Shape Control of Soft Nanoparticles and Their Assemblies - American

Review pubs.acs.org/cm

Shape Control of Soft Nanoparticles and Their Assemblies Chao Chen,†,§ Ross A. L. Wylie,†,§ Daniel Klinger,‡ and Luke A. Connal*,† †

Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville 3010, Australia Institute of Pharmacy, Department of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2-4, Berlin 14195, Germany

‡

ABSTRACT: Soft nanoparticles with precisely controlled shape and morphologies hold great potential for the preparation of novel materials with tailored chemical and biophysical properties. In this review, we highlight the synthetic approaches and hierarchical strategies to manipulate the shape and morphology of nanostructures assembled from four major building units, namely block copolymers, peptide amphiphiles, proteins and nucleic acid building blocks. Special attention is given to anisotropic, stimuli-responsive nanoparticles that are tuned by assembly conditions. Their tunable nature is of particular significance as it allows the design of smart and dynamic materials. The immediate and potential applications of these shape controlled nanostructures are also summarized together with their limitations.

1. INTRODUCTION In natural nanomaterials, shape is a significant parameter as it enables highly complex functionalities. Achieving the same degree of control over the shape of synthetic nanoparticles is an interesting challenge that requires bringing together a variety of disparate concepts from a multitude of diverse disciplines. Combining the ability to control particle shape with the inherent functionality of (synthetic) macromolecular building blocks represents a multidisciplinary hierarchical approach to the fabrication of highly complex materials with new functionalities. Moreover, materials with unique and complex nanostructured order possess many functional properties including targeting abilities and optical tunability, and the expansions of the structures available upon design will create even further functional materials with a range of desired proprieties.1,2 These properties are a function of their structure, size and composition. Therefore, effective tailoring of nanoparticles into desired arrangement becomes the key to realize the performance of nanomaterials.3 Soft nanomaterials offer great potential because each hierarchical level has room for innovation. The synthetic preparation and modification of functional macromolecular building blocks offers challenges and opportunities as well as the design of new physical assembly methods. However, these two areas are not independent of each other and it is the intersection of the disciplines of synthetic (polymer) chemistry, colloidal chemistry and interfacial physics, that enables the development of powerful new tools for the preparation of new materials. With the increasing ability to control the introduction of chemical functionality into synthetic and natural building blocks, new methods of shape control can be envisioned. Polymer chemists have a large and ever-expanding toolbox of materials that can be utilized and designed for controlled self© 2017 American Chemical Society

assembly. Block copolymers (BCPs) have emerged as a promising building block to access nanostructures of extreme complexity.1,2,4 Although systems of one-dimensional (1D) and two-dimensional (2D) confinement are extensively studied theoretically and experimentally, three-dimensional (3D) confinement systems with higher structural order still remain a challenge. Peptide amphiphiles (PAs) is another emerging building blocks that finds novel applications in regeneration medicine. This type of building block bridges synthetic materials and biological macromolecules as it is composed of amino acids as well as synthetic hydrophobic tails. Utilizing a bioinspired approach, protein and nucleic acid building blocks also have the capacity to assemble into complex aggregates. Unlike other building blocks, the understanding of interactions of these biological macromolecules allows precise control and thus the design of their assemblies is often based on simulation and calculation. The ability to design the chemistry of these building blocks is paramount to controlling their final selfassembly. Noncovalent interactions, such as metal coordination, host−guest interactions and hydrogen bonding are often utilized to guide the architecture of formed aggregates. The design of these interactions and the strict and systematic control of self-assembly conditions and reaction conditions have spurred the development of new techniques to control the shape of soft nanostructured systems. The collaboration of traditional disciplines such as chemistry, physics and biochemistry facilitates the design of new hierarchical materials that uniquely combine shape control with inherent chemical functionality, thereby representing Received: November 3, 2016 Revised: February 10, 2017 Published: March 1, 2017 1918

DOI: 10.1021/acs.chemmater.6b04700 Chem. Mater. 2017, 29, 1918−1945

Review

Chemistry of Materials

Figure 1. Summary of control strategies for micellar BCP assemblies. (a) Shape-controlled micelles through polymerization, governed by BCP packing parameter. (b) Morphology and shape of micellar assemblies governed by interactions between copolymers and surrounding medium. This is achieved through solvent quality control and introduction of external stimuli. (c) Crystallization-driven self-assembly and its superstructure. (d) Multicompartment micelle and its precursor. Reprinted with permission from ref 10, ref 11, ref 12, ref 13 and ref 14. Copyright 2013 and 2014 American Chemical Society, 2008 Royal Society of Chemistry, 2013 John Wiley and Sons, 2012 Nature Publishing Group.

assemblies as well as fully hydrophobic nanoparticles and highlight state-of-the-art techniques that go beyond traditional assemblies and into complex shape-controlled nanoconstructs. 2.1. Influence of BCP Geometry. Ahmed and Discher reported the well-known correlation between morphologies of amphiphilic diblock copolymer assemblies and the volumetric ratios of their different blocks ( fA and f B, with fA + f B = 1).15 For a symmetric diblock copolymer, where fA and f B are equal, the polymer chains prefer to aggregate into membranes or sheet/disc-like micelles.16 As the volume fraction of one block decreases, the polymer aggregates change their shape to cylinders and further into energetically favorable spheres as the system has lower interfacial area and increased configurational entropy.17 The first instance is reported by Eisenberg and Zhang in 1995. In this seminal work, they observed a morphological evolution of BCP aggregates from spheres to cylinders, to bilayers and eventually to inverted micelles when one block is decreased.18,19 The packing parameter is another indictor to predict micellar shape. It not only takes into account the volume of the hydrophobic chain but also the crosssectional area of the hydrophilic core and the length of the hydrophobic chain.20 These factors crucially depend on the respective molecular weights (Mw) as well as on the interaction between the hydrophilic block and the surrounding aqueous phase. Therefore, controlling the shape of micellar assemblies can occur via adjusting either of the two factors. This leads to different shape control strategies for dynamic assemblies such as (a) changing Mw of respective blocks during the assembly, (b) changing solvent conditions and (c) introducing external stimuli. 2.1.1. Increasing BCP Mw During Self-assembly. This concept is based on the self-assembly of BCPs during their polymerization. Here, starting from one block and changing the molecular weight of the second block upon chain growth leads to continuous changes of the BCP symmetry (i.e., the packing parameter).10 Thus, the shape/structure of the assembly

highly interesting materials for a broad variety of applications such as therapeutic delivery,5−7 photonic bandgap materials8 and optochemical sensing.9 This review provides an overview of the varied approaches to control the shape of soft nanomaterials in a reliable and predicable manner. We provide a comprehensive review not limited to one particular material of choice but open to many potential materials and methods to control the shape of soft nanoparticles. We highlight the stateof-the-art of nanoarchitectures based on two different classes of macromolecular building blocks: synthetic materials (e.g., BCPs and PAs) and biological macromolecules (e.g., proteins and DNA). These building blocks, which are often seen as specialized materials are often studied without much communication between disciplines; however, the strategies used to control their assemblies are in many ways similar to each other. Therefore, we hope this review can provide a reference for the many methods developed in shape control of nanomaterials and open up new ways of controlling shape further enabling function of soft nanoparticles.

2. BLOCK COPOLYMER ASSEMBLIES For amphiphilic BCPs, shape control of micellar assemblies can be achieved through the interaction of the BCP with the solvent, the crystallization of the core-forming blocks or more dynamically through external stimuli. In contrast, for fully hydrophobic BCPs, the shape of solid nanoparticles is strongly correlated to their internal morphology. Therefore, shape control can be achieved by tuning the morphology of the selfassembled BCP in the colloidal confinement. There are many common methods used in both systems to manipulate BCP assemblies, such as controlling temperature, polymer block weights and solvent composition. However, the resulted shape evolution may be attributed to different mechanisms. Therefore, we aim to categorize the shape control strategies from the mechanistic viewpoint, as summarized in Figure 1. In this section, we focus on the shape-controlled BCP micellar 1919


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of the disk-to-cylinder structure transition was investigated by adding THF back to the system. Through increasing addition of THF into the 90 vol % water content system, disk−cylinder intermediates are observed at 70 vol % water content and disks are observed at 45% water content, representing the reversible process of disk-to-cylinder transition. In a similar fashion, Kempe et al. recently reported nonspherical faceted and cauliflower-like particles formed from PS-block-poly(2-ethyl-2-oxazoline) (PS-b-PEtOx) through solvent exchange methods and choice of solvent mixtures based on THF, a good solvent for copolymers, and ethanol and water as nonsolvents for the PS block.27 The authors also investigated the influence of block weights and assembling temperature on particle structures, demonstrating a new set of tools to prepare nonconventional shapes formed from amphiphilic copolymers (shown in Figure 2). Although in this work the authors did not

changes correspondingly. Armes and co-workers demonstrated the polymerization-induced self-assembly (PISA) of poly(glycerol monomethacrylate)-block-poly(2-hydroxypropyl methacrylate) (PGMA-b-PHPMA) via aqueous dispersion polymerization using reversible addition−fragmentation chain transfer (RAFT) chemistry.21,22 PGMA with a fixed molecular weight is used as a chain transfer agent (CTA) for the in situ polymerization of HPMA to generate a series of PGMA-bPHPMA diblock copolymers. When the targeted degree of polymerization (DP) of PHPMA block equals 90, PGMA47-bPHPMA90 (where the subscript denotes DP) exclusively forms spherical micelles. With increasing targeted length of coreforming PHPMA block, morphology transitions from spheres through worm-like micelles (DP = 130) to vesicles (DP = 160) are observed.22 The in situ structural evolution is assessed by periodical sampling of polymer solution during the RAFT polymerization. Significantly, the in situ morphologies obtained at a given time during the synthesis correspond closely to the final morphologies observed at full conversion when the in situ degree of polymerization is targeted. This implies that the unreacted HPMA monomers do not affect the self-assembly process of the copolymer. PISA is a one-pot technique and a range of shapes, such as branched worms, bilayer octopi and jellyfish, can be targeted through, providing a unique mechanistic insight of the sphere-to-worm and worm-to-vesicle transitions. Also, this dynamic strategy has been facilitated by the advances in polymer synthesis which offers a wide range of controlled polymerization techniques. Another advantage of PISA is the uniquely high solids content that can be utilized and thereby promises scale-up production of BCP assemblies. 2.1.2. Changing Solvent Composition During SelfAssembly. Similar to the Flory−Huggins parameter, which specifies the degree of incompatibility between two blocks in bulk, the solvent quality influences the interactions between copolymers and surrounding mediums. In this process, changes in solvent composition lead to different solvent−polymer interactions, thereby influencing the conformation of the individual blocks. As a result, a varied shape/structure can be observed through this process. Pioneering work by Wooley and Pochan groups demonstrated the shape transformation of BCP aggregates using a system of poly(acrylic acid)-block-poly(methyl acrylate)-block-polystyrene (PAA-b-PMA-b-PS) triblock copolymer, 2,2′-(ethylenedioxy)diethylamine (EDDA) and tetrahydrofuran (THF)/water solvents.11,23,24 This unique BCP system with PAA−diamine complexes forms discrete spherical micelles due to phase separation of unlike blocks. When THF is introduced, the spherical micelles change their intramicellar geometry and aggregate into disk-like nanostructures. With further addition of THF, unidirectional packing of these nanostructures is observed, which is ascribed to the electrostatic interactions between PAA−diamine complexes.25 In the extended work of the same BCP system, Wooley and Pochan groups demonstrated different pathways to produce toroidal PAA-b-PMA-b-PS micelles from their lamellar precursor by adding water to the water/THF mixtures.11 The authors also reported the ability to induce a disk-to-cylinder change of PAA-b-PMA-b-PS by adjusting the water/THF ratio. When the water content increases from 30 to 90 vol %, BCP assemblies transform from disks to disk−cylinder intermediates, cylinders, and eventually mixtures of cylinders and spheres. In this process, the solubility of the hydrophobic PS and PMA blocks declines, thus resulting in shrinkage of the hydrophobic core and an increase in the interfacial curvature.26 Reversibility

Figure 2. (top) TEM images of PS-b-PEtOx particles with different morphologies after self-assembly from adding THF into (a) water, (b) ethanol, (c) ethanol−water mixture at 1:1 volume ratio. (bottom) TEM images of PS-b-PEtOx particles assembled in the same fashion but THF is removed at different temperature: (d) 20 °C, (e) 40 °C and (f) 60 °C. Scale bar: (a) 500 nm, (b) 1 μm, (c) 200 nm, (d−f) 100 nm. Reprinted with permission from ref 27. Copyright 2015 John Wiley and Sons.

elaborate the mechanistic influence of temperature, we postulate that the increase in the assembling temperature increases combinatorial entropy, which is supported by the disordered structure (i.e., homogeneous) at high temperatures (Figure 2d−f). The above works are of particular significance since their results indicate that a myriad of structured particles from the same BCP system can be accessed by introducing multiple variables to the system.11,23,24,26−28 2.1.3. Stimuli-Responsive Shape Control. Apart from “intrinsic” shape controlling methods, external stimuli such as light, pH, redox and temperature can be used to change dynamically the shape of the BCP assemblies. Here, changing the interaction between solvent and the respective responsive block allows tuning the BCP volumetric ratio and thereby the structure of the assembly. Recently, the introduction of tertiary amines29,30 and amidines31 into BCPs has regained interest since it was demonstrated that such polymers (e.g., poly(N,Ndimethylaminoethyl methacrylate) (PDMAEMA)) exhibit a tunable water solubility with respect to CO2 gas.30,32 Therefore, the macroscopic self-assembly of BCPs containing a PDMAEMA block can be controlled by introducing and removing CO2 gas. Using the same stimulus, the Yuan group developed a 1920


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on the vast potential of these systems to generate very elaborate and unique morphologies of semicrystalline BCP micelles by utilizing the “living” character of such crystallization-driven assemblies. Of special interest is here the combination of different building blocks and their continuous or stepwise addition. Manipulation of crystallization conditions opens up new pathways to access a large variety of unique morphologies. For example, Mihut and co-workers presented an experimental phase map of semicrystalline polybutadiene-block-PEO (PB-bPEO) copolymers in dilute n-heptane solutions.42 Here, the thermally controlled crystallization of the PEO block forms micelles with a PB corona. By reducing the temperature at which self-assembly occurs, the crystallinity of PEO increases correspondingly. Simultaneously, the solvent quality for PB reduces drastically which causes less steric repulsion in the PB corona thereby resulting in a shape change from spheres to worm-like structures. Schmalz and co-workers also reported worm-like micelles with tailored functionality using SEM (polystyrene-block-polyethylene-block-poly(methyl methacrylate)) through crystallization-driven self-assembly (CDSA). In this work, polyethylene is a semicrystalline block placed in the middle of the triblock copolymer. Through control of solvent quality, worm-like crystalline-core micelles with a patch-like microphase-separated polystyrene/poly(methyl methacrylate) (PS/PMMA) corona are obtained. 43,44 The Xu group investigated the influence of crystallization temperature on the micellar morphologies of poly(ε-caprolactone)-block-PEO (PCL-b-PEO), wherein the PCL block is a core-forming crystalline block.45 For low Mw PEO blocks it is observed that a higher self-assembly temperature tends to induce lamellar micelles whereas spherical micelles or cylindrical micelles are formed at lower temperatures. However, for PCL-b-PEO with longer PEO blocks it is found that the crystallization temperature has opposite effects on the morphology. A mechanism of two competitive factors, namely the perfection of PCL crystals in the core and the deformation of the soluble PEO block, is proposed to elucidate the opposite observations with respect to crystallization temperature.45,46 The same authors also observed morphology transitions from spherical through rod/worm-like to lamellar architectures when the length of the PCL block increases in the PCL-b-PEO copolymer for low weight PEO blocks.47 Similarly, the Su group suggested that crystallization temperatures have a strong influence on BCPs structure formation. Su and co-workers prepared lamellar structures with elongated truncated lozengeshaped single crystals from poly(2-vinylpyridine)-block-PCL (P2VP-b-PCL) at 20 °C.48 When the temperature is increased to 30 °C, the crystallization process is suppressed and only spherical structures are observed. In such amphiphilic BCPs with one crystalline block, this influence of crystallization temperature can be used to control shape by switching crystallization on or off. If self-assembly above the crystallization temperature gives a specific structure, cooling down the system then leads to a shape transition because crystallization sets in. Generally, for semicrystalline BCPs the accessible structures vary significantly from those observed for noncrystalline BCPs. For the conventional systems, spherical micelles are the most common architecture as it is more energetically favorable. Consequently, only a narrow range of noncrystalline BCPs are able to form asymmetric architectures with extreme aspect ratios. On the contrary, BCPs with crystalline coil-forming

strategy to produce CO2-responsive BCPs based on amidinecontaining poly(ethylene oxide)-block-poly((N-amidine)dodecyl acrylamide) (PEO-b-PAD). In this study, the vesicular nanostructures with a radius of approximately 60 nm expanded to 120 nm upon introducing CO2 gas.33 The Zhao group also reported a similar observation: poly(N,N′-dimethyl acrylamide)-block-poly(N,N′-diethylaminoethyl methacrylate) (PDMA-b-PDEAEMA) vesicles with cross-linked PDEAEMA expand and swell in the presence of CO2.12 Zhao and Yan also demonstrated the CO2-responsive feature using a triblock copolymer, PEO-b-PAD-b-PS. The intermediate PAD blocks become water-soluble when protonated, which is controlled by the introduction of CO2 gas. With increasing fraction of hydrophilic sections, the triblock copolymers undergo shape transformation from tubules through vesicles to spherical architectures,12 as schematically illustrated in Figure 3 with

Figure 3. CO2-switchable amidine-containing triblock copolymer PEO-b-PAD-b-PS (top) and CO2-driven shape transformation behavior (middle). Insets a, b and c are TEM images of PEO-bPAD-b-PS aggregates at different levels of CO2 stimulus (bottom). Scale bars: a is equal to 500 nm, b and c are equal to 200 nm. Reprinted with permission from ref 12. Copyright 2013 John Wiley and Sons.

corresponding TEM images. Although solvent exchange methods modify the solution chemistry, the introduction of CO2 gas changes the polymer chemistry, and both strategies rely on the change of interactions between copolymers and surrounding medium. 2.2. Influence of BCP Crystallization. Crystallizationassisted self-assembly has become an emerging pathway to construct complex BCP assemblies with various shape and functionality. This increasing interest is facilitated by the recent development of new synthetic strategies that gives easy access to semicrystalline BCPs.34,35 Controlling the self-assembly process of such block copolymers with one semicrystalline block is highly complex and remains a significant challenge.36−40 This is in strong contrast to noncrystalline BCPs where excellent agreement between theoretical and experimental studies has been demonstrated.2,25,41 In this section, we first highlight how the combination of crystallization and selfassembly results in entirely different mechanisms of structure formation. These can be exploited to precisely manipulate the shape of BCP micelles with crystalline-cores. Second, we focus 1921


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Figure 4. (A) Rectangular hollow platelet micelles by living CDSA of PFS-b-P2VP/PFS blends initiated by the cylindrical micelles seeds of PFS-bPDMS in a mixture of hexane and isopropanol. P2VP is immobilized via coordination of the pyridyl groups with platinum nanoparticles. (B) Patchy and hollow platelet comicelles formed through the sequential addition of the PFS-b-P2VP/PFS, PFS-b-PDMS/PFS and PFS-b-P2VP/PFS blend unimers. The perforated rectangular platelets and hollow rectangular rings are formed after cross-linking and redispersal in THF. Reprinted with permission from ref 63. Copyright 2016 American Association for the Advancement of Science.

followed by cross-linking of P2VP, a hollow platelet is formed upon selective dissolution using THF (Figure 4A). The AFM image and height retrace confirmed the removal of PFS-bPDMS cylindrical micelles. Similar to the epitaxial growth in cylindrical comicelles, the sequential addition of different polymer blends gives a platelet consisting of several rings of different materials. Through selective immobilization, these rings can detach upon dispersal in a good solvent, as schematically illustrated in Figure 4B. We postulate that the sequential growth of the 2D structures is of particular importance as this leads to encoded information with high data density. Success has already been achieved in 1D linear comicelles64 and this may be further applied to multidimensional structures. The example of 2D platelet micelles also demonstrates the power of blending crystallizable homopolymer and BCPs. Cambridge et al. used the same blending method to produce micelles consisting of elongated lamellae with long protruding fibers based on PFS homopolymer and PFS-b-PI. However, in this study pure PFS platelets were used as seeds instead of a cylindrical seed.65 This hierarchical strategy can also be applied to form nanotubes, as first reported by the Liu group. Here, the authors produced BCP nanotubes from PI-block-poly(2-cinnamoylethyl methacrylate)-block-poly(tert-butyl acrylate) (PI-b-PCEMA-b-PtBA) through selective cross-linking and degradation.66 When polymer−medium interactions are utilized in addition to living CDSA of cylindrical comicelles, it opens up control of multidimensional architectures. This is achieved through manipulating solvent qualities with respect to each moiety of BCPs. In Section 2.1, we highlighted the influence of solvent composition on amphiphilic BCP assembly from the viewpoint of BCP geometry, however the mechanism of how solvent quality affects comicelle superstructures is different. In the coassembly of P−H−P and H−P−H cylindrical comicelles with hydrophobic (H) or polar (P) segments, comicelles are able to assemble either side-by-side or end-to-end depending on the solvent quality. Moreover, the supermicellar arrangement can be controlled by the length of P and H segments giving irregular network, chain networks and even 3D superlattices, as illustrated in Figure 5 where P segment is PFS-b-P2VP and H segment is PFS-b-PDMS.67 On the basis of the same strategy, Li et al. produced “cross” supermicelles using amphiphilic

blocks tend to form nanofiber structures under a wide range of assembly conditions.13,49−61 The Manners and Winnik groups found an unexpected rod-like morphology formed by poly(ferrocenyldimethylsilane)-block-poly(dimethylsiloxane) (PFSb-PDMS) in which PFS forms the core and PDMS forms the corona. The authors suggested that the formation of rod-like micelles is attributed to crystallization of the core polymer.49 The formation of these structures was investigated through epitaxial growth of BCP seeds with crystalline cores. Patra et al. explored this epitaxial growth using a different BCP, i.e., poly(3hexylthiophene)-block-PDMS (P3HT-b-PDMS), to produce monodisperse nanocylinders with a P3HT core and a PDMS corona through CDSA using seed micelles as initiators.54 These seed micelles are prepared by sonication. Upon adding P3HTb-PDMS unimers, cylindrical micelles grow into long chains by continuous addition of unimers to the reactive chain ends without termination. Analogously to living polymerizations, the length of the resulted nanofibers is controlled by the ratio of added unimer to seed. Though this type of epitaxial growth is extremely desirable, the technique of unimer addition can only be extended to a few other BCPs with crystalline coil-forming blocks, such as polyisoprene-block-poly(ferrocenylmethylsilane) (PI-b-PFMS)58 and PFS-block-poly(N-isopropylacrylamide) (PFS-b-PNIPAM).62 Although the crystalline core provides a scaffold for nanofiber growth, the functionality of corona forming blocks affords design of smart nanomaterials such as thermoresponsive nanofibrillar hydrogels when PNIPAM is involved. Because of the fact that both sides of crystallite seeds are active, the addition of BCP unimers to seeds leads to bidirectional epitaxial growth giving an A−B−A centrosymmetric cylindrical comicelle. With the aim to create A−B or A− B−C noncentrosymmetric cylindrical comicelles, Manners and Winnik groups developed a strategy by combining CDSA of crystalline BCPs in solution, selective micelle corona crosslinking and selective middle block dissolving to induce unidirectional growth.55 This structural hierarchies through selective immobilizing and dissolution is a versatile strategy that can extend to arrangement of 2D nanostructures. As an example illustrated in Figure 4, Qiu et al. produced hollow and patchy rectangular platelet micelles from crystallizable BCP and homopolymer blends.63 The 2D platelet is assembled by adding PFS-b-P2VP unimer to cylindrical micelles of PFS-b-PDMS, 1922


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comicelle can form superstructures via side-by-side stacking; however, other interesting supermicelles such as “cross” and multiple “cross” have been found when L1 and DP2 are manipulated, as depicted in Figure 6. A mechanistic insight of the coassembly and influence of L1 and DP2 has been proposed and a phase diagram summarizing the possible superstructures and their corresponding conditions has been produced. This allows the prediction of superstructures when the detail of cylindrical comicelle is given. The same group also explored this “cross” feature of supermicelles through a different driving force, namely hydrogen-bonding (H-bonding) interactions. In analogy to the P−H−P or H−P−H system, the use of Hbonding interactions requires design of polymeric segment with desired properties. Li et al. investigated BCP systems possessed a cyrstallizable, core-forming PFS block together with a coronaforming segment that was either hydroxyl-functionalized poly(methylvinylsiloxane) (PMVSOH) as H-bonding donor (HD), P2VP as H-bonding acceptor (HA) or PtBA as noninteractive block (N).69 Therefore, a cylindrical triblock comicelle consisting of a middle H-bonding acceptor segment and two noninteractive terminal segments is denoted as N− HA−N. Not only the “cross” supermicelles can be assembled, end-to-end or side-by-side supermicelles are also possible when the position of HA and HD segment is controlled. The authors also demonstrated a hierarchical strategy in combination of sequential addition of different unimers and selective crosslinking of segments to produce “windmill”-like supermicelles.69 From the above examples, it is clear that living CDSA is a powerful method to manipulate the structures of BCP assemblies. In particular, the living character allows sequential coassembly which enables construction of hierarchical architectures with great complexity. With the development of polymer chemistry, living CDSA is also capable to produce stimuli-responsive intermediate structures.70 This hierarchical strategy to produce superstructures can further extend to noncrystalline systems, which are discussed in the following section. 2.3. Multicompartment Micelles and Superstructures. Multicompartment micelles and their superstructures further expand the structural complexity that can be engineered from BCPs.44,71−74 By using mixtures from two different BCPs that have the same hydrophilic corona block but two different hydrophobic blocks, multicompartment micelles can be formed with a phase-separated core. This general concept can further lead to the assembly into superstructures by utilizing the interactions between the same core materials in two different micelles, and thereby leading to the buildup of a longer hierarchical structure that is stabilized by the hydrophilic corona blocks.14,75 Concepts to tune the shape of mixed micelles by varying self-assembly conditions and composition are also introduced in this section.76,77 Wooley and Pochan groups reported beautiful works in multicompartment and multigeometry assemblies. These were formed from simple diblock copolymers, PAA-b-PB and PAA-bPS, and polystyrene-coated gold nanoparticles (PS-AuNPs) via kinetic control.71 In this study, BCPs are first dissolved in THF, a good solvent for both PS and PB blocks: this is followed by the addition of EDDA, thus forming hydrophilic EDDAcomplexed PAA blocks. Owing to the incompatibility of PS and PB blocks,78−80 local phase separation is observed within the aggregate core of PS and PB blocks when water is added either quickly or slowly. Figure 7 shows control over shape and internal morphology of phase-separated nanoparticles via the

Figure 5. Multidimensional superstructures assembled from P−H−P or H−P−H (H = PFS-b-PDMS, P = PFS-b-P2VP) triblock comicelles through end-to-end stacking (a−c), and side-by-side stacking (d and e). The PFS core-forming block and the PDMS and P2VP coronaforming blocks are indicated by orange, red and green colors, respectively. The supermicelles are affected by the length of each individual comicelle. (a) TEM image of an irregular network formed by the addition of decane to a solution of P50 nm-H190 nm-P50 nm comicelles. (b) TEM image of chain networks formed by the addition of decane to a diluted solution of P145 nm-H110 nm-P145 nm. (c) TEM image of a 3D superlattice formed d by H105 nm-P160 nmH105 nm triblock comicelles by the addition of isopropyl alcohol. (d) TEM images of side-by-side stacking formed by P−H−P comicelles with small P section. (e) TEM of side-by-side stacking formed by P− H−P comicelles with large P section. Reprinted with permission from ref 67. Copyright 2015 American Association for the Advancement of Science.

cylindrical triblock comicelle of M(PFS-b-PtBA)-b-M(PFS-bPDMS)-b-M-(PFS-b-PtBA), where M denotes micelle segment. In this example, PFS-b-PtBA is the P segment and PFS-bPDMS is the H segment. Li et al. investigated not only the influence of solvent quality on supermicellar arrangement but also the length of P segment (L1) and degree of polymerization of PtBA (DP2).68 Under certain conditions, the cylindrical 1923


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Figure 6. (A) Chemical structures of PFS-b-PDMS and PFS-b-PtBA, abbreviated as H and P, respectively. The P−H−P triblock comicelle is prepared through CDSA. L1 is the length of H section and L2 is the length of PtBA corona, which is directly related to its degree of polymerization. The boxed section (middle) shows 4 scenarios of different values of L1 and L2, which provides a mechanistic insight for the formation of supermicelles. (B) Schematic representations of the supermicelles formed in methanol by the triblock comicelle P−H−P with different value of L1 and L2. The phase diagram (right) summarizes the influences of L1 and DP2 (to which L2 is related) on the supermicellar structures formed by the amphiphilic triblock comicelle P−H−P. “I” denotes individual cylinders, “C” denotes “cross” micelles, “MC” denotes multiple “cross” and “B” denotes cylinder bundle. Reprinted with permission from ref 68. Copyright 2016 American Chemical Society.

strategy by making more complex polymeric double helices using the same BCPs system.82 The structure of helices are similar to what reported by Dupont et al.; however, the latter system uses poly(n-butyl methacrylate)-block-PCEMA-blockPtBA (PBMA-b-PCEMA-b-PtBA), which relies on the control of solvent quality.83 Higher-ordered complex multicompartment superstructures can be accessed by precise hierarchical assembly of preformed BCP nanoparticles with phase-separated cores. The Müller and Walther groups elegantly demonstrated a general concept of directed self-assembly: stepwise reduction of the degree of conformational freedom lead to the formation of multicompartment micelles (MCMs) composed of linear ABC tri-BCPs.14 This construction strategy largely contrasts Wooley and Pochan groups’ kinetically controlled approaches as it aims to avoid the undesirable kinetic traps.24,71 In the hierarchical pathways, as illustrated in Figure 8, the ABC tri-BCP is first dissolved in a nonsolvent for the middle block B, yielding a micellar subunit with B core and compartmentalized corona of A and C (Figure 8a). Subsequent addition of a nonsolvent for block-A through dialysis triggers the collapse of block-A forming intermediate subunits (Figure 8b,c). Depending on the volume ratio of A and B blocks, the rearrangements and phase segregation between blocks A and C give secondary aggregation. Figure 8d−f shows corresponding TEM images of a PS-b-PB-b-PMMA model system.14 Interestingly, the football MCMs and linear

speed of water addition. In the rapid water-induced assembly pathway, BCPs are kinetically trapped resulting in a shell−core spherical shape. In contrast, PAA-b-PS and PAA-b-PB are able to adopt their preferred interfacial curvature in the slow pathway, thus forming spherical or cylindrical particles,71 as shown in Figure 7d,i. The authors also demonstrated the formation of micelle-like aggregates with PS-AuNPs trapped in the PS domain of the hydrophobic cores. In further studies of this BCP blending strategy, the same authors used a similar binary system of PAA-b-PS and PAA-b-PI copolymers, and EDDA diamine to construct disk−cylinder hybrid nanoparticles.28 In analogy to the coassembly of PAA-b-PS and PAA-b-PB, the formation of multigeometry particles of PAA-bPS and PAA-b-PI blends also relies on the incompatibility of the unlike hydrophobic blocks, that is, in the latter case, polystyrene and polyisoprene.28 When this strategy is utilized to coassemble sphere-forming PAA-b-PB with vesicle-forming PAA-b-PMA-b-PS tri-BCP, disk-sphere hybrid nanoparticles are obtained via a kinetically controlled pathway. Another approach of utilizing demixing blocks to control the shape of BCP particles is to exploit the phase separation of the corona-forming block as reported by Cheng and co-workers.81 The authors made polymeric Janus particles from mixed-shell micelles and assembled poly(2-vinyl naphthalene)-block-PAA (P2VN-b-PAA) and PEO-b-PAA into tubular superstructures and nanosheets. The Cheng group further advanced this 1924


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structures to minimize energetically unfavorable interfaces of S patch and nonsolvent.75 Figure 9b shows an example of decorated linear superstructure formed from both building units. The authors also reported that the overall size of x-SBM noticeably affects the number of particles attached to each segment of the SDMS superstructure chain, i.e. -S segment of SDMS can accommodate ca. eight s-SBM units (Figure 9c) or one m-SBM unit (Figure 9d). As for the l-SBM unit, it is too large for lateral decoration and acts instead as a selective endcapping agent (Figure 9e). This character of l-SBM particle can be used to tailor the length of the worm-like supracolloidal chain through manipulation of the l-SBM to SDMS ratio. This inspiring example shows the fantastic potential of self-assembly to give highly complex structures of well-defined shape and morphology when a synthetic chemistry approach to selfassembly is applied. In the latest work, the same authors reported a myriad of multicompartment nanostructures obtained from an ABC triblock copolymer where A/B (polystyrene/polybutadiene) are cores and C (poly(tert-butyl methacrylate)) is the corona. When the ratio of block length NC/NA is controlled, the tri-BCP assembles into various morphologies such as spheres, cylinders and bilayer sheets. The insoluble blocks undergo phase separation to core A and surface patch B, where NB controls the patch morphology. Therefore, the combination of control over these independent parameters allows constructing of extreme versatile morphology and decoration when a single BCP system is used.86 Instead of using preformed micelles as building blocks, various BCP superstructures can also be accessed directly through self-assembly of copolymer mixtures. Altering the composition of the mixture then results in different shapes and morphologies. As an example, Yoshida demonstrated worm-like structures by using mixtures of different poly(methacrylic acid)block-poly(methyl methacrylate-random-methacrylic acid) (PMAA-b-P(MMA-r-MAA)) copolymers with different compositions.77 Worm-like vesicles are found when the fraction of the copolymer with a long PMAA block (PMAA-L) is increased. In another example, Cai and co-workers made superhelical virus-like structures using poly(γ-benzyl-L-glutamate)-block-poly(ethylene glycol) (PBLG-b-PEG) and homopoly(γ-benzyl-L-glutamate) (homo-PBLG).76,87 The hybrid aggregates of PBLG-b-PEG and homo-PBLG form helices including rings and rods whereas pure PBLG-b-PEG selfassembles into spheres. These virus mimicking structures are of particular interest due to their potential application in biomedical research. In this attempt, the Gu group made viral capsid-mimicking nanoarchitectures through cooperative electrostatic and/or hydrogen bonding between polymers.88 Other interactions, such as host−guest interactions, can also be applied to manipulate nanoarchitectures. As an example, Wooley and co-workers reported a hierarchical assembly strategy of utilizing PAA-b-PS and crown ether functionalized PAA-b-PMMA to assemble into 1D chains, 2D rings and 3D superstructure aggregates.89 Here, the crown ether grafted PAA-b-PMMA copolymer provides interparticle interactions ascribed to its host−guest chemistry property. Zhou and coworkers also constructed large vesicle aggregates through host− guest interactions between functionalized blocks using “branched polymersomes” as subunits.90 2.4. BCP Self-Assembly in 3D Confinement. Fully hydrophobic block copolymers have proven to self-assemble into a range of interesting nanoparticles,91−93 in which the shape of the final particle crucially depends on the phase

Figure 7. TEM images of PAA-b-PB and PAA-b-PS blend nanoparticles formed via fast water addition (a−c), and slow water titration (d−i). All nanoparticles are formed in a 1:4 volume ratio of THF and water mixture with an amine to acid molar ratio 1:2. The PAA-b-PB to PAA-b-PS molar ratio is (a) 6:1; (b) 3:1; (c) 1:6; (d) 1:0; (e) 6:1; (f) 3:1; (g) 2:1; (h) 1:3; (i) 0:1. The PB phase of the nanoparticles is stained by OsO4. The TEM image insets in panels a−i are high magnification of typical particles, cartoon insets in panels a−i represent the approximate relative proportion of each block domain within the multicompartment BCP nanoparticles. Scale bars: insert scale bars in panels a−c are equal to 20 nm; all other scales bars are equal to 100 nm. Reprinted with permission from ref 71. Copyright 2011 Royal Society of Chemistry.

MCMs in Figure 8 are very similar to Liu and co-workers’ patchy nanoparticles with segregated surface chains84 and hamburger-like micelles,85 respectively. The latter structures are assembled from PtBA-b-PCEMA-b-PSGMA, where PSGMA denotes sucinnated poly(glyceryl monomethacrylate). In these seminal works of soft patchy nanoparticles, the authors demonstrated unprecedented diversity of well-defined morphologies and, most importantly, exhibited highly homogeneous populations that are remarkably monodisperse in size. The TEM image and its Fourier-transformed insert of “Football” MCM in Figure 8d are evidence of such a homogeneous structure. Groschel et al. further coassembled patchy nanoparticles into well-ordered hierarchical superstructures.75 Colloidal building blocks consisting of SBM (polystyrene-block-polybutadieneblock-poly(methyl methacrylate)) and SDM (polystyrene-blockpoly(3-butenyl(dodecyl)sulfane)-block-poly(methyl methacrylate)) are prepared separately by self-assembly through solvent exchange. SBM and SDM are rearranged into monovalent xSBM particles (x indicates the size of particle, x = s (small), m (medium) or l (large)) and divalent SDMS particles as monomeric units. The superscript indicates that the M corona is attached to either a B or D core, and bold letters represent assembled subunits distinguished from the free polymer chains.75 Both building units are illustrated schematically in Figure 9a. Upon reduction of solvent quality for S patches, the building blocks undergo self-assembly into linear super1925


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Figure 8. Mechanism of the directed hierarchical self-assembly of well-defined MCMs. (a) ABC tri-BCP is forced into micellar subunit. (b−e) Upon dialysis, these subunits assemble via refinement of the corona structure into various micellar structures with well-defined number of patches depending on the volume ratio of A and B. (f) Worm-like aggregates may form under certain conditions. Cartoon represents generic ABC tri-BCPs whereas TEM images are PS-b-PB-b-PMMA. All scale bars are 50 nm except where otherwise stated. Reprinted with permission from ref 14. Copyright 2012 Nature Publishing Group.

These dispersed emulsion droplets provide the 3D confinement for BCP self-assembly. Upon removal of organic solvent, BCPs are solidified giving dispersed nanoparticles with rearranged morphologies. Carefully designed synthetic strategies to control interfacial energies through functional surfactants has been demonstrated to be a powerful route to BCP particles with unique nonconventional shapes.75 In the pioneering work of the groups of Yang and Yi, the authors demonstrated the interface-driven structure evolution of PS-b-PB from onion-like particles to striped ellipsoids using a mixture of two amphiphilic BCPs surfactants, PS-b-PEO and PB-b-PEO, functioning as domain active interface-tuning agents.94,95 In addition, the authors also added polystyrene homopolymer (hPS) in the emulsion phase to control the structure of BCP assemblies: PSb-PB/hPS blends were reported to give many other interesting structures. Spheres with internal helical PB domains and prolate particles with hexagonally packed PB domains could be obtained in dependence on the amount of hPS homopolymer.95

separation of the BCP. This dictates the internal morphology that drives the evolution of the overall nanoparticle shape. Therefore, controlling the shape of a particle to deviate from the natural sphere requires the realization of spatially anisotropic BCP morphologies in the particle interior. However, due to a variety of factors, the BCP morphology in a nanoparticle is more complex than in the corresponding bulk. Much like in thin films, interfacial tensions and consummation effects in small confinements both influence the morphology and thereby the shape. It is therefore of high importance to be able to control all these factors to be able to control the shape of nanoparticles. It has been demonstrated that the interfacial interaction between BCP and surrounding medium strongly influences the phase separation and thereby the morphology and shape of the particles. Control over the BCP morphology/orientation requires careful adjustments of interfacial tensions between the individual blocks and the aqueous medium. In this technique, BCPs are first dissolved into an organic solvent and then emulsified using surfactants in aqueous medium. 1926


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controlled Au-NPs as surfactants.100 The authors first prepared supramolecular modified PS-b-P4VP via hydrogen bonding with 3-n-pentadecylphenol (PDP), giving a comb-like structure of PS-b-P4VP(PDP).101 After emulsification in the presence of cetyltrimethylammonium bromide (CTAB), PS-b-P4VP(PDP) forms spherical particles with internal cylindrical P4VP(PDP) domains. Because of the favorable interaction of the PS layer with the CTAB surfactants at the particle surface, the particles exhibit an outer PS layer. On the contrary, upon addition of small amount of Au-NPs, BCP particles transform from spherical to convex lens shape with hexagonally packed dimples. In a recent study, Kim and co-workers further investigated the shape and morphology transition of PS-bP4VP(PDP) using surface-engineered graphene quantum dots (GQDs).102 The authors first synthesized alkylamine-grafted GQDs using hexylamine (HEX) and oleylamine (OLA), which have preferential interactions with PS and P4VP block, respectively. Although particles stabilized by GQD-HEX assemble into spheres with PS as outmost layer, GQD-OLA induces spherical particles with P2VP(PDP) as outer layer due to the preferential wetting of respect blocks. The authors also demonstrated the morphological evolution of PS-b-P4VP(PDP) from traditional spheres to convex lens-shaped particles when a mixture of GQD-HEX and GQD-OLA is used as surfactant.102 The feasibility of using alkyl ligands to tune the surface properties of GQDs has demonstrated the potential of GQD surfactants in producing shape-controlled colloidal particles. The use of Au-NPs and surface-engineered GQDs as surfactant for preparation of structured particles poses a significant fabrication limitation; as a result, the Zhu group introduced a facile strategy to achieve reversible transformation of PS-b-P4VP nanoparticles using poly(vinyl alcohol) (PVA) to adjust the particle/medium interfacial properties.103 In this work, the authors prepared the nanoparticles based on an

Figure 9. (a) SBM and SDM building blocks. (b) Representation of linear worm-like supracolloidal chain. (c−e) These depict the linear chain formed from small, medium and large SBM particles, respectively. In panels c and d, M corona is removed for clarity. Reprinted with permission from ref 75. Copyright 2013 Nature Publishing Group.

Inorganic nanoparticles (NPs) can also function as surfactants to tailor the shape and internal morphology of BCPs when the NP location is precisely controlled at the interface between the two polymeric domains.96−98 As a recent example, the Hawker group developed a simple, yet powerful strategy to control the shape of PS-block-poly(4-vinylpyridine) (PS-b-P4VP) particles using gold nanoparticle (Au-NP) surfactants. A morphology transition and overall shape change from spherical, onion-like particles to stacked lamellae ellipsoids were observed upon addition of Au-NPs.99 In a similar manner, Kim and co-workers developed a facile strategy to produce convex lens-shaped BCP particles with highly ordered and defect-free nanoporous channels using size-

Figure 10. (a) Schematic representation and TEM images of PS-b-P2VP particles assembled at different conditions. (b) pH responsiveness of lamellar ellipsoids with cross-linked P2VP domains at different pH value. (c) Morphological evolution of P2VP-b-PDMS using different surfactant. Reprinted with permission from ref 104 and ref 106. Copyright 2014 John Wiley and Sons and 2016 CSIRO Publishing. 1927


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Chemistry of Materials emulsion technique pioneered by Liu and co-workers.84 The morphological transition from onion-like spheres to ellipsoidal stacked lamellae is achieved through solvent annealing and it is found that the concentration of PVA in aqueous solution is critical in determining the particle morphology. The Hawker group also reported similar strategy to synthesize ellipsoidal PSb-P2VP nanoparticles and provided some mechanistic insights. In this system, the particle/medium interfacial properties are tuned using a surfactant package, namely a combination of CTAB and modified CTAB with a terminal hydroxy group (HO-CTAB).104 Because of the selective wetting ability of the two surfactants to different domains, the surfactants mixtures can accurately tune interfacial energies between BCP blocks and blocks with surrounding medium. For instance, HO-CTAB shows preferential interactions with P2VP whereas CTAB is selective for PS. Thus, increasing the HO-CTAB content in the surfactants mixture results in a shape transition from onion-like spherical to axially stacked lamellae structures and eventually to inverse onion-like particles,104 as illustrated schematically in Figure 10a. In addition to surfactant mixtures, Klinger et al. also demonstrated the ability to tune the aspect ratio of the ellipsoidal particles by manipulating the lamellae thickness through the molecular weight of the BCPs. In the same system, P2VP chains can be cross-linked to form hydrogel discs.104,105 The formed hydrogel layers enable a reversible anisotropic shape transformation of the whole ellipsoidal particles in response to a pH change, as shown in Figure 10b. Such a dynamic, stimuli-responsive material is of significant interest as it is the first example combining shape anisotropy, internal morphology and stimuli-responsive features in one single system. Using the same surfactant mixture, Chen et al. reported similar morphological transition of P2VP-b-PDMS from onionlike spheres to pyramid-like lamellae, as illustrated in Figure 10c.106 However, it is found that in this particular system, a neutral interface can be obtained when CTAB is used as sole surfactant. It becomes obvious that controlling the assembly of BCPs via the polymer−medium interface offers great potential for the fabrication of highly functional dynamic materials (e.g., shape changing particles). Therefore, it is of high interest to expand this self-assembly method to more functional BCPs. As has been demonstrated by Gallei and co-workers, this concept can also be used to generate ferrocene-containing PFS-b-P2VP particles. In this system, the self-assembly is additionally strongly influenced by the crystallization of the PFS block.107 Consequently, different assembly conditions/compositions lead to different structures such as ellipsoids with axially stacked lamellae or nanosheets with hexagonal PFS cylinders. Furthermore, the ferrocene-containing PFS block rendered these particles redox responsive. By adding an oxidant such as FeCl3 a shape transition of the particles was observed. This can be attributed to a change of PFS polarity from hydrophobic to hydrophilic upon oxidation.108,109 The redox-active character of PFS-based polymers therefore allows changes in the properties of these assemblies and thus expands the scope of anisotropic particles. Moreover, the combination of redox-responsive PFS with pH-responsive P2VP domains allows a multistimuliresponsive behavior which represents a powerful platform for a wide range of applications.107,110−116 From the examples above, we can see that the control of anisotropic BCP nanoparticles crucially relies on the interfacial properties. However, Higuchi and Yabu groups demonstrated that the anisotropic internal morphology of BCP assemblies can

be achieved through control of solvent quality and temperature without using surfactants. Higuchi and co-workers pioneered the preparation of BCPs particles with different morphologies via self-organization during precipitation.117 Particle formation from BCP solutions is induced by evaporating a good solvent from a binary system of good and poor solvents. Depending on the evaporation temperature, PS-b-PI formed ordered stacked lamellar structures or onion-like structures from THF/water mixtures.118 Disordered structures were found at low evaporation temperature (10 °C). This may be attributed to the low mobility of polymer chains at this temperature. Russell and Hayward further investigated a similar system and observed that depending on the overall size of PS-b-PI particles, the core of onion-like sphere is either PI or PS block whereas the outer layer of the particles is always PS.119 In addition to solvent evaporation, exchange of solvents can also be achieved via dialysis method.120−122 However, both methods produced particles that exhibit anisotropic morphologies (stacked stripes) but are still spherical. This can be attributed to the fact that these morphologies are kinetically trapped. Consequently, they are not able to cause a deviation from the spherical shape. In other words, the shape of such hydrophobic systems can ultimately be controlled if the particles are in thermodynamic equilibrium. In addition to these considerations, the size of the colloidal confinement also affects the inner morphology and thereby the particle shape. The phase separated BCP structure crucially depends on the relative size of the particle in comparison to the domain size of the BCP. From the seminal work by Stucky and co-workers, new and interesting morphologies can be formed in a physically confined environment due to the fact that confinement-induced entropy loss and structural frustration play dominant roles in determining molecular arrangements.123 Therefore, the confined particle may not allow true deviations from the spherical shape. From these examples, it can be seen that all these factors have to be taken into account. To realize truly shape in anisotropic particles, the following things are required: the phase separation of BCP has to be in an equilibrium state and has to occur in confinements bigger than the domain size of the BCP so that consummation effects can be minimized.

3. PEPTIDE AMPHIPHILES BUILDING BLOCKS In comparison to synthetic materials, biologically derived components such as lipids, amino acids and nucleotides have advantages in biocompatibility and biodegradability. Peptides, specifically, are a promising and powerful platform for the design of self-assemblies with controlled nanofeatures due to the versatility afforded by the diverse amino acid library and precise control of their sequential arrangement.124−126 Much like BCP building blocks, peptide amphiphile (PA) also consists of two chemically distinctive entities, namely a short hydrophobic segment on one end of a hydrophilic oligopeptide sequence. An example of a typical PA synthesized from the Stupp group is illustrated in Figure 11, which is composed of four chemical entities.4 In addition to the hydrophobic domain (traditionally an alkyl tail) and hydrophilic peptide sequence, the PA contains a third segment of acidic or basic amino acids and a terminus (such as an epitope or a pharmacological agent) for integration of bioactive signals. As highlighted above, BCP building blocks are able to selfassemble into a myriad of nanostructures when assembly conditions are carefully controlled. In the direct contrast, PAs are reported to self-assemble into mostly nanofibers with some 1928


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Although the cylindrical nanostructure of PA assemblies is found to be remarkably imperturbable to changes within its central region, efforts have been made to control the shape and morphology of PA assembles through design at molecular level.132−134 Cui et al. demonstrated flat nanobelts assembled from PAs with alternating hydrophobic and hydrophilic amino acids. Such alternating sequences of amino acids eliminate all interfacial curvature giving giant flat nanobelts as illustrated in Figure 12C. The structural motif used in this work, VEVE,

Figure 11. Molecular structure of a representative peptide amphiphile with four rationally designed chemical entities: 1 is a hydrophobic alkyl tail; 2 is a short peptide sequence that forms intermolecular β-sheets; 3 is an acidic amino acid that provides charge and enhanced solubility in water; 4 is a terminus consisting of an epitope for interactions with cell receptors. The TEM images demonstrate the most common selfassembled structures of PAs. Depending on the molecular design, they assemble into nanofibers (K3 PA) and spheres (KLAK PA) respectively. Reprinted with permission from ref 4 and ref 127. Copyright 2012 and 2013 John Wiley and Sons.

scenarios into spherical micelles (Figure 11). This is mainly due to the nature of molecular structure of PA where the peptide domain has a strong propensity to form β-sheet hydrogen bonds which in turn governs the one-dimensional growth of PA assemblies.128 The Stupp group has reported a simulation work of self-assembly behavior of PAs in water from a mechanistic viewpoint.129 In this work, only β-sheet hydrogen bonds and hydrophobic interactions are taken into account, and the repulsive forces due to charged groups are neglected. It is reported that these two types of interactions lead to onedimensional fibrillar nanostructures and spherical micelles respectively, and it is the strength of these two competing factors determines the final structure of PA assemblies. With relatively weak hydrogen bonding, PA self-assembles into spherical micelles with interspersed β-sheet throughout their corona. With increasing hydrogen bonding, the spherical assemblies are disrupted giving fibrillar nanostructures where β-sheets grow along the nanofiber. Experimental results are found to comply to the calculation and it is reported that the first four amino acids closest to the hydrophobic domain are determinant in the formation of cylindrical micelles.130 In experiment, electrostatic repulsion also contributes to the final nanostructure in an aqueous environment. Therefore, it is the interplay of these energy contributions that governs the size, shape and interfacial curvature of PA self-assembly. Liao et al. also investigated the mechanism of the solution self-assembly of PA into nanofibers using a model system of NapFFKYp. The solution self-assembly pathway of this specific PA starts from peptide nucleation to nanofibers and eventually to higher order twisted nanofibers, which is dominated by hydrophobic and ion−ion interactions according to the molecular dynamic simulation.131

Figure 12. (A) Molecular structure of the PA forming giant nanobelt. (B) Illustration of the bilayer packing geometry. (C) TEM image of nanobelt assembled from VEVE. (D) PA isomers with different amino acids sequence and their corresponding assembled structures: nanobelts of VEVE; rigid cylindrical nanofibers of VVEE; twisted nanoribbons of EVEV. Reprinted with permission from ref 132 and ref 133. Copyright 2009 and 2014 American Chemical Society.

orients in a way similar to lipid with bilayer packing geometry so that valine can minimize solvent exposure in aqueous conditions (Figure 12B). The same authors also reported helical and twisted nanobelts in a more recent work using similar strategy at the molecular level.133 Interestingly, PA isomers with identical composition but a different sequence of their four amino acids assemble into drastically different types of one-dimensional nanostructures under the same conditions. Aqueous samples of 0.5 wt % of different PAs were prepared and aged for 2 weeks to eliminate any possible kinetic effects on nanostructures. As shown in Figure 12D, VEVE assembles into a nanobelt morphology, VVEE assembles into rigid cylindrical nanofibers and EVEV forms twisted nanoribbons. In the followed kinetics studies, the twisted nanoribbons assembled from EVEV undergoes a structural evolution through helical ribbons eventually to nanotubes over a course of 2 months. The influence of kinetics implies that an optimized preparation protocol and careful selection of self-assembly pathway may be required for their applications.135 1929


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now constitute viable “artificial” building block for creating novel architectures.143 The general strategy to build protein-based assemblies can be reduced to a three-step process. First, the building blocks are selected. These range from peptides to single proteins or to oligomeric assemblies of proteins. Next, because the shape of the final protein assembly relies on the specific interfaces (either protein−protein or metal−protein) of its building blocks, the proteins and protein interfaces are modified as required before finally self-assembling into superstructures. The simplest assembly method is based on the fusion of existing naturally dimer-forming and trimer-forming proteins into oligomeric building blocks, as outlined in Section 4.1. More complicated methods involve the re-engineering or modification of the protein interfaces to either specifically interact with each other (Section 4.2) or with metal ions and nanoparticles (Section 4.3). These strategies for protein assemblies are schematically summarized in Figure 13.

Afforded by the versatile supramolecular chemistry of PA building blocks, their assemblies possess stimuli-responsive properties. The Tong group demonstrated the pH-responsive PA nanofibers and hierarchical self-assembly into higher complexity.136 Just like the superstructures formed from BCP building blocks, the realization of hierarchical self-assembly relies on control of different noncovalent interactions that promotes aggregation at different stages. Here in Tong’s work, electrostatic interactions from oppositely charged amino acids pairing is utilized to form higher order bundled nanofibers. This complementarily attracting designer sequence promotes lateral assembly of nanofibers. On the contrary, when the charged residues are arranged in a complementary-repulsive fashion, nanofibers become well-dispersed in solution. The charge of amino acid on surface region of the PA nanofibers is selectively altered through control of pH. For instance, when the surface region of PA is composed of alternating arginine and aspartic acid sequence, lower pH (below the pKa of arginine) will result in an alternating pattern of positive and negative charges on the surface of nanofibers. The choice of amino acids in the design of PA building blocks together with pH control also enable the regulation of interfiber and intrafiber interactions.136 In comparison to other building blocks where shape and morphology are tunable giving large number of novel nanoarrangements, self-assembly of PA has so far largely been directed to form high aspect ratio assemblies. However, the versatile supramolecular chemistry permits added functionalities such as incorporation of metalloporphyrin137 and metal nanoparticles.134,138 This type of building block bridges synthetic materials and biological materials with potential to combine DNA and coiled coil as a template in virus mimic studies.139 Furthermore, the synthetic nature of PA allows design at molecular level which affords dynamic responsive features. For instance, incorporation of photocleavable nitrobenzyl ester group between β-sheet region and the bioactive epitope provides the possibility of using light to control peptide epitope presentation on the PA nanofiber surface.140 Use of other external stimuli, such as pH, can also be realized when corresponding functional entity is incorporated.141

4. SELF-ASSEMBLED MODULAR POLYPEPTIDE AND PROTEIN BUILDING BLOCKS Although self-assembly by synthetic polymeric building blocks demonstrates remarkable structural complexity, natural building blocks such as peptides and proteins enable reliable and predictable self-assembly into higher-order structures of exquisite complexity and function.142 The specific control over structure and shape of these assemblies is based on the selective interactions between peptide or protein interfaces, determined by the respective amino acid sequence. These interactions may be hydrophobic−hydrophobic interactions, electrostatic interactions or hydrogen bonding. Additionally, the interaction between structural elements such as β-sheets of different proteins can be used as coordinating element. Regarding the programing of a desired self-assembled structure, the primary challenge lies in predicting the interactions between different amino acid sequences and thus the structural features. Additional sequences make predictions exponentially more difficult and time-consuming to solve. However, because of advances in peptide/protein synthesis and computational power, coupled with various simplification techniques, it is now possible to exploit natural protein interfaces such that these too

Figure 13. Schematic summary of protein assembly methods. (A) Illustration of nanohedra formed from fused (oligo)proteins. (B) Coiled-coil assemblies through specific interactions between amino acid sequence. (C) Illustration of interfacial metal coordination in protein assemblies. The particular example here demonstrates Cd2+mediated conformational switching between nanofibrills and discrete three helix bundles. Reprinted with permission from ref 144, ref 145 and ref 146. Copyright 2012 American Association for the Advancement of Science, 2012 and 2013 American Chemical Society.

4.1. Assembly Through Fused Oligo-Protein Natural Interfaces. Protein fusion is the joining of two proteins to create a novel, larger structure that can then be used as a building block by exploitation of its natural protein interfaces. When protein self-assemblies are designed, as was first demonstrated in 2001,147 proteins with distinct, naturally occurring intersurface interactions are utilized. By artificially fusing proteins (A or B) that are able to form natural macromolecular complexes either with themselves or another complementary protein (e.g., A:A or A:C dimers) new building blocks are generated (e.g., a :A−B: block) that are capable of 1930


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Figure 14. (a) Schematic illustration of the various interactions between the elements of the heptad repeat which makes up coiled-coils. Leaf shapes indicate the direction. Hydrophobic residues are located at a and d positions. Polar residues at opposing e and g positions have ion-pairing or Hbonding interactions. The b, c and f positions are distant from the interface. (b) Schematic illustration of modular design of coiled-coil PNTs. (c) TEM images of fibers formed from PNT modules. Scale bar: 2000 nm, inset scale bar: 200 nm. (d) Schematic illustration showing the assembly of SAGE particles. Linkage of the green homotrimer to the red and blue hetrodimer via disulfide bonds results in “Hubs”, which when mixed, selfassemble into a s sphere. (e) (i) Design of the sphere with (ii) AFM image. (iii and iv) TEM images of the sphere, scale bars: (ii) 40 nm; (iii) and (iv) 500 nm. Reprinted with permission from ref 143, ref 145 and ref 153. Copyright 2012 and 2015 American Chemical Society, 2013 American Association for the Advancement of Science.

complexing with both proteins. Much like synthetic monomers, these multifunctional oligomeric building blocks can selfassemble into bigger structures (−A:A−B:B−A:A−). A breakthrough was made by Lai et al. in 2012144 when instead of a peptide chain, a short α-helical linker was used to fuse a naturally trimeric protein (bromoperoxidase) and a naturally dimeric protein (the M1 virus matrix protein). This allowed for predictable orientations between the two component parts, and resulted in the development of protein cages144,148,149 and arrays150 as outlined below. Yeates and co-workers have focused on exploiting the new αhelical linker to create more homogeneous and complicated cage-like assemblies. For example, an A−B component in the original nanocage design intersected at half of the well-known tetrahedral value of 109.5°144 This structure would then regularly self-assemble into a 12 subunit protein cage, more regularly than earlier attempts.147,148 This concept has recently enabled the creation of the largest and most complex assembly to date: a 24-subunit cuboid protein cage with octahedral symmetry, size-controlled openings of ca. 100 Å and an outer diameter of 225 Å.149 Further research continues on improving the stability of these assemblies by investigations on mutant designs. In addition to individual, discrete nanohedra assemblies, hierarchical shape control has been successfully achieved by creating 2D protein arrays, termed crysalins.150 Drawing inspiration from bacterial S-layers, these assemblies are based on a similar oligomeric protein fusion technique as the nanohedra above. However, crysalins are forced by genetic fusion to align along rotational symmetry axes of equal order. In contrast to nanohedra, crysalin hierarchical assembly is limited to 2D arrays rather than 3D structures due to the constrained

symmetry. In addition, this geometry places fewer restrictions on the required linker and termini, allowing for a larger number of components. 4.2. Controlling Interactions Using Interactions between Amino Acid Sequences. Another method of developing shape-controlled peptide and protein assemblies is based on designing amino acid sequences for specific interprotein interactions thus leading to a particular orientation. The sequences are computationally designed to varying degrees and through a range of synthetic techniques can create assemblies such as nanotubes and fibrils, and wireframe structures designed from coiled-coils. Coiled-coils are common natural components of both globular and fibrous proteins. These structures present great potential as polypeptide building blocks as their interactions are well understood. A coiled-coil consists of α-helices wrapped around each other, each with a pseudorepeating heptameric sequence of amino acids, a type of “repeat”. By exploiting or editing this characteristic repeating sequence, the interactions between the helices can be modified, leading to control over bulk shape. The Woolfson group has demonstrated that the resulting increasing refinement and expansion of a de novo toolkit of coiled coils145 can be used for solving synthetic biological problems. For example, redesigning the termini of previous designs145,151 has allowed for the modular assembly of synthetic peptide-based nanotubes (PNTs) and fibers.143 The modules were constructed using long-lived barrel motifs152 with controlled internal diameters and chemistries (see Figure 14). Modularity was achieved by placing charged residues at the Ctermini of the peptide sequences to complement oppositely charged side chains at the N-terminal repeat sequence. This was enhanced by minimal changes to existing peptides near the N1931


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Chemistry of Materials termini residues at the a and d positions of the heptad sequence repeat, leaving them exposed (Figure 14a). Finally, the end to end assembly of the barrels was assumed to occur through hydrophobic and electrostatic interactions. Another development by the Woolfson group is the development of unilamellar cage-like spheres of approximately 100 nm diameter from coiled-coil peptides, termed SAGEs.153 Analogous to the protein fusion method discussed above, the design comprises two types of synthetic coiled-coil structures, a heterodimer and a homotrimer, specifically designed for intercoiled-coil linkage via disulfide bonds (Figure 14d). When the two types of coiledcoils are mixed, a hexagonal lattice network forms around the “hubs”, which then closes to form a cage. The design of the coiled-coils allows for control over chemistry, self-assembly, reversibility and size of such particles, with the ultimate goal of controlling compartmentalization. Coiled-coils have also been utilized as the edges in discrete assemblies. Jerala and co-workers demonstrated the formation of a tetrahedron from a single polypeptide chain of concatenated coiled-coils.154 The six edges were formed by specific interactions between the 12 coiled-coil dimers, e.g., coil 1 will only interact with coil 5. These pairs were selected from previous work on designed coiled-coils by the Jerala155 and Woolfson156 groups. The vertices are flexible peptide linkers made from helix interrupting residues Ser-Gly-Pro-Gly placed to delineate coils. The chain was produced by synthetic gene encoding; the designed polypeptide chain was codon optimized for Escherichia coli, and expressed in the bacteria before being purified and refolded via dialysis. It is hoped that this shape control strategy can be extended in the future by using longer peptide chains (i.e., more heptad repeats) and additional coiledcoil pairs to create larger or more complicated assemblies, respectively. In addition to such experimental developments, the increasing number of computational approaches to predict protein folding has become an important tool for the de novo design of completely new building blocks for protein selfassembly. In contrast to the previous method of small iterations on existing binding motifs, King, as part of the Baker group, pioneered a method of computationally redesigning naturally complementary protein interfaces to create desired symmetric shapes and structures. 157,158 The method first utilizes symmetric docking of the protein building blocks in a target symmetric architecture. These interfaces are then evaluated for designability and the amino acid sequence is redesigned for enhanced interaction to drive the self-assembly. The designed protein is then expressed by E. coli via gene encoding. It has been shown that this method can be employed with identical trimer oligo-proteins157 or two different oligo-proteins158 to form the desired protein cages in close agreement with the computationally designed models. It is proposed that by expanding the number of protein combinations, this method will allow for the design of functional protein nanomaterials tailored to specific applications. In fact, this approach has very recently been utilized to produce 2D arrays by extending the oligo-proteins into a complete lattice.159 Other research from the Baker group has focused on utilizing the naturally modular constructions of repeat proteins.160,161 Analogous to repeating coiled-coil peptides, repeat proteins consist of repeating homologous sequences containing the amino acid repeats. These larger structures typically stack together around a hydrophobic core due to short ranged intrarepeat and inter-repeat interactions between residues.

Current repeat protein engineering practices include changing the residues on existing repeat proteins, varying the number of repeat molecules, and fusing naturally occurring repeat proteins. The Baker group has since developed a general computational method for building idealized repeat proteins that integrates available sequence families and structural information with Rosetta de novo protein design calculations.160 The method has a high degree of success; after synthetic genes were encoded into E. coli, 80% of the idealized proteins were expressed and soluble. More than 40% were folded and monomeric with high thermal stability. Crystal structures determined for members of three families are within 1 Å root mean squared (rms) deviation to the designed models. In one instance, this method was applied for the family of leucine-rich repeat (LRR) proteins in order to demonstrate control over shape and curvature.161 It involves a three-step process: First, the protein building blocks with specific curvatures are designed using a repeated protein idealization method in the Rosetta program.160 The second step is the design and expression of the junction molecules to link the curved modules. There are two designs: (a) fusion of the repeats from the two curved modules (often with redesigned residues to reduce side chain clashes and cavities), and (b) a “junction” design involving a wedge molecule which provides localized curvature between the two repeat proteins. In the third step, all proteins were created using genetic fusion and expression by E. coli. Their combination then leads to the desired de novo repeat protein. This process provides enormous control over the curvature of these designed proteins, and the hope is that this could greatly facilitate the creation of high affinity protein reagents and therapeutics. 4.3. Metallic Coordinated Assemblies. The difficulty in predicting the self-assembly of proteins due to the heterogeneity of surface interactions can be somewhat mitigated by exploiting the directionality and strength of metal coordination interactions. Metals can efficiently coordinate and control aspects such as geometry, stability, specificity, symmetry, reversibility and orientation. In comparison to the noncovalent interactions of amino acid sequences that are based on multivalency, metal coordination requires a much smaller surface thereby simplifying the design.142 Ions of Fe, Cu and Zn are particularly prevalent in natural protein assemblies and have high affinities for the most common metal-binding residues (His, Cys, Asp, Glu). These ions are often utilized to stabilize quaternary or supramolecular protein structures, mediate transient protein−protein interactions and serve as catalytic centers.162,163 Transferring this effective concept of metal-ionic coordination to new synthetic protein assemblies requires the development of selective multidentate coordination sites specifically on the target protein surface.162 Many strategies exist, including synthetic modification of proteins to create binding sites, reverse engineering existing sites and rationally designing de novo proteins to create specific binding sites. In the following section, important examples of each approach will be discussed to highlight the potential of this concept for the generation of new complex shape-controlled nanomaterials. The Tezcan group has achieved great progress in creating porous crystalline protein frameworks using a self-developed strategy called Metal Templated Interface Redesign (MeTIR).163 The strategy involves optimizing the initially noncomplementary and nonideally packed interfaces around the protein metal coordination site, which acts as a template. The Tezcan group has optimized cytochrome cb562, using both natural and unnatural residues in conjunction with computa1932


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Figure 15. Summary of strategies to assemble novel nanostructures from DNA building blocks. (A) Utilization of the hybridization-based DNA bond technique to create modular tiles from three types of DNA single strands (L, M and S). These can then combine to form complex wireframe structures. (B) Design of a DNA origami box assembled from the six DNA sheets which are color-coded as the circular map. The circle shows a sequence map of single-stranded DNA genome of the M13 bacteriophage with regions used to fold the six DNA sheets shown as colored arrows. (C) Utilization of the nanoparticle-templated DNA bond technique to create star-satellite particles of specific radius. The example shows a 24-helix bundle (length, 100 nm; diameter, 16 nm) as spacer. The TEM image shows a nanocluster with a planet of 60 nm AuNP and satellites of 10 nm AuNPs, scale bar: 100 nm. Reprinted with permission from ref 180, ref 181 and ref 182. Copyright 2009 and 2013 Nature Publishing Group, 2009 Royal Society of Chemistry.

tional modeling142,164 and strategic placement of disulfide bonds.165,166 The MeTIR strategy has been used to computationally design dimeric cb562 protein building blocks that could arrange through Zn2+ coordination into infinite 1D nanotubes and 2D and 3D arrays with a crystalline order.142 These assemblies closely resemble natural micro- and nanostructures and by virtue of being metal-mediated could be further adjusted by changes in metal concentration, pH and the inclusion of buffers. Other assemblies have also been created; Bai et al. adapted this strategy in the formation of nanoscale glutathione S-transferase (GST) nanorings, which utilized dimeric building blocks templated by Ni2+ ions.167 The Tezcan group has also developed a reverse MeTIR (rMeTIR) strategy to develop protein assemblies reliant on metal coordination sites for self-assembly.168 This involves the installation of metal-coordination motifs onto the monomeric protein, followed by the removal of key interfacial interactions to destabilize the protein. The result is a protein that can only self-assemble via coordination with the appropriate metal ion. In the first example of this strategy, the extensive C2 symmetric interface of ferritin was first grafted with a pair of stable, squareplanar His4-Cu coordination sites, which was followed by the elimination of conserved residues that form hydrogen bonding interactions across the interface. A variant was produced (MIC1) that was isolated as a monomer then assembled into a 24-mer cage by Cu2+ coordination. It is hoped that this method can be adapted to any protein−protein interface that possesses the appropriate geometry to accommodate the low-energy metal-binding site, which would allow the chemically controllable association and dissociate of natively interacting protein partners. De novo proteins, as outlined previously, offer the opportunity to design protein interfaces from scratch. Kuhlman and co-workers developed the first de novo computationally designed proteins which coordinate with metals by inclusion of

metal-binding sites using the Rosetta software.169 An idealized coordination site for a Zn+ ion is created by computationally designing a number of different designs, attaching zinc-binding two-residue His/Cys motifs, and then filtering results through further iterative computational modeling and design. Criteria include symmetry, computed binding energy and binding energy per unit of interface surface area. This approach allows for careful control over the shape of the protein molecules, and has delivered a homodimer of the natively monomeric Rab4binding domain of rabenosyn. Further work developed the active site for carboxyester and phosphorester hydrolysis.170

5. DNA BUILDING BLOCKS The application of nucleic acids for the design and construction of nanoscale materials has been widely touted as an exciting future in nanotechnology. The specificity of the Watson−Crick base pairing interactions, combined with advances in chemistry and computer-aided design171−173 now allows generating arbitrary synthetic oligonucleotide sequences. This enabled the use of DNA as a material for the construction of complex, functional nanoscale assemblies as first proposed by Seeman174 and Mirkin175 in 1996. An excellent recent review176 by these two pioneers broadly defines their two approaches to achieve rigidity in DNA nanoconstructs as “Hybridization-based DNA Bonds” and “Nanoparticle-Templated DNA Bonds.”177−179 The same terminology will be reused here. The outstanding stability of the DNA-based connections has allowed the development of a wide range of unique architectures with great structural stability. In a first approach, hybridization-based DNA bonds utilize intricate oligonucleotide crossovers to create rigid scaffolds from which assemblies with defined shape and structure can be fabricated. It can be further separated into DNA tiles, a modular self-assembling technique (Section 5.1), and DNA origami, which utilizes a number of smaller “staple” strands to stitch different parts of a much longer strand 1933


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Figure 16. (a) Simple, four junction tile, with long strand (L) medium strands (M) and short strands (S) highlighted in blue, green and black, respectively. (b) Schematic showing how strands combine to form junctions, and complementary sticky ends can join to create polyhedral. (c) Schematic of more advanced A- and B- n-junction tiles; a links with a′ and b links with b′. (d) Simple polyhedra (tetrahedron, dodecahedron, buckyball) designed from simple tiles shown in panel b. (e) Advanced polyhedra (ninja star, triakis tetrahedron, Pentakis dodecahedron) created using tiles similar to those shown in (c). Reprinted with permission from ref 185 and ref 186. Copyright 2014 John Wiley and Sons.

long strand, n medium strands and n short strands (Figure 16a). The reported strategy utilizes two types of tiles; “D-tiles” direct the assembly of “A-tiles,” and cannot associate with themselves. Of the two sets of sticky ends on A-tiles, one is complementary with other A-tiles, allowing for larger selfassemblies, while the other is complementary to the D-tiles (Figure 16c). A number of new assemblies were able to be fabricated, such as the ninja star ((A6)2(D2)3) and pentakis dodecahedron ((A6)20(D5)12). This technique has also been utilized to create smart nested, tetrahedral assemblies.188 An interesting approach to modular assembly of 2D and 3D designs from single-strand DNA (ssDNA) is used in the DNA brick technology, published by the Yin group in 2012.189,190 The general concept is outlined below in Figure 17. This approach features a library of oligonucleotides that are conceptually split into four sections (Figure 17A). Each section is designed to hybridize to a neighboring independent section to gain rigidity. For example, in the 3D designs, the 32 nt is conceptualized as four 8 nt domains (although it is not restricted to this number; different domain lengths give different packing lattices). Controlling the basepairs that are used in crossover allows for control over the dihedral angle between adjacent hybridized segments. Bricks follow a counterclockwise rotation with each successive layer, so every fourth layer follows the same arrangement, creating a highly complex, rigid structure with directional bonding (Figure 17C). Self-assembly is achieved in a single reaction as the particular sequence edges and corners are created through half-bricks. Although the yield from this process is low, and the annealing time can take up to a day, the complexity of the produced assemblies is comparable to typically more complex DNA origami assemblies (Figure 17D). This technique has most recently been used to create crystals with controlled expansion in one or two dimensions after reaching a prescribed depth,191

together (Section 5.2). In an alternative approach, nanoparticletemplated DNA bonds make use of a nanoparticle core to template directional interactions on the basis of core geometry (Section 5.3). These are summarized in Figure 15. 5.1. Hybridization-Based DNA Bonds: Tiles. Tiles are among the first motifs of DNA nanotechnology which allow for rigidity and directional interactions. These are typically doublestranded DNA with multiple crossovers (such as the double, triple and paranemic designs) at predefined points (a basic tile is shown in Figure 16a). Here, the coplanar single strands switch their connectivity to a different helix, creating a rigid, discrete structure.183 These nanoconstructs function as modular building blocks which can assemble into higher order assemblies and lattices. The original assemblies included 2D lattices and Seeman’s cube.184 More recent achievements include significantly more complex porous wireframe polyhedra and 3D DNA bricks; although such sophisticated shapes are still difficult when compared to the DNA origami method, outlined above. An innovation by the Mao group focused on the utilization of multiple identical tiles as basic building blocks to create much larger 3D assemblies. In 2008, this approach resulted in a threepointed star tile consisting of just seven strands: a long repetitive single strand, three identical medium strands and three identical short peripheral strands (Figure 16b). The flexibility of this modular construct positively correlates with the strand length. The termini of each branch of the tile could be modified to carry complementary single strand overhangs, termed “sticky ends”, which allow for the association between tiles. It is this interaction that allows for the creation of complex shapes such as a tetrahedron, a dodecahedron, a buckyball187 and an icosahedron.185 The most recent innovation generalizes the Mao group’s previous tile fabrication, while also creating more complex tiles that self-assemble into moderately complex, symmetrical shapes.186 An n pointed star therefore contains one 1934


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an openable lid by the Kjems group in 2009.180 This was achieved by adding unpaired flexible single-stranded segments into single-layer 2D origami and allowing the faces to selfassemble into a container structure. The cube could open to a specifically coded aptamer, which acts as a genetic key. Further development in this field involves a “robotic” successor to the Kjems cube, a hexagonal-based barrel by Douglas, Bachelet and Church.198 This device works similarly to the cube in that the rear is bonded covalently, and the front is bonded by DNA staple strands. The staple strands respond to specific aptamers and proteins in a manner similar to logical AND gates; both locks are required to be activated simultaneously, whereupon the lock mechanism is reconfigured and the device releasing its payload. The complexity of DNA origami assembly is often limited by the length of the strand. One method of circumventing this limitation is by a hierarchical assembly technique whereby each scaffold acts as an individual monomer. “Stacking” of DNA scaffold monomers to create superstructures by programming each monomer with sequence-programmed connectors allows for the full transfer of this concept of directed self-assembly to the fabrication of 3D materials.199,200 Recent research has allowed for the faster and more extensive growth of these assemblies: the relatively fast synthesis (1.5 h) of a 100 × 100 nm biomacromolecular breadboard was achieved.201 This is a highly noteworthy result as it opens the field for the development of nanoelectronic and nanophotonic devices. The breadboard structure consists of a number of modular components called “tpads” (named so because of the T-shape) that, when modified, could influence the shape, size and functionality of the breadboard. A similar strategy has emerged which allows or disallows self-assembly according to the concentration of Mg2+ ions.202 This new strategy utilizes vertical linkers (which run perpendicular to the duplex angle), which is difficult due to the strong electrostatic repulsion of the negatively charged DNA backbones. Another limitation of typical DNA origami has been the development of finer curved surfaces, as DNA origami is typically rastered onto a scaffold. The Yan group therefore developed a method of utilizing the DNA origami technique to introduce smoother curvatures into 3D nanoscale objects.203 The basic design proceeds as follows: First, a series of conceptual concentric circles of dsDNA is designed to outline the curvature of the 3D shape. Next, the crossovers are introduced to ensure rigidity in the structure. If out-of-plane curvature is desired, it is necessary to exploit the natural 10.4 bp/turn curvature in DNA. By calculating the necessary angle between circles for curvature, specific basepairs can be selected for crossover to closely match the angle. The extent of the curvature is then determined by the number and position of the crossovers. The scaffold is then threaded through the whole design to include all crossovers, and the remaining spaces are completed by staple strands, finishing the design process. A conceptual change to DNA origami was presented in 2009 when pleated sheets of DNA were introduced.204 Given the DNA origami’s tendency to be rastered onto a 2D scaffold, the sheets were designed to fold back upon themselves, often in a honeycomb lattice due to the 120° dihedral angle (although other lattices may be used205). The design process is likened to carving out a sculpture from a block: first, the shape is designed by removing segments; next a scaffold strand is introduced that covers a subset of predetermined positions; finally, the staples are introduced to cover the remaining spaces, ensuring that all

Figure 17. Overview of the DNA Brick method. (A) Breakdown of a single brick (B) schematic showing the linkage of two bricks, simplified to Lego bricks. (C) Demonstration of anticlockwise rotation of bricks between layers. (D) Demonstration of various brick assemblies. Reprinted with permission from ref 191. Copyright 2014 Nature Publishing Group.

an improvement over previous DNA crystals that expanded in three dimensions.192 5.2. Hybridization-Based DNA Bonds: DNA Origami. Scaffold-based assembly, popularized as DNA origami, has become the premier nucleic acid self-assembly technique following ground-breaking studies conducted by Yan et al.193 and Rothemund.194 Functionally, this process differs from DNA tile-based assembly as it involves hundreds of short oligonucleotide “staple” strands binding two distinct points within a long single strand DNA scaffold, collectively allowing for the DNA to be folded into an arbitrary 2D or 3D shape. This allows for faster synthesis, extremely high yields, high structural fidelity with few errors, high tolerance to stoichiometric imbalances and enzymatic stability.194,195 Importantly, although DNA tiles offer a simpler approach in modular assembly, the addition of the scaffold strand in DNA origami allows for significantly more complex and sophisticated assemblies. Although early employment of this technique gave an impressive array of 2D shapes and designs, newer research has resulted in the development of highly complex 3D DNA nanostructures.196 Other recent advances have raised the possibility of in vivo origami assembly, controlled through a stimulus such as temperature.197 However, such a task is daunting given the need to express hundreds of oligonucleotides within a fully functioning cell. This section focuses on this new research area, highlighting hierarchical assembly of multilayered and immobilized assemblies for shape control. The DNA origami method can be used to create 3D shapes by simply controlling the orientation of the scaffold and the staple strands. One famous example for the power of this method was the construction of a single-layered DNA box with 1935


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Figure 18. Different techniques for the fabrication of nanoparticle-templated DNA bonds. (a) Schematic overview of the fabrication of origami scaffolds for use in NP-templated DNA bonds realized in Schreiber’s work in (b, i−iv). (b, (i)) Chiral origami nanocluster (planet, 80 nm Au-NP; satellites, 9 × 10 nm Au-NPs in a right-handed helix). (ii) Gold-enhanced origami nanocluster. Scale bar: 100 nm. (iii) Ag−Au nanocluster (planet, 80 nm Au-NP; satellites, 20 nm silver nanoparticles (Ag-NPs)). Scale bar: 100 nm. (iv) Close packed lattice of gold-enhanced origami nanoclusters. Scale bars: 200 nm. (c) Scheme for the generation of functionalized, patchy colloids with valence realized in (d, (i)) as a tetravalent colloidal assembly (AB4) and in (ii) as an isomeric assembly formed by modifying patch size, analogous to ethylene. Scale bars: 2 μm. Reprinted with permission from ref 181 and ref 222. Copyright 2012 and 2014 Nature Publishing Group.

positions are no more than five positions from a scaffold crossover. This ensures structural rigidity and, although the folding time can take up to 1 week, resolutions of 10−100 nm can be achieved in a variety of shapes. The Shih group has enhanced this method by allowing for greater curvature.206 Using the crossovers as reference points, convex and concave faces are created during the design phase by adding and subtracting basepairs, respectively. This creates regions of local tensile or compressive strain (due to over or underwinding of the helix, respectively), which is imparted on its neighbors. The accumulation of various strains results in the bulk curvature or smooth bending of the origami structure along the helix-parallel axis, as opposed to the stepwise contortions of previous attempts. Greater curvature can be achieved by more extreme addition and subtraction of base pairs. Hybrid DNA nanotechnology techniques are also possible: Scheible et al. recently described the fabrication of a cube (side length approximately 10 nm) using a technique that borrows elements from both DNA brick and DNA origami.207 For such compact assemblies, the attractive interaction between the DNA cross-links must overcome the repulsive forces between closely packed DNA helices. Because of the reduced crossover density of smaller assemblies, this is difficult for the DNA brick approach. In contrast, it is simply difficult to produce (either synthetically or from an M13 phage) a short scaffold strand for DNA Origami. Thus, this hybrid approach utilizes short oligonucleotide strands to create assemblies via the DNA brick method but also several elongated and linked strands throughout a larger portion of the assembly, similar to a DNA origami scaffold. DNA origami also offers the possibility to generate shape-controlled assemblies by controlling the immobilization of other discrete soft matter particles such as proteins,208−210 viral capsids211 and carbon nanotubes212 onto surfaces. Very recently, DNA origami has been used as a

template for the control of the shape of a polymeric backbone.213 In this example, 9-mer ssDNA oligonucleotides were densely synthesized directly onto the surface of a conjugated (2,5-dialkoxy)paraphenylenevinylene (APPV) brush polymer. The polymer brush could then be immobilized onto a DNA template to create both 2D and 3D shapes. 5.3. Nanoparticle-Templated DNA. Another DNA-based approach to creating shape-controlled soft matter is based on nanoparticle-templated DNA bonds, which are designed to emulate the concept of an atom and molecular bonding (Figure 18). Early examples175 used a gold nanoparticle to create a nucleus, with a dense packing of functionalized nucleic acids on the surface acting as “valence bonds.”214 The ionic or metallic bonds responsible for the crystalline lattice of the inorganic core material provide the rigidity necessary for directional interactions; a dense shell of ligands means that the design considerations employed for DNA tiles and origami are not necessary. However, because of a natural affinity of the nucleic acids for the gold NP, a thiol moiety is often required to orientate the oligonucleotides in a common surface-normal direction. After the particles are fabricated, an annealing step allows for the creation of a crystallized lattice due to the hybridization of the nucleic acids. The development of this technique allows for the creation of facile building blocks with varying properties dependent on a range of core materials and the specific functionalization of the nucleic acids. Recent advances outlined below have allowed for the more complex permutations to achieve desired shapes and functionalities. The Sleiman group have used the NP-templating technique to create nanotubes and prisms215 using a face-oriented approach. First, variably sided DNA “rings” are templated with either rigid metal216,217 or organic218 vertices to form building blocks. Two rings are then connected using either single-stranded or double-stranded DNA linkers, allowing for 1936


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6. POTENTIAL APPLICATIONS Biology controls shape of soft nanostructures to impart properties, hence many of the potential applications that have been developed or are in development are bioinspired. A classical example is the folding of enzymes to control a range of highly specific reactions, which has driven some of the work in protein self-assembly. Optical properties are also potentially tuned using shape, which are highlighted by the camouflage techniques of many marine and land animals. For example, the color shift in chameleons through tuning of a lattice of guanine nanocrystals within a superficial thick layers of dermal iridophores.227 Inspiration from these could lead to next generation camouflage and optical derives using shape controlled nanostructures. Below, we discuss some of the current application focus of the four building blocks we have reviewed. Nanostructures prepared from these building blocks have vast potential applications in drug delivery. Especially the nanoparticles assembled from BCPs where the distinctive chemistry of two sections permit controlled release of the payload. For example, Robb et al. prepared a novel drug delivery vehicles with controlled morphologies based on poly(allyl glycidyl ether)-b-poly(lactide) (PAGE-b-PLA). As shown in Figure 19, the biodegradable PLA block is first

control over the size of the prism. These prisms can then be modularly assembled into nanotubes with controlled length.219,220 Most interestingly, because of the nature of the DNA linker strands, the tubes can be selectively loaded and unloaded using a specific DNA sequence.221 These new materials may have application as conducting or semiconducting nanowires, in plasmonics, or in drug delivery. The versatility of this general particle-templated approach can be seen in the following example by the Mirkin group, where the metallic core was replaced with soft matter. By attaching oligonucleotides to the proteins, DNA−DNA interactions replaced the existing protein−protein interactions allowing the assembly of lattices and arrays of protein catalase crystals.223 The functionalization of the proteins was achieved via a strain-promoted cycloaddition reaction between surfacebound azides and dibenzocyclooctyne (DBCO) moieties at the 5′ termini of the synthetic oligonucleotides. The protein−DNA assemblies were then hybridized by heating above the protein melting temperature and very slowly cooling to room temperature at a rate of 0.01 °C/min. This resulted in a rhombic decahedron structure of the crystalline proteins. Relatively recently (2008), combining DNA bonds with anisotropic particles was used to create core−satellite assemblies. First demonstrated using triangular gold particles,224 these assemblies achieve shape control based on the original shape of the gold nanoparticle. This has since been expanded to create lattices or arrays of anisotropic particles spaced and shape-controlled by DNA bonds linking them.225 Especially interesting is the combination of well-defined nanoparticles with the previously mentioned DNA origami. The Yan group grew long ssDNA on a gold NP using rolling circle amplification in situ.209 The addition of staple strands bent the strand into long 2D DNA belts which could be further functionalized for molecular transport. A similar approach was taken by Schrieber,181 who also utilized the DNA origami method to create linkages in planet-satellite nanoclusters. In such systems, the DNA origami technique allows for the precise modification of the size and distance of the spacers and their functionalization with nanoscale components. This enables the study of short and long-range interactions between nanoparticles and dyes in solutions, and gives greater control over designed superstructures. Schreiber’s planet−satellite assemblies and a brief scheme are shown in Figure 18b. Finally, anisotropy of the core nanoparticles can also be realized as a spatially controlled chemical functionality. The Pine group has developed polystyrene cores with functionalized patches on the particle surface that contain biotin and DNA.222 First, clusters of amine-modified polystyrene spheres (n = 1−7) are packed into highly symmetric arrangements. A chemically inert polymer is then spherically grown from the center of the cluster by a swelling and cross-linking processes. The process only covers the core of the cluster leaving the part of the original cluster exposed as “patches”. These are then functionalized with the biotin and the sequence-specific DNA oligonucleotides. The functionalization of the patches with complementary pairs allows for colloidal self-assembly into various constructs, often seen as analogues of common chemical elements or compounds. It is proposed that higherorder assemblies may one day be fabricated such as a diamond lattice.226 A schematic and examples of this process can be seen in Figure 18c.

Figure 19. Example of model drug release based on PAGE-b-PLA nanoparticles. The PLA block is biodegradable. Reprinted with permission from ref 91. Copyright 2012 Royal Society of Chemistry.

functionalized with fluorescent model drug via copper catalyzed azide alkyne cycloaddition “click” chemistry. Aqueous dispersion of BCP nanoparticles with phase-separated interiors are obtained through solvent exchange. Upon degradation of the PLA scaffold under physiological conditions, the covalently attached model drug is released. Besides the spherical delivery vehicles, nonconventional shapes of nanoparticles have shown great promise as carrier materials especially in cancer treatments.228 Worm-like polymer brushes, for instance, are promising to be the next generation of delivery medium because they exhibit high tumor cell penetration in combination with long circulation times.229 Cylindrical micelles have also found applications in biomedicine with advantages in prolonged circulation time of their payloads.230 These examples also demonstrate why shape control of nanostructures is important when it comes to biomedical applications. PA assemblies have found numerous applications particularly in regenerative medicine. As for traumatic bone loss, traditional 1937


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Chemistry of Materials Table 1. Assembly Strategies and Preparation Parameters in Shape Control for Different Building Buildingsa building blocks BCPs

PA

assembly strategy

example of assembled structures

geometry-driven

rods,11 toroid,23 spheres,12 vesicles12

∼80−400

crystallizationdriven multigeometry

dots,52 rods,13 stars,55 irregular42 spheres,71 wormlike14,75 onion-like,104 stacked lamellae88 nanofibers237

micrometers

interfacialdriven molecular design

nanobelts133 proteins

DNA

oligoprotein fusion interface interactions metal coordinated self-assembly using tiles scaffold-based assembly nanoparticletemplated

cage-like,144 crysalins150 spheres,153 fibrils143

range of size (nm)

∼50−100 ∼100−500 ∼10 in diameter ∼80 in diameter ∼20

representative materials used

pros and cons pros: large library of available BCPs, versatile chemical modification

pros: versatile supramolecular chemistry cons: limited shape control

rgeneration medicine, drug conveyer, templates

pros: extremely versatile structures

high affinity therapeutics, catalyst, templates

controlled release delivery vehicles, templates

cons: deviated assemblies, inconsistent in morphologies

nanorings167

∼200

natural proteins such as streptavidin coiled-coils from natural proteins ions of Fe, Cu

buckyball,187 polyhedral185

∼20−100

DNA strands

pros: extremely high fidelity, good enzymatic stability

arbitrary

∼100−400

DNA origami, DNA bricks

cons: complexity limited by DNA strand length

satellites,181 patchy assemblies,222 cages218

∼300−500

DNA and metal or colloids templates

∼100−400

potential applications

amphiphilic copolymers, such as PAA-b-PMA-bPS crystalline blocks, such as PCL, PFS pairs of copolymers, such as PAA-b-PI+PS-b-PAA hydrophobic copolymers, such as P2VP-b-PS amino acids sequence with alkyl tails

cons: difficulties in expressing proteins

nanobreadboard for nanoelectronic and nanophotonic devices

a

The size of assemblies only refers to low aspect ratio structures (spheres, stars, ellipsoids). Linear 1D assemblies have extreme aspect ratio and the length of which can extend to micrometer scale.

although reverse strategies of creating DNA-origami-shaped metallic particles have also been employed, allowing for specific-shaped partnerships.196 Pal et al. reported directed self-assembly of DNA to generate anisotropic plasmonic nanostructures with programmable positioning of gold nanorods (AuNRs).236 The precise orientation of NRs scaffolded by DNA is of particular importance with potential applications to explore interactions between anisotropic NRs and other molecules, for instance, geometrically dependent photonic interactions between AuNRs and molecular fluorophores. Other nanoparticle-templated DNA structures such as the work done by Sleiman218 will allow for the creation of nanowires of tunable size and geometry. These advances hold great promise in development of nanoelectronic and nanophotonic devices. In addition to these fields, the same technology can be used in drug delivery and therapeutics. This is also true of DNA tile and origami techniques, most evident in Mao’s various tile polyhedral,185−188 Kjems’ opening cube180 and “robot” by the Church group.198 The robot was of particular interest as it was capable of entering cells in tissue culture and in response to specific stimulation, releasing antibody fragments as payload, triggering a fluorescent response. This type of molecular logic gate may also have application in molecular computing. The capacity for highly complex self-assembly and functional nanodevices made possible by the specificity of the DNA bond means the DNA nanotechnology has great potential for both biomedicine and nanoelectronics. Other potential applications, along with preparation parameters and pros and cons for these building blocks, are tabulated in Table 1. The authors are in no doubt that with the further evolution of shape controlled soft nanoparticle even further applications will be achieved. In Table 1, it should be noted that the size distribution of these nanoassemblies is

metal implants lack bioactive components, which limits their ability to prompt regeneration. Through standard silanization and cross-linking chemistry, PA nanofibers displaying the RGDS epitope can be used to functionalize traditional titanium alloys and therefore allow added bioactivity around the implant.231 Shah et al. also reported applications in cartilage regeneration in a rabbit chondral defect model using specially designed PA molecule with a binding sequence to transforming growth factor β-1.232 Caged protein nanoparticles also found their applications in drug delivery due to their desirable features. Compared to BCP nanoparticles, caged proteins are biodegradable and have ideal sizes for endocytosis.233 Drug loading can be achieved through covalent conjugation, pore entry and physical interactions such as protein-carrier affinity. Alternatively, drugs can be released via biodegradation, diffusion or a reducing environment. Though the small size of protein cages poses a potential drawback of low drug loading capacity, this could be mitigated when targeting ligands are attached. For instance, Zhen et al. reported that protein nanoparticles incorporated with RGD amino acid sequence can target drugs to tumor due to the affinity for upregulated integrin receptors of endothelial cells of tumor vessels.234 There are a number of studies of protein and drug systems reached in vivo phase, and in particular, delivery of CpG drug using Qβ protein cages for cancer immunotherapy has reached phase 2 clinical trial, emerging as a promising candidate for immune-based treatments.235 DNA building blocks have application in numerous fields such as nanoelectronics, nanophotonics and drug delivery and therapeutics due to the sequence-specific binding properties of DNA. In one example, this specificity has been exploited to fabricate modular, hierarchically assembling nanoscale breadboards.201 Further investigation will focus on the placement of different nanoparticles inside the cavity each component, 1938


Review


future, the authors hope to see well-defined methods to create designer shapes. This will enable the design and the interaction of complex building blocks of differing shapes. By utilizing these tools and engineering complex designs, we may start to realize truly some of nature’s function, which may lead to macromolecular motors, advanced camouflage and selective catalysis. Finally, we believe the best examples reported thus far to engineering complex shape control come from a new way of thinking about self-assembly: a synthetic approach. Advanced organic and polymer chemistries pay significant attention to reaction conditions (stoichiometry, oxygen content, water content, temperature and reaction times) to design a successful reaction. Applying this type of careful and systematic design to self-assembling conditions will create new and complex nanostructures with elegant control over the shape and therefore function of soft nanoparticles. Although the building blocks highlighted in this paper are often categorized in different fields of research, they all provide access to shape controlled nanoassemblies. We hope the selected examples can provide inspiration and open up a new way to approach selfassembly in each area by learning from the different fields.

extremely wide, even in the same structure assembled from same materials. Moreover, the length of linear 1D assemblies formed by unimer addition often extend to micrometer. Therefore, the selected range of size of these assemblies in Table 1 is a representative example.

7. CONCLUSIONS AND OUTLOOK Over the recent years, the development of nanoarchitectures and shape-controlled nanoparticles has attracted incredible attention. This can be attributed to the fact that such novel architectures are highly promising for a variety of innovative applications in many different areas. Synthetic methods to control the shape of soft nanoparticles can roughly be categorized into self-assembly or templating/patterning methods. In both cases, tailoring the overall properties such as shape, size and functionality of the final architectures represents the key challenge. In a synthetic approach, these requirements are addressed by programming the building blocks accordingly on a molecular level. From this, various building blocks such as (commodity) polymers, peptides amphiphiles and biomaterials have emerged as valuable candidates that offer great control over the final material. In synthetic polymers, parameters like degree of polymerization, polymer architecture, solvent quality and selectivity govern the arrangement of these building blocks into nanoparticles of defined shapes. Additionally, the process of preparation can also be manipulated to access kinetically trapped architectures. Higher complexities of aggregates including branched stars or rods with superhigh aspect ratio are achieved through hierarchical pathways. In analogy with polymeric building blocks, interactions between functional groups can be utilized in the assembly of PA, proteins and DNA building blocks, thus permitting novel structures and design strategies. In comparison to the polymeric assembly (BCPs and PAs), this field of protein and DNA assembly is much more complex and can give access to a myriad of arrangements. However, transferring these concepts to applications is still in its early stages and requires further development of scalability and processing methods. Even though the highlighted examples show an outstanding variety of architectures that can be accessed, the current level of complexity is still insignificant when compared to natural systems. Producing biomimetic functional materials requires higher complexity of synthesized aggregates, a challenge that remains. Future ways to approach slowly nature’s complexity require a better and profound understanding of the respective self-assembly mechanisms. It is often the complex interplay of various interactions that governs the self-assembly of these systems, and therefore the understanding of the synergy of all these interactions is another challenge. Here, kinetic investigations via in situ microscopy may play a crucial role to investigate the time-dependent mechanism and dynamic behaviors of these systems. In particular, the availability and tools developed by ultrahigh resolution optical microscopy techniques will play a role here. Computational modeling will play an increasingly crucial role in the rational design of proteins interactions, nanoassemblies and structures. Extension of these types of principles into synthetic systems will further enable complex designs to be realized in such systems. However, to realize this truly in synthetic systems further innovation is required in the synthesis of sequence-controlled238,239 and perfectly defined polymers and oligomers.240,241 The development of these emerging fields will also feed the innovation in the area, leading to the ultimate goal of controlling the final shape of soft nanoparticles. In the

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AUTHOR INFORMATION

Corresponding Author

*(L.A.C.) E-mail: [email protected]. ORCID

Luke A. Connal: 0000-0001-7519-977X Author Contributions §

These authors contributed equally. All authors have given approval to the final version of the paper. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by a Victorian Endowment for Science Knowledge and Innovation (LAC).

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REFERENCES

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Shape Control of Soft Nanoparticles and Their Assemblies - American

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