Inorganic Nanoarchitectonics for Biological ApplicationsKatsuhiko Ariga,*,†,‡ Qingmin Ji,† Michael J. McShane,§ Yuri M. Lvov,∥ Ajayan Vinu,†,⊥

and Jonathan P. Hill†,‡

†World Premier International (WPI) Research Center for Materials Nanoarchitectonics (MANA), National Institute for MaterialsScience (NIMS), 1-1 Namiki, Tsukuba 305-0044, Japan.‡Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), 1-1 Namiki,Tsukuba 305-0044, Japan§Biomedical Engineering Department and Materials Science and Engineering Program, Texas A&M University, 337 ZachryEngineering Center, MS 3120, College Station, Texas 77843-3120, United States∥Institute for Micromanufacturing, Louisiana Tech University, 911 Hergot Ave, Ruston, Louisiana 71272, United States⊥Australian Institute for Bioengineering and Nanotechnology (AIBN), Corner College and Cooper Rds (Bldg 75), The University ofQueensland, Brisbane Qld 4072, Australia

ABSTRACT: Inorganic structures and their assemblies play important roles inartificial materials for biological applications. In this short review, we brieflysummarize recent research on bioapplicable materials supported by inorganicstructures possibly reflecting the concept of nanoarchitectonics, according toclassification of unit nanostructures (nanoparticles, nanospheres, nanosheets, layer-structures, and nanotubes), internally nanostructured materials (mesoporousmaterials), organized assemblies (mainly layer-by-layer (LbL) assemblies), andhierarchical structures. Bioapplications such as sensing, drug delivery, and cellimaging are described.

KEYWORDS: bio, nano, inorganic, mesoporous, layer-by-layer assembly, hierarchical structure

■ INTRODUCTIONBiomaterials have well-evolved complex structures that realizevarious functions in biorelated systems. Conversely, there existdifferent strategies for preparing functional materials, micro-fabrication in top-down processes1 and self-assembly inbottom-up processes,2 where great varieties of componentsare available. This characteristic is especially powerful inpreparation of inorganic and hybrid materials.3 These structurescan be used as scaffolds and/or frameworks to immobilizeorganic and biorelated materials in appropriate positions,structures, and orientations. Also, inorganic structures andtheir assemblies play important roles as scaffolds in artificialmaterials for biological applications.Nanoarchitectonics4,5 refers to the technology of arranging

nanoscale structural units in desired, designed, and definedways, including techniques to create nanostructures from atomsor molecules and strategies for their assemblies into higherdimensions. This approach includes not only simple con-struction of nanomaterials but also organization upon mutualinteractions, where factors such as statistical and thermalfluctuations must be taken into account. Sophisticatedfunctions observed in biological systems are apparentlyaccomplished through this concept. Biological systems might

be regarded as the most successful example of nano-architectonics.6

Therefore, material construction based on the concept ofnanoarchitectonics represents a powerful means to producemore advanced materials for biological applications. In thisreview, we briefly summarize recent research on bioapplicablematerials supported by inorganic structures possibly reflectingthe concept of nanoarchitectonics, according to classification ofunit nanostructures, materials nanostructured inside, organizedassemblies, and hierarchical structures, where research onmesoporous materials and layer-by-layer (LbL) assembly ishighlighted.

■ UNIT NANOSTRUCTURENanostructured inorganic materials are often of suitabledimensions for active interaction with biological systems, ascan be seen in their facile penetration into cells and organs.They also have unique physical properties that depend on their

Special Issue: Materials for Biological Applications

Received: August 3, 2011Revised: November 17, 2011Published: November 22, 2011

Review

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dimensions, known as a result of confinement effects.7 Researchactivities on biological applications of nanomaterials aresummarized here according to their morphologies.a. Nanoparticles, Nanocrystals, and Quantum Dots.

Nanoparticles have been used as media for immobilization ofbiomaterials and delivery of bioactive drugs. Thornton andHeise described a method for the release of macromolecularguests from inorganic silica particles coated with a bioactivepeptide shell through enzymatic hydrolysis of the peptide.8

Maitra and co-workers prepared nanoparticles of magnesiumand manganese phosphates encapsulating pDNA for pH-dependent release.9 Boyer, Davis, and co-workers coated ironoxide nanoparticles with poly(oligoethylene glycol) methylether acrylate and poly(dimethylaminoethyl acrylate) for thecomplexation of siRNA, as nanocarriers with antifoulingshells.10 Epple and co-workers prepared calcium phosphatenanoparticles that were coated with single- and double-strandedoligonucleotides to specifically inhibit protein synthesis onHeLa-EGFP cells.11 Kreyling and co-workers investigated thedistributions of poly(ethylene glycol)-modified gold nano-particles after intravenous and intratracheal applications.12

Vogel and co-workers demonstrated the incorporation ofhydrophobic quantum dots into the bilayer membrane of lipidvesicles, in regards to size matching between particles andmembranes.13 Horrocks, Datta, and co-workers reportedintracellular internalization and toxicity of alkyl-capped siliconnanocrystals in human neoplastic and normal primary cells.14

Arruebo and co-workers investigated various nanoparticles fortheir cytotoxicity, internalization, aggregation in medium, andreactive oxygen species production, using tumoral and normalhuman blood cells.15

Pellegrino prepared bifunctional conjugates of gold and ironoxide nanoparticles and oligothiophene fluorophores whosedifferent colors could be used for multiplexing detection.16

Gunnarsson, Enejder, and co-workers combined multiphotoninduced luminescence with coherent anti-Stokes Ramanscattering microscopy to monitor the incorporation ofnanoparicles in human epidermal keratinocytes and squamouscarcinoma cells.17 Rivier̀e, Roux, and co-workers appliedluminescent hybrid nanoparticles with a paramagnetic Gd2O3core as contrast agents for both in vivo fluorescence andmagnetic resonance imaging for dual modality imaging withfree circulation of the nanoparticles in the blood vessels withoutundesirable accumulation in lungs and liver.18 Moghe and co-workers demonstrated that albumin-encapsulated rare-earthnanoparticles are useful for imaging cancer cells in vitro and thepotential for targeted imaging of disease sites in vivo.19 Di et al.reported an efficient and biofriendly fluorescence resonanceenergy transfer (FRET) system based on lanthanide-dopedinorganic nanoparticles, CePO4:Tb treated with rhodamine B.

20

Landry and co-workers reported that porous silica micro-particles containing a Gd chelate can be injected and tracked inreal-time by magnetic resonance imaging (MRI).21

b. Microspheres and Microcapsules. Hu, Lou, and co-workers synthesized rattle-in-ball hollow structures withmultilevel interior architectures as efficient drug deliveryvehicles exhibiting high anticancer efficacy against MCF-7carcinoma cells.22 Ying and co-workers synthesized polymer-inorganic nanocomposite microspheres and accomplished bothsustained protein release with tunable gradient and delayedprotein release with tunable lag time.23 Mann and co-workersprepared drug-loaded silica or titania porous microspheres bysonication of nanoparticle suspensions confined within droplets

of drug molecules showing storage/release properties.24 Cormaet al. constructed nanospheres to encapsulate bioactivemolecules from a liposomal core and a network shell formedby silica and organic ester fragments.25 Álvarez-Puebla and co-workers developed multifunctional submicrometer reactorscomprising catalytic gold nanoparticles confined inside hollowsilica capsules for antigen biosensing.26 Ionic liquids have beenutilized as designer solvents toward self-assembly of enzymes inthe form of nanocapsules, which act as templating nanoreactorsfor the synthesis of enzyme-encapsulated hollow silica nano-containers. The enzyme was found to retain its activity in thesesilica nanocontainers for multiple cycles.27

We reported the fabrication of metallic (Pt) microcapsuleswith sufficient accessibility and electroactivity at both interiorand exterior surfaces (open-mouthed Pt microcapsules) (Figure

1).28 The open-mouthed Pt microcapsules were prepared bytemplate synthesis using polystyrene spheres, where surface-fused crystalline nanoparticles formed a capsule shell.Subsequent removal of the polystyrene spheres inducedformation of mouth-like openings. A substantial increase oftheir electrode capability for methanol oxidation and catalyticactivities for carbon monoxide (CO) oxidation was achieved.Notably, activity-loss during CO oxidation as a result ofundesirable particle agglomeration was drastically suppressedusing the open-mouthed microcapsules. The obtained structurecan be compared with living cells. Cells’ capsular structures areattributed to sophisticated functions that depend on differ-entiation between the interior and exterior environments.However, functionalities of inner surfaces of artificial capsularstructures have not been fully explored. Our microobjectseffectively used potential capability of capsular inner surfacesand could be unique mimics of cells. Therefore, these open-mouthed capsules have been named metallic cells.

c. Nanosheets and Layered Nanostructures. Twodimensionally expanded nanostructures are called nanosheetsand often form regular layer-structures, as seen in layereddouble hydroxide (LDH). These nanostructures can accom-modate drug molecules within their interlayer spaces and canbe used for biomedical applications.Choy and co-workers reported that the optimum size of

LDH nanoparticles (50 to 200 nm) was selectively internalizedinto cells through clathrin-mediated endocytosis with enhancedpermeability and retention (Figure 2).29 Kriven and co-workersmade in vivo test to administer small-sized (100−200 nm)LDH to adult male Sprague−Dawley rats, for use of LDH as aninjectable drug delivery vehicle.30 Choy and co-workers

Figure 1. Metallic cells with Pt shell and open mouth.

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hybridized indole-3-acetic acid and layered metal hydroxide,such as zinc basic hydroxide salt and zinc aluminum layereddouble hydroxide, seeking a useful method for suspendedrelease through the formation of coordination bonds.31 Thesame research group modified the surfaces of LDH materialswith the cancer-cell-specific ligand, folic acid.32 They alsointercalated donepezil molecules into smectite clays (laponiteXLG, saponite, and montmorillonite) whose release rate wascontrolled by its effective replacement by bulky cationicpolymer.33 Lu and co-workers investigated an LDH nano-particle-based delivery system of siRNA to mammalian cells invitro via endocytosis, where the influence of LDH nanoparticleson cell viability and proliferation was negligible.34 Choy and co-workers reported that a hybrid of methotrexate (MTX) andLDH could bypass the MTX resistance and eventually inhibitcancer cell proliferation very effectively.35 They also proved thatthe internalization of LDH nanoparticles via clathrin-mediatedendocytosis leads to the efficient delivery of MTX−LDH incells and thus enhances drug efficacy.36

Mann and co-workers reported that polymer hydrogelsprepared by noncovalent cross- l ink ing of poly-(vinylpyrrolidone) in the presence of small amounts of anexfoliated synthetic organoclay could be reversibly dried andreconstituted in the form of highly swollen materials forsustained drug release.37 Wu and Sailor used pH responsive,chitosan-based hydrogel film to cap the pores of a porous SiO2layer.38 The pH-dependent volume phase transition of theformer materials was used to release insulin trapped in theporous SiO2 layer. Rabiei and co-workers prepared silver-dopedfunctionally graded hydroxyapatite coatings on glass andtitanium substrates by ion beam assisted deposition method.39

Release rates of silver ions were modulated due to dissolutionof functionally graded coatings.d. Nanotubes. As typical one-dimensional nanostructures,

nanotubes such as carbon nanotubes,40 boron nitride (BN)nanotubes,41 lipid nanotubes,42 and fullerene nanotubes43 havebeen widely researched. El-Safty et al. prepared nanofilters inwhich silica nanotubes are well-aligned with anodic aluminamembrane nanochannels.44 The nanofilter membranes canseparate proteins such as cytochrome c, myoglobin, hemoglo-bin, lysozyme, and β-lactoglobulin. Grandcolas et al. inves-tigated antibacterial activity of silver nanoparticles photo-deposited on titania nanotubes.45 Hanagata and co-workersprepared hollow silica nanotubes for enhanced proliferation anddifferentiation of osteoblast cells.46

Lvov and co-workers have investigated a novel type ofnanotube, halloysite (Al2Si2O5(OH)4·H2O), which is a two-layered (1:1) tubule aluminosilicate with multilayer walls.Below pH 8.5, the tube’s inner lumen has a positive surface,promoting the loading of negatively charged macromolecules.Halloysite can be regarded as a green material because it is anatural product. Halloysite-modified solid substrates promote

stem cell growth and are a viable nanoscale container for theencapsulation of biologically active molecules. Sustained releaseof drugs and other chemical agents from Halloysite nanotubeshas been demonstrated,47 as well as nanoconfined synthesis inthe tube lumen48 and preparation of bone implant poly(methylmethacrylate) nanocomposites doped with 5−10% of halloy-site. Doping of paint with halloysite nanotubes loaded withanticorrosion agents for protective coating was also inves-tigated.49

■ INTERNALLY NANOSTRUCTURED MATERIALS:MESOPOROUS MATERIALS

a. Outline. Mesoporous materials of various shapes,geometries, and compositions with interior and exteriorsurfaces decorated with organic functionalities have hugepotential in a variety of bioapplications.50 Mesoporous silicais synthesized through silica formation using template micelleassemblies, followed by template removal.51 This syntheticstrategy has been extended to the preparation of mesoporouscarbon through the carbonization of a carbon source within amesoporous silica template, followed by selective silicaetching.52 A similar strategy has been applied in the synthesisof mesoporous carbon nitride53 and mesoporous boron nitrideand their families.54 Use of cage-type mesoporous silicatemplates provides a novel nanocarbon, carbon nanocage,55

which possesses a huge surface area, large pore volume, andcage-type porous structure, leading to efficient materialssequestration from solution.56 Carbon nanocage can be usedfor nucleotide selection57 and DNA protection fromintercalators (Figure 3).58 Mesoporous structures can be

conjugated with biomaterials. For example, biological peptidesegments can be covalently immobilized,59 leading tocontrolled media for photonic reactions and organicsyntheses.60 Silica syntheses in the presence of chiral peptidesurfactants sometimes results in mesoporous silica with twistedmorphology.61 Mesoporous materials with huge surface areasand pore volumes are appropriate media for storage ofbiological materials, including proteins.62

b. Drug Delivery. Yu and co-workers prepared biocompat-ible hollow mesoporous silica spheres using porous CaCO3templates with preloaded doxorubicin (DOX) for cancertherapy due to extracellular protection and pH-sensitiverelease.63 Vallet-Regı ́ and co-workers synthesized mesoporoussilica−zirconia mixed oxides with tunable acidity via spray-drying process as controlled release vectors of bisphosphonatesfor bone implant technologies.64 Zhu and co-workers reported

Figure 2. Size-dependence of LDH uptake to cell.

Figure 3. DNA protection through removal of intercalators by carbonnanocage.

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sonochemical synthesis of mesoporous spheres of calciumsilicate hydrate constructed from nanosheets, with extremelyhigh drug-loading capacity.65 Zheng demonstrated hollowmesoporous zirconia nanocapsules as effective vehicles foranticancer drug (DOX) delivery.66 Bein and co-workersprepared core−shell mesoporous silica nanoparticles with anexternal coating of a hydrophilic polymer shell, poly(ethyleneglycol), to reduce the rate of degradation of silica in simulatedbody fluid.67 In addition, solid core/mesoporous shell (SC/MS) silica nanoparticles for drug-delivery application wouldhave important contributions. These interesting nanoarchitec-tures seem to provide an obvious advantage over the LbLapproach in terms of single-step synthesis of polymer andpolypeptide nanocapsules for drug-delivery applications.68

Fujiwara and co-workers demonstrated controlled drugdelivery responding to photoreaction of coumarin grafted tomesoporous silica (Figure 4).69 Bao, Zhu, and co-workers

demonstrated that coumarin grafted on mesoporous silicananoparticles acted as both the phototrigger for drug releaseand a fluorescence group for cell luminescence imaging.70 Zink,Nel, and co-workers reported use of mesoporous silicananoparticles capable of controlled drug delivery based onthe function of cyclodextrin nanovalves that are responsive tothe endosomal acidification conditions in human differentiatedmyeloid and squamous carcinoma cell lines.71 Park, Kim, andco-workers reported stimulus-responsive mesoporous silicawith cyclodextrin gatekeepers via disulfide unit and theirglutathione-induced controlled release characteristics of doxor-ubicin (DOX).72

Cai and co-workers reported mesoporous silica nanoparticlesend-capped with collagen, whose cleavage with variousreducing agents resulted in the controlled release of targeteddrugs delivery.73 Martıńez-Mañ́ez and co-workers immobilizedoligonucleotides on mesoporous silica, where pore openingoccurs by displacement with a target complementary strand.74

The same research team prepared mesoporous silica with anazide group to attach the capping peptide sequence.75 Deliveryof entrapped drugs could be triggered in the presence of aprotease. Ren, Qu, and co-workers used a polyvalent nucleicacid/mesoporous silica particle conjugate for intracellular drugdelivery responding to both external and endogenousactivation.76 Bein and co-workers also proposed programmable

DNA-based molecular valves on the pore mouths of novelcore−shell colloidal mesoporous silica for drug delivery.77 Yongand co-workers reported mesoporous silica nanoparticlescapped with aptamer-modified gold nanoparticles for con-trolled-release systems based on aptamer−target interaction.78

c. Imaging. Liong et al. synthesized mesostructured silicaspheres with superparamagnetic iron oxide nanocrystals andfluorescent dye molecules for the delivery of anticancer drugsinto human cancer cells for magnetic resonance andfluorescence imaging.79 Hyeon and co-workers developedmesoporous dye-doped silica nanoparticles decorated withmagnetite nanocrystals.80 In vivo passive targeting andaccumulation of the nanoparticles at the tumor sites wasconfirmed by both T2 MR and fluorescence imaging. Hyeon,Gilad, and co-workers proposed the mesoporous shell onnanoparticles for optimal access of water molecules to themagnetic core and effective longitudinal relaxation enhance-ment of water protons as nanoparticle magnetic resonancecontrast agents by providing positive contrast on T1 weightedimages at high magnetic field strengths.81 Shi and co-workerssynthesized Fe3O4-containing mesoporous nanocapsules ascontrast agents of MRI to demonstrate the simultaneousimaging and therapeutic multifunctionalities of the compositenanocapsules.82 Che, Shi, and co-workers assembled apositively charged polyelectrolyte and negatively chargedfluorescent quantum dots onto the surface of ellipsoidalFe3O4−SiO2 mesoporous silica composite, having combinedmerits of tunable fluorescence/magnetic properties.83

■ ORGANIZED STRUCTURES: LAYER-BY-LAYERASSEMBLY

Although much effort has been made to create individualbioactive nanomaterials, their sophisticated assembly isprobably necessary for the creation of advanced materials.Assembling functional nanomaterials using appropriate techni-ques such as Langmuir−Blodgett (LB) method84 and layer-by-layer (LbL) adsorption85 are crucial for nanoarchitectonics ofnanomaterials. In particular, the LbL technique can be used forassembly of both biological objects and inorganic nanomateri-als. Therefore, LbL has become a key technique inbioapplications of inorganic nanomaterials.

a. Outline. The LbL method has available a vast variety ofchoices of materials, including biological substances such asproteins,86 nucleic acids,87 saccharides,88 and virus particles,89

as well as various organic polymers,90 molecular assemblies,91

and various inorganic substances.92 This methodology is notonly limited to fabrication of ultrathin films on flat surfaces butalso can be applied to assemblies using colloidal particles.93 Thelatter method is followed by destruction of the central core,resulting in hollow capsules. Although electrostatic interactionis used as the major assembly driving force, metalcoordination,94 hydrogen bonding,95 charge transfer,96 covalentbonding,97 biospecific interactions,98 stereocomplex forma-tion,99 and electrochemical coupling100 can be used. LbLassembly does not require harsh chemical conditions, and so, itis suitable for application to biomaterials. It provides lessdensely packed structures, which are advantageous for materialdiffusion through films, as demonstrated in various enzymereactors.101

Here, a few examples of biorelated research are shown. Singhand McShane developed luminescent microspheres encapsulat-ing glucose oxidase for implantable glucose sensors and tunedtheir response range by adjusting microsphere porosity.102

Figure 4. Photocontrolled drug delivery from mesoporous silica.

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Hammond and co-workers prepared LbL films by combining apermanent microbiocidal polyelectrolyte film with a hydrolyti-cally degradable top film that offers controlled and localizeddelivery of therapeutics.103 De Smedt and co-workers fabricatedLbL microcapsules capable of ejecting nanoparticles using arigid covalently cross-linked LbL membrane around themicrogel core.104 Caruso and co-workers reported the in vitrouse of drug-loaded biodegradable LbL capsules to sensitize p-glycoprotein-mediated multidrug resistant colorectal cancercells.105 Komatsu et al. reported the synthesis, structure, andhepatitis B virus trapping capability of multilayered proteinnanotubes having an anti(hepatitis B surface antigen) antibodylayer as an internal wall.106 Lvov and co-workers encapsulatedbacterial spores in organized ultrathin shells using LbLassembly to assess the biomaterial as a suitable core anddetermine the physiological effects of the coating.107

Rigid inorganic nanostructures are used for the fabrication ofhigher-order biomimetic structures. Katagiri et al. preparedorganic−inorganic lipid bilayer vesicles through covalentcoating of bilayer surface with silica monolayer structure.108

The obtained robust vesicles could be assembled intomulticellular mimics by LbL assembly.109 Paunov and co-workers proposed the fabrication of yeastosomes, which consistof a spherical monolayer of living yeast cells held together bycolloid interactions.110 Templating of microbubbles with cellsand LbL coating with cationic polyelectrolyte provided thismulticellular assembly.b. Biosensor. Hybridization of inorganic components with

organic/biological materials through LbL assembly is oftenuseful for biosensor applications. Lee and co-workers preparedthree-dimensional arrays of multilayered nanostructures ofproteins based on LbL assembly of bacterial protein nano-particles and DNA on a patterned array of gold dots for themultiplexed bioassays of breast and colorectal cancermarkers.111 Kim and co-workers fabricated combined LbLassemblies of gold nanoparticles and multiwalled carbonnanotubes on a glass substrate for a highly sensitive plasmonicbiosensor using a conventional UV−vis instrument.112 Anexcellent detection limit as low as 0.5 nM for streptavidin and3.33 nM for antihuman serum albumin was demonstrated.Pieces of graphene can be disassembled from graphite, and

then, reassembled into LbL structures. Wang, Zhang, and co-workers fabricated the LbL assembly of graphene multilayersthat were used for the enzyme-based biosensing of maltose.113

We also developed a LbL sensor using graphene nanosheets inthe LbL assembly with ionic liquid.114 Composites of graphene-sheet/ionic liquid (GS-IL) behave as charge-decorated nano-sheets and were assembled alternately with poly(sodiumstyrenesulfonate) (PSS) by LbL adsorption on a quartz crystalmicrobalance (QCM) resonator (Figure 5). Exposure of thecomposite films to various saturated vapors caused an in situdecrease in frequency of QCM due to gas adsorption. SomeGS-IL films showed significantly higher selectivity (more than10 times) for benzene vapor over cyclohexane despite theirsimilar molecular sizes, molecular weights, and vapor pressures.Detection of vapors can be repeated through alternate exposureand removal of the subject solvents. In addition, the GS-ILfilms have a variety of potential practical applications, includingenvironment remediation through the capture of atmosphericCO2.Zhu and co-workers fabricated nanoarchitectures of nitrogen-

doped carbon nanotubes, thionine, and gold nanoparticles viaLbL assembly, which provided an effective matrix for

concanavalin.115 Xu and co-workers constructed a LbL-typeglucose biosensor by integrating Prussian Blue nanoparticles aselectron mediators.116 Shiu and co-workers deposited PrussianBlue on multiwalled carbon nanotubes that were immobilizedby LbL assembly with poly(diallyldimethylammonium chlor-ide) (PDDA), with excellent sensitivity to the electrochemicalreduction of hydrogen peroxide.117 Liu, Tang, and co-workersfabricated a biosensor based on nanocomposite films of CdTequantum dots and glucose oxidase.118 The linear sensing-rangeand sensitivity of glucose determination can be adjusted bycontrolling structures. Ruedas-Rama and Hall prepared anenzyme-linked analytical nanosphere sensor, responding toenzyme−substrate turnover in the vicinity of a quantum dotdue to coimmobilized enzyme and pH sensitive ligand.119

Xiang, Yuan, and co-workers prepared LbL-assembled poly-styrene microsphere composite with quantum dots.120

Dramatic signal amplification by the numerous quantum dotsat each DNA binding resulted in subfemtomolar level detectionof uropathogen-specific DNA sequences. Cooper and co-workers proposed the application of quantum dot barcodes ona magnetic bead to perform multiplexed assays using fourdifferent immunoconstructs.121 Dong et al. assembled CdTequantum dots and polyelectrolyte on polybeads that wereattached to DNA probes specific to breast cancer as a DNAbiosensor.122

c. Imaging, Drug Delivery, and Others. Ivanisevic andco-workers investigated transverse proton relaxivity of one-dimensional DNA templated nanostructures with gold−ironoxide and gold−cobalt iron oxide as magnetic resonanceimaging contrast agents.123 Yang, Wu, and co-workerssynthesized LbL multifunctional carbon-nanotubes-based mag-netic fluorescent nanohybrids as multimodal cellular imagingagents for detecting human embryonic kidney 293T cells viamagnetic resonance (MRI) and confocal fluorescence imag-ing.124 Rosenzweig and co-workers immobilized mercaptoaceticacid-modified CdSe/ZnS quantum dots onto polyelectrolytemultilayers, which were incorporated in microfluidic channelswith FRET (fluorescence resonant energy transfer) sensingcapabilities in enzymatic assays for minimizing their toxicity.125

Daḧne and co-workers developed LbL oligonucleotide particlesfor a FRET based nucleic acid diagnostic system.126 Single-nucleotide polymorphism assays showed that a single mismatchof target DNA can be easily distinguished. Komatsu and co-workers reported multistep organic transformations on ananodiamond surface that gain the requisite functions by LbLassembly through covalent bonds as a cellular imaging agent byintroducing them into HeLa cells.127

Schneider and co-workers developed a drug multilayer-basedcarrier system for delivery of water-insoluble drugs, such asanticancer drug 5,10,15,20-tetrakis(3-hydroxyphenyl)-

Figure 5. LbL assembly of graphene nanosheet.

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porphyrin.128 The adaptation of the LbL technique resulted indrastically increased drug deposition efficiency. Hammond andco-workers fabricated LbL films containing negatively chargedPrussian Blue nanoparticles and positively charged gentamicin,a small hydrophilic antibiotic, through the LbL assembly.129

The same research team reported systemically deliverable LbLnanoparticles for cancer applications where the final layeradsorbed generates a critical surface cascade.130 Li and co-workers reported the integration of LbL capsules as vehicleswithin polypeptide multilayer films for sustained release ofmultiple oppositely charged drug molecules.131 Katagiri et al.fabricated magnetoresponsive microcapsules, comprising poly-electrolyte multilayers, lipid bilayers, and Fe3O4 nano-particles.132 The magnetically induced release was attributedto the phase transition of the lipid membrane, caused by heat ofFe3O4 nanoparticles under magnetic stimuli, not to rupture ofthe capsules.Rutledge, Hammond, and co-workers reported LbL assembly

for immobilizing TiO2 nanoparticles on a porous support whilemaintaining a high catalytic efficiency for photochemicaldecomposition of bisphenol A.133 Wu and co-workersfabricated LbL capsules from PSS and a positively chargedbiomacromolecule, protamine, onto calcium carbonate micro-particles to form inorganic silica layer through a biomimeticmineralization process.134 Harsh condition tolerance and long-term storage stability of the encapsulated enzyme were allnotably improved as a result of the shielding effect of theinorganic shell. Calvo and co-workers used Trametes trogiilaccase as a biocatalyst for oxygen cathodes composed of theLbL assembly.135 Kinetic data relevant to the operation ofbiofuel cells under stagnant conditions of O2 mass transportwas obtained.Drug delivery often requires good dispersion of a poorly

soluble reagent. Lvov and co-workers developed sonication-assisted LbL encapsulation of low-solubility drugs.136 Powder ofinsoluble materials was placed in an aqueous solution of poly-cation and subjected to powerful sonication. This method wasapplied for production of stable nanocolloids of poorly solublecancer drugs (tamoxifen, paclitaxel, curcumin) and thenextended to inorganic materials.137 LbL nanocolloids ofBaSO4 nanocolloids would be useful as X-ray contrast fillerfor biological tissue. LbL polyelectrolyte shells can also beassembled on preliminarily formed inorganic cores, such as goldnanoparticles, providing them with new properties.138 Thus,25-nm diameter gold colloids with LbL shells were fabricated asthe smallest core coated with LbL polyelectrolyte shells.Coating inorganic materials with architectural polymericmultilayers may provide them with stealth properties, whichwould allow increases in their circulation time in blood after theinitial injection.

■ HIERARCHICAL ASSEMBLYHierarchy is important in relaying events across differentstructural dimensions, resulting in harmonized functions. Thedevelopment of biological mimics with hierarchical structures isthought to be useful for the construction of highly functionalmaterials. This could be realized by assembling prestructuredmaterials into further organized structures. Subjecting meso-porous materials to the LbL assembly would be one of theavailable strategies in fabrication of hierarchical structures.139

a. Layer-by-Layer Assembly within Mesopores. LbLassembly within or onto mesoporous materials is firstintroduced. Wang and Caruso demonstrated the coating of

mesoporous silica spheres with LbL assembly to preparedensely enzyme-loaded particles.140 Target enzymes were firstloaded into mesoporous silica spheres, followed by coating ofthe spheres with LbL multilayers. This encapsulation resulted inhigh enzyme contents, enhanced enzyme activities, higherenzyme stabilities against pH, prevention of enzyme leakage,and protection of the encapsulated enzyme from proteolysis.Caruso and co-workers also demonstrated the subsequentremoval of the silica templates for the formation of micrometer-sized nanoporous polyelectrolyte spheres.141 Cross-linkingbetween the polyelectrolytes is effective for increased structuralintegrity to the nanoporous polyelectrolyte spheres. Theyextended this idea to the preparation of nanoporous proteinspheres.142

They also demonstrated mesoporous silica particle-mediatedwater-insoluble drug loading and subsequent generation of apolymer multilayer shell using the LbL technique.143 Kumarand Hong reported preparation of LbL films of azobenzene-containing polyelectrolyte on a porous alumina membrane forphotoswitching permeability control.144 Cai and co-workersfabricated hybrid multilayers composed of chitosan/gelatin, inwhich mesoporous silica nanoparticles loaded with β-estradiolas a nanoreservoir-type drug delivery.145 Such nanoreservoirstructures display great potential to maintain bone homeostasisand in a wide range of applications such as implant technology,tissue engineering, gene therapy, and regeneration medicine.

b. Layer-by-Layer Assembly of Mesoporous Materials:Sensor Application. We have been researching LbLassemblies of mesoporous materials for biorelated applications.The first example demonstrated selective sensing of teacomponents by LbL assembly of mesoporous carbon, CMK-3.146 Surface oxidation of carbon using ammonium persulfateenabled us to introduce negative carboxylate groups to CMK-3147 and their LbL assembly, using appropriate polyelectrolyteon a QCM plate (Figure 6).

Sensing performances were investigated in aqueous solutionwhere frequency shifts of QCM upon adsorption of tannic acidgreatly exceed those for catechin and caffeine. The superioradsorption capacity of tannic acid likely originates in itsmolecular structure; that is, multiple phenyl rings of the tannicacid molecule can interact with the carbon surface through π−πinteractions and hydrophobic effects as well as size fitting oftannic acid to the CMK-3 nanochannel. These observationsalso promoted our understanding of molecular interactionswithin nanospaces, especially nonspecific interactions inaqueous media, a full exploration of which might clarifyimportant phenomena including those of biological systems.

Figure 6. LbL film of mesoporous carbon CMK-3 for biomaterialssensing.

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Mesoporous carbon capsules (1000 × 700 × 300 nm3) with35-nm-thick mesoporous walls with a uniform pore sizedistribution centered at 4.3 nm for diameter and a specificsurface area of 918 m2 g−1 were synthesized. Surfactant-covering enables us to assemble noncharged substances in theLbL process with aid of counterionic polyelectrolytes, whichwere used to detect specific molecules in the gas phase (Figure

7).148 Generally, aromatic hydrocarbons such as benzene andtoluene are better detected in this sensing system than aliphatichydrocarbons such as cyclohexane, indicating the crucial role ofπ−π interactions on volatiles’ adsorption in the carbon capsulefilm. Selectivity could be easily tuned by impregnation withadditional recognition components. The carbon capsule filmimpregnated with lauric acid showed the greatest affinities fornonaromatic amines and the second highest affinity for aceticacid. In contrast, impregnation of dodecylamine into the carboncapsule films resulted in a strong preference for acetic acid.Such designed materials will find widespread applications assensors or filters because of their designable guest selectivity.c. Layer-by-Layer Assembly of Mesoporous Materials:

Controlled Release Applications. Mesoporous silica cap-sules were integrated into LbL structures for development of anovel mode of drug delivery, stimuli-free automodulateddelivery. Anionic silica capsules were deposited on a QCMresonator using LbL assembly (Figure 8).149 The LbL assembly

between the hollow capsules and polyelectrolytes wasperformed with the aid of anionic silica nanoparticles as acoadsorber. After immersing the compartment film on the

QCM resonator into water and drying under nitrogen flow, thenet change in weight of the film after each cycle was measuredin air by using QCM. Surprisingly, the frequency shifts uponwater evaporation from the mesoporous nanocompartmentfilms possess a stepwise profile even though no externalstimulus was applied.The observed stepwise release is assumed to originate from a

combination of two processes, water evaporation from thepores and capillary penetration into the pores. Initially, waterentrapped in mesopore channels evaporates to the exterior,which is observed as the first step of water release. After most ofthe water has evaporated from the mesopore channels, waterenters that region from the capsule interior probably by rapidcapillary penetration. Subsequently, water again evaporatesfrom mesopores to the exterior and is apparent as the secondevaporation step. These processes are repeated in steps. Inaddition, the water evaporation rate at each step can becontrolled by varying several factors such as temperature andthe coadduct materials (silica particle and polymer). Thisrelease profile was used in a demonstration of the controlledrelease of various fluid drugs such as fragrance molecules. Thissystem is a rare example of a stimulus-f ree controlled releasemedium, which operates in a stepwise manner with prolongedrelease efficiency, a feature useful for controlled-release drugdelivery, which is of great utility for development of energy-lessand clean stimulus-f ree controlled drug release applications.

■ SUMMARY AND PERSPECTIVEIn this review, we have briefly summarized biorelatedapplications of inorganic nanostructures and their assemblies.From these examples, we can understand that the well-sophisticated organization and the arrangement of inorganiccomponents are both important keys for advanced functions.One of the best approaches is a combination of the versatileand biocompatible LbL method with nanofabricated inorganicstructures such as the mesoporous materials. These structuresare constructed similarly to nanoscale architectures, and therelated approaches can be included in the novel concept,nanoarchitectonics. This concept can be applied to a hugevariety of bioinorganic composites, although these have notbeen introduced here.150 However, designing complexstructures using only bottom-up assembly techniques mayhave only limited success. These approaches should be mergedwith well-developed top-down microfabrication methods inorder to provide interfaces between biomimetic structures anddevices.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: ARIGA.Katsuhiko@nims.go.jp.

■ ACKNOWLEDGMENTSThis work was partly supported by World Premier InternationalResearch Center Initiative (WPI Initiative), MEXT, Japan, andthe Core Research for Evolutional Science and Technology(CREST) program of Japan Science and Technology Agency(JST), Japan.

■ REFERENCES(1) (a) Wu, S.; Tsuruoka, T.; Terabe, K.; Hasegawa, T.; Hill, J. P.;Ariga, K.; Aono, M. Adv. Funct. Mater. 2011, 21, 93. (b) Ohno, T.;Hasegawa, T.; Tsuruoka, T.; Terabe, K.; Gimzewski, J. K.; Aono, M.Nat. Mater. 2011, 10, 591.

Figure 7. LbL film of mesoporous carbon capsule for gaseous guestdetection.

Figure 8. LbL film of mesoporous silica capsule and nanoparticle forautomatic ON/OFF materials release.

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mailto:ARIGA.Katsuhiko@nims.go.jp

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