 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 components into clusters to enable multifunctionality. Composite nanoparticle clusters can be fabricated by simply starting with a mixture 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 evaporation at room temperature, while at a higher evaporation
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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 dierent zone axes. Scale bars: 20 nm. Adapted with permission from ref. 3.

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 nanoparticle 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 for increasing 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 facecentered 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
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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.

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 polystyreneco-methacrylic acid (poly-St-co-MAA) copolymer.37 In these assemblies, the polymers acted as glue for clustering nanoparticles 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
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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 nanoparticles because it relies heavily on electrostatic interactions. Many technologically important high quality nanoparticles,
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their packing density in the lateral dimensions because electrostatic 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 nanoparticles 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 polyelectrolyte 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 micrometers, which may limit their potential applications. 2.3. Comparison of one-step and multi-step methods

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Fig. 5 (a) Schematic illustration showing the procedure of layer-bylayer 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. Adapted with permission from ref. 4.

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 mercaptosilica 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 on the 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 structure. As indicated by the two dotted lines in Fig. 5c, the dierent locations of Fe and Cd clearly suggest that the g-Fe2O3 nanoparticles 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 reaction 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
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One-step syntheses of CNC structures are more convenient and time-saving than those involving multiple steps. Moreover, clusters obtained through this method typically have

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 applications that require high uniformity, for example, in the construction 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 nanoparticles 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.

Fig. 7 (a) Schematic illustration of surface treatment methods for CNC structures. (b) TEM image of silica coated Fe3O4 CNCs.

calcination, silica coating, and polymer coating, as schematically illustrated in Fig. 7a. 3.1. Direct calcination

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 functional 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 aggregations. Here we summarize the three main surface treatment methods reported for nanoparticle cluster structures: direct
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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 mesoporous microspheres 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 aggregation 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 silica shell 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 possibilities for further surface modication through well-developed silane chemistry. For example, we have demonstrated that a monolayer of hydrophobic alkyl chains of n-octadecyltrimethoxysilane
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(ODTMS) can be grafted onto the silica surface through covalent SiOSi bonds, making the Fe3O4 CNC@SiO2 colloids dispersible in most nonpolar solvents such as 1,2-dichlorobenzene, toluene, chloroform, and hexane.49 In another demonstration, we have functionalized the Fe3O4 CNC@SiO2 colloids with [3-(methacryloyloxy)propyl] trimethoxysilane (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-isopropylacrylamide (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 mesoporous 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

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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 seedemulsion 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-22,43dioxo-3,6,9,12,15,18-hexaoxa-21,44-diazahexatetraconta-31,33diyn-1-oic acid (DA-PEG) were rst assembled into chain structures by manipulating the electric dipoledipole interactions, 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 nanoparticles. 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 applications, 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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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
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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 concentration 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 composites 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 crystalline 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 calcination, 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 photoelectrochemical (PEC) cell applications.65,66
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(5) Clusters facilitate surface modication. Ligand exchange for individual nanoparticles usually involves several complex steps and in many cases is detrimental to the physical properties 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 applications 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 characteristics 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 interparticle attraction is induced instantly in the superparamagnetic 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 appropriate 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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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.

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 orientation 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 structure, in particular their size and shape, throughout their pretreatment, 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
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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 cyclohexane 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 benzene at high temperature (B350 1C). Conducting the hydroconversion reactions 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
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intensively studied because of its high selectivity for phosphopeptide trapping. In addition, nanoparticles have many superior 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 diculties in the application of nanoparticles for bio-separation. First, they cannot be conveniently separated from the solution mixture by conventional methods such as centrifugation because 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 eectively enriching phosphopeptides from digests of phosphoprotein (a-casein), nonfat milk and human serum sample. As shown in Fig. 10, after enrichment using the mesoporous TiO2 clusters, 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 nanoparticle clusters compared to solid TiO2 spheres, which can be attributed to their high specic surface area and the clean TiO2 surface. 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 dispersibility. The calcination at high temperatures in air removes

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the organic surfactants and makes the TiO2 surface fully accessible to phosphopeptides. As a result, the porous TiO2 clusters show attractive performance for selective enrichment of phosphopeptides, with advantages including high adsorption 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 conveniently 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 applications. 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.
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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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Fig. 10 (a) Schematic illustration of the selective enrichment process of phosphorylated peptides by taking advantage of the special anity between the phosphate groups and titania surface of the mesoporous CNCs. (b and c) Typical TEM images of TiO2 CNCs and solid spheres. (df) MALDI mass spectra of the tryptic digest of a-casein (d) direct analysis, (e and f) analysis after enrichment using TiO2 CNCs and solid spheres. Adapted with permission from ref. 29.

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 nanoparticles 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.
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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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