Amphiphilic building blocks for self-assembly: from amphiphiles to supra-amphiphiles

The process of self-assembly spontaneously creates well-defined structures from various chemical building blocks. Self-assembly can include different levels of complexity: it can be as simple as the dimerization of two small building blocks driven by hydrogen bonding or as complicated as a cell membrane, a remarkable supramolecular architecture created by a bilayer of phospholipids embedded with functional proteins. The study of self-assembly in simple systems provides a fundamental understanding of the driving forces and cooperativity behind these processes. Once the rules are understood, these guidelines can facilitate the research of highly complex self-assembly processes. Among the various components for self-assembly, an amphiphilic molecule, which contains both hydrophilic and hydrophobic parts, forms one of the most powerful building blocks. When amphiphiles are dispersed in water, the hydrophilic component of the amphiphile preferentially interacts with the aqueous phase while the hydrophobic portion tends to reside in the air or in the nonpolar solvent. Therefore, the amphiphiles aggregate to form different molecular assemblies based on the repelling and coordinating forces between the hydrophilic and hydrophobic parts of the component molecules and the surrounding medium. In contrast to conventional amphiphiles, supra-amphiphiles are constructed on the basis of noncovalent interactions or dynamic covalent bonds. In supra-amphiphiles, the functional groups can be attached to the amphiphiles by noncovalent synthesis, greatly speeding their construction. The building blocks for supra-amphiphiles can be either small organic molecules or polymers. Advances in the development of supra-amphiphiles will not only enrich the family of conventional amphiphiles that are based on covalent bonds but will also provide a new kind of building block for the preparation of complex self-assemblies. When polymers are used to construct supra-amphiphiles, the resulting molecules are known as superamphiphiles. This Account will focus on the use of amphiphiles and supra-amphiphiles for self-assembly at different levels of complexity. We introduce strategies for the fabrication of robust assemblies through self-assembly of amphiphiles. We describe the supramolecular approach for the molecular design of amphiphiles through the enhancement of intermolecular interaction among the amphiphiles. In addition, we describe polymerization under mild conditions to stabilize the assemblies formed by self-assembly of amphiphiles. Finally, we highlight self-assembly methods driven by noncovalent interactions or dynamic covalent bonds for the fabrication of supra-amphiphiles with various topologies. Further self-assembly of supra-amphiphiles provides new building blocks for complex structures, and the dynamic nature of the supra-amphiphiles endows the assemblies with stimuli-responsive functions.     

Molecular self-assembly into one-dimensional nanostructures

Self-assembly of small molecules into one-dimensional nanostructures offers many potential applications in electronically and biologically active materials. The recent advances discussed in this Account demonstrate how researchers can use the fundamental principles of supramolecular chemistry to craft the size, shape, and internal structure of nanoscale objects. In each system described here, we used atomic force microscopy (AFM) and transmission electron microscopy (TEM) to study the assembly morphology. Circular dichroism, nuclear magnetic resonance, infrared, and optical spectroscopy provided additional information about the self-assembly behavior in solution at the molecular level. Dendron rod-coil molecules self-assemble into flat or helical ribbons. They can incorporate electronically conductive groups and can be mineralized with inorganic semiconductors. To understand the relative importance of each segment in forming the supramolecular structure, we synthetically modified the dendron, rod, and coil portions. The self-assembly depended on the generation number of the dendron, the number of hydrogen-bonding functions, and the length of the rod and coil segments. We formed chiral helices using a dendron-rod-coil molecule prepared from an enantiomerically enriched coil. Because helical nanostructures are important targets for use in biomaterials, nonlinear optics, and stereoselective catalysis, researchers would like to precisely control their shape and size. Tripeptide-containing peptide lipid molecules assemble into straight or twisted nanofibers in organic solvents. As seen by AFM, the sterics of bulky end groups can tune the helical pitch of these peptide lipid nanofibers in organic solvents. Furthermore, we demonstrated the potential for pitch control using trans-to-cis photoisomerization of a terminal azobenzene group. Other molecules called peptide amphiphiles (PAs) are known to assemble in water into cylindrical nanostructures that appear as nanofiber bundles. Surprisingly, TEM of a PA substituted by a nitrobenzyl group revealed assembly into quadruple helical fibers with a braided morphology. Upon photocleavage of this the nitrobenzyl group, the helices transform into single cylindrical nanofibers. Finally, inspired by the tobacco mosaic virus, we used a dumbbell-shaped, oligo(phenylene ethynylene) template to control the length of a PA nanofiber self-assembly (<10 nm). AFM showed complete disappearance of long nanofibers in the presence of this rigid-rod template. Results from quick-freeze/deep-etch TEM and dynamic light scattering demonstrated the templating behavior in aqueous solution. This strategy could provide a general method to control size the length of nonspherical supramolecular nanostructures.     

Stimuli‐Responsive Polymeric Nanoparticles for Nanomedicine

Nature continues to be the ultimate in nanotechnology, where polymeric nanometer‐scale architectures play a central role in biological systems. Inspired by the way nature forms functional supramolecular assemblies, researchers are trying to make nanostructures and to incorporate these into macrostructures as nature does. Recent advances and progress in nanoscience have demonstrated the great potential that nanomaterials have for applications in healthcare. In the realm of drug delivery, nanomaterials have been used in vivo to protect the drug entity in the systemic circulation, ensuring reproducible absorption of bioactive molecules that do not naturally penetrate biological barriers, restricting drug access to specific target sites. Several building blocks have been used in the formulation of nanoparticles. Thus, stability, drug release, and targeting can be tailored by surface modification. Herein the state of the art of stimuli‐responsive polymeric nanoparticles are reviewed. Such systems are able to control drug release by reacting to naturally occurring or external applied stimuli. Special attention is paid to the design and nanoparticle formulation of these so‐called smart drug‐delivery systems. Future strategies for further developments of a promising controlled drug delivery responsive system are also outlined.     

Supramolecular Materials from Inorganic Building Blocks

Inorganic materials of nanometric dimensions and controllable morphologies are now widely available permitting their use as building blocks in supramolecular structures. Incorporation of inorganic blocks into hybrid structures can yield unique materials that have no naturally occurring or organic synthetic analogues. In this short review, we describe the construction and functions of supramolecular materials prepared using inorganic building blocks, with emphasis on material-like components. Examples described in this review are categorized as (i) inorganic structures within organic assemblies (silica-supported Langmuir monolayers, organic–inorganic lipid bilayer vesicles etc.), (ii) organic components in inorganic nanospaces (mesoporous materials including biocomponents such as peptides and proteins), (iii) organic/inorganic nanohybrid blends (nanorod-liquid crystal blends and surfactant-guided gold nanostructures), and (iv) hierarchic structures (layer-by-layer assemblies of mesoporlous carbons and capsules).     

Enzymatic hydrogelation of small molecules

Enzymes, a class of highly efficient and specific catalysts in Nature, dictate a myriad of reactions that constitute various cascades in biological systems. Self-assembly, a process prevalent in Nature, also plays important roles in biology, from maintaining the integrity of cells to performing cellular functions and inducing abnormalities that cause disease. To explore enzyme-regulated molecular self-assembly in an aqueous medium will help to understand and control those important biological processes. On the other hand, certain small organic molecules self-assemble in water to form molecular nanofibers and result in a hydrogel, which is referred to as a "supramolecular hydrogel" (and the small molecules are referred to as "supramolecular hydrogelators"). Supramolecular hydrogelators share common features, such as amphiphilicity and supramolecular interactions (pi-pi interactions, hydrogen bonding, and charge interactions among the molecules, among others) that result in nanostructures and form the three-dimensional networks as the matrices of hydrogels. In this Account, we discuss the use of enzymes to trigger and control the self-assembly of small molecules for hydrogelation, which takes place in vitro or in vivo, extra- or intracellularly. Using phosphatase, thermolysin, beta-lactamase, and phosphatase/kinase as examples, we illustrate the design and application of enzyme-catalyzed or -regulated formation of supramolecular hydrogels that offer a new strategy for detecting the activity of enzymes, screening for enzyme inhibitors, typing bacteria, drug delivery systems, and controlling the fate of cells. Since the expression and distribution of enzymes differ by the types and states of cells, tissues, and organs, using an enzymatic reaction to convert precursors into hydrogelators that self-assemble into nanofibers as the matrices of the hydrogel, one can control the delivery, function, and response of a hydrogel according to a specific biological condition or environment, thus providing an accessible route to create sophisticated materials for biomedicine. Particularly, intracellular enzymatic hydrogelation of small molecules offers a unique means for scientists to integrate molecular self-assembly with inherent enzymatic reactions inside cells for developing new biomaterials and therapeutics at the supramolecular level and improving the basic understanding of dynamic molecular self-assembly in water.     

Synthesis and Self-Assembly Properties of Bola-Amphiphilic Glycosylated Lipopeptide-Type Supramolecular Hydrogels Showing Colour Changes Along with Gel–Sol Transition

Supramolecular hydrogels formed by self-assembly of low-molecular-weight amphiphiles (hydrogelators) have attracted significant attention, as smart and soft materials. However, most of the observed stimuli-responsive behaviour of these supramolecular hydrogels are limited to gel–sol transitions. In this study, we present bola-amphiphilic glycosylated lipopeptide-type supramolecular hydrogelators that exhibit reversible thermochromism along with a gel–sol transition. The bola-amphiphiles have mono-, di-, tri- or tetra-phenylalanine (F) as a short peptide moiety. We investigate and discuss the effects of the number of F residues on the gelation ability and the morphology of the self-assembled nanostructures.     

Self-Assembling Peptide-Based Functional Biomaterials

Peptides can self-assemble into various hierarchical nanostructures through noncovalent interactions and form functional materials exhibiting excellent chemical and physical properties, which have broad applications in bio-/nanotechnology. The self-assembly mechanism, self-assembly morphology of peptide supramolecular architecture and their various applications, have been widely explored which have the merit of biocompatibility, easy preparation, and controllable functionality. Herein, we introduce the latest research progress of self-assembling peptide-based nanomaterials and review their applications in biomedicine and optoelectronics, including tissue engineering, anticancer therapy, biomimetic catalysis, energy harvesting. We believe that this review will inspire the rational design and development of novel peptide-based functional bio-inspired materials in the future.     

Supramolecular Nanofibers Self-Assembled from Foldamers: Structure Control through Preassembly

We used a helical polymer backbone (polyacrylamide) as a scaffold to organize perylene diimide chromophores into well-defined foldamers, which further undergo self-assembly into supramolecular tube-like arrays in aqueous media, as revealed by cryo-TEM imaging. The arrays are supramolecular polymers, whose structure is templated by folded primary building blocks, representing a useful tool for directing self-assembly . Exciton migration in the supramolecular arrays was studied by transient absorption and revealed a moderate exciton diffusion propensity.     

Sequence-Dependent Nanofiber Structures of Phenylalanine and Isoleucine Tripeptides

The molecular design of short peptides to achieve a tailor-made functional architecture has attracted attention during the past decade but remains challenging as a result of insufficient understanding of the relationship between peptide sequence and assembled supramolecular structures. We report a hybrid-resolution model to computationally explore the sequence–structure relationship of self-assembly for tripeptides containing only phenylalanine and isoleucine. We found that all these tripeptides have a tendency to assemble into nanofibers composed of laterally associated filaments. Molecular arrangements within the assemblies are diverse and vary depending on the sequences. This structural diversity originates from (1) distinct conformations of peptide building blocks that lead to different surface geometries of the filaments and (2) unique sidechain arrangements at the filament interfaces for each sequence. Many conformations are available for tripeptides in solution, but only an extended β-strand and another resembling a right-handed turn are observed in assemblies. It was found that the sequence dependence of these conformations and the packing of resulting filaments are determined by multiple competing noncovalent forces, with hydrophobic interactions involving Phe being particularly important. The sequence pattern for each type of assembly conformation and packing has been identified. These results highlight the importance of the interplay between conformation, molecular packing, and sequences for determining detailed nanostructures of peptides and provide a detailed insight to support a more precise design of peptide-based nanomaterials.     

Charge transport in vertically aligned, self-assembled peptide nanotube junctions

The self-assembly propensity of peptides has been extensively utilized in recent years for the formation of supramolecular nanostructures. In particular, the self-assembly of peptides into fibrils and nanotubes makes them promising building blocks for electronic and electro-optic applications. However, the mechanisms of charge transfer in these wire-like structures, especially in ambient conditions, are not yet fully understood. We describe here a layer-by-layer deposition methodology of short self-assembled cyclic peptide nanotubes, which results in vertically oriented nanotubes on gold substrates. Using this novel deposition methodology, we have fabricated molecular junctions with a conductive atomic force microscopy tip as a second electrode. Studies of the junctions' current-voltage characteristics as a function of the nanotube length revealed an efficient charge transfer in these supramolecular structures, with a low current attenuation constant of 0.1 ?(-1), which indicate that electron transfer is dominated by hopping. Moreover, the threshold voltage to field-emission dominated transport was found to increase with peptide length in a manner that depends on the nature of the contact with the electrodes. The flexibility in the design of the peptide monomers and the ability to control their sequential order over the nanotube by means of the layer-by-layer assembly process, which is demonstrated in this work, can be used to engineer the electronic properties of self-assembled peptide nanotubes toward device applications.     

Three‐dimensional crystalline supramolecular nanostructures from self‐assembly of rod–coil molecules incorporating lateral carboxyl group in the middle of the rod segment

We report the synthesis and self‐assembling behaviour of coil–rod–coil molecules 1a–1c and 2a–2c , which incorporate lateral carboxyl or ester groups in the middle of the rod segment. The self‐assembling behaviour of these molecules was investigated in the bulk using differential scanning calorimetry, polarised optical microscopy and small‐angle X‐ray scattering. Our results reveal that hydrogen bonds strongly influence the self‐assembling behaviour of rod‐like building blocks. Molecules 1a–1c , which incorporate carboxyl groups in the middle of rod segments, self‐assemble into two‐dimensional (2‐D) columnar, three‐dimensional (3‐D) body‐centred tetragonal and 3‐D hexagonal close‐packed assemblies in the crystalline state. However, molecules 2a–2c , which contain ester groups in the centre of rod segments, self‐assemble into unexpected lamellar, hexagonal perforated lamellar and 2‐D columnar nanostructures in the bulk, indicating that hydrogen bonds impede intermolecular stacking in this rod–coil system. © 2015 Society of Chemical Industry     

Supramolecular Nanofibers of Peptide Amphiphiles for Medicine

Peptide nanostructures are an exciting class of supramolecular systems that can be designed for novel therapies with great potential in advanced medicine. This paper reviews progress on nanostructures based on peptide amphiphiles capable of forming one-dimensional assemblies that emulate in structure the nanofibers present in extracellular matrices. These systems are highly tunable using supramolecular chemistry, and can be designed to signal cells directly with bioactive peptides. Peptide amphiphile nanofibers can also be used to multiplex functions through co-assembly and designed to deliver proteins, nucleic acids, drugs, or cells. We illustrate here the functionality of these systems, describing their use in regenerative medicine of bone, cartilage, the nervous system, the cardiovascular system, and other tissues. In addition, we highlight recent work on the use of peptide amphiphile assemblies to create hierarchical biomimetic structures with order beyond the nanoscale, and also discuss the future prospects of these supramolecular systems.     

Dimeric Resorcin[4]arene Capsules in the Solid State

Supramolecular chemistry research is focused on the study of weak non-covalent intermolecular — that is, supramolecular — interactions as the driving force in self-assembly and molecular recognition. Dimeric resorcin[4]arenes capsules have been a focus of our research for the last 15 years. This review describes the solid state complexation studies of unsubstituted phenolic resorcin[4]arenes and pyrogall[4]arenes towards the formation of dimeric capsules and assemblies using ionic and neutral species as guest molecules and templates. The multitude of different crystal structures obtained during these studies demonstrates the versatile nature of resorcin[4]arenes and pyrogall[4]arenes (2-hydroxy-resorcin[4]arenes) as supramolecular hosts in crystal engineering.     

Recent advances in nanofibrous assemblies based on β‐sheet‐forming peptides for biomedical applications

Amyloid fibrils are supramolecular polymers with β‐sheet‐rich structures formed by polymerization of protein/peptide with intermolecular interaction. Amyloid fibrils have been miscast as toxic villains since they have historically been studied as pathogens associated with serious diseases, including Alzheimer's and Parkinson's disease. However, recent studies on their toxicity and formation mechanism and discovery of their functionality in nature correct the misconception and strongly facilitate the possible use of β‐sheet‐forming peptides in designing novel nanomaterials. Self‐assembly based on β‐sheet‐forming peptides can provide highly ordered nanostructures under certain conditions. Therefore, ingenious design of the building block peptides allows the construction of nano‐assemblies, which contain large quantities of bio‐functional molecules, including drugs and bioactive peptides, and exhibit unique properties, such as assembly or disassembly in response to external stimulus or specific molecules. These properties provide a novel strategy for the creation of innovative nanomaterials, especially for biomedical applications. Here, we describe recent progress in the biomedical application of fibrous assemblies based on β‐sheet‐forming peptides, such as the suppression of aberrant protein aggregation, controlled release, tissue engineering and other applications. This review focuses not only on the function of the nanofibrous assemblies but also on the functions of component molecules, namely amyloidogenic peptides. © 2016 Society of Chemical Industry     

Order/Disorder in Protein and Peptide-Based Biomaterials

Nature utilizes both order and disorder (or controlled disorder) to achieve exceptional materials properties and functions, while synthetic supramolecular materials mostly exploit just supramolecular order, thus limiting the structural diversity, responsiveness and consequent adaptive functions that can be accessed. Herein, we review the emerging field of supramolecular biomaterials where disorder and order deliberately co-exist, and can be dynamically regulated by considering both entropic and enthalpic factors in design. We focus on sequence-structure relationships that govern the (cooperative) assembly pathways of protein and peptide building blocks in these materials. Increasingly, there is an interest in introducing dynamic features in protein and peptide-based structures, such as the remarkable thermo-responsiveness and exceptional mechanical properties of elastin materials. Simultaneously, advances in the field of intrinsically disordered proteins (IDPs) give new insights about their involvement in intracellular liquid-liquid phase separation and formation of disordered, dynamic coacervate structures. These have inspired efforts to design biomaterials with similar dynamic properties. These hybrid ordered/disordered materials employ a combination of intramolecular and supramolecular order/disorder features for construction of assemblies that are dynamically reconfigurable. The assembly of these dynamic structures is mainly entropy-driven, relying on electrostatic and hydrophobic interactions and is mediated in part through the adopted (unstructured) protein conformation or by introducing an oppositely charged guest for peptide building blocks. Examples include design of protein building blocks composed of disordered repeat sequences of elastin-like polypeptides in combination with ordered regions that adopt a secondary structure, the co-assembly of proteins with peptide amphiphiles to achieve reconfigurable, yet highly stable membranes or tyrosine-containing tripeptides with sequence-controlled order/disorder that upon enzymatic oxidation give rise to melanin-like polymeric pigments with customizable properties. The resulting hybrid materials with controlled disorder can be metastable, and sensitive to various external stimuli giving rise to insights that are especially attractive for the design of responsive and adaptive materials.     

Dual Stimuli-Responsive Cross-Linked AIE Supramolecular Polymer Constructed through Hierarchical Self-Assembly

Herein, we report the successful construction of a new family of dual stimuli-responsive AIE cross-linked supramolecular polymer through the strategy of hierarchical self-assembly. A novel dipyridyl donor building block G1 containing tetraphenylethylene (TPE) moiety was designed and synthesized. Notably, two nitrile units were attached onto G1 , which were employed as the guest for the further host-guest interaction with pillar[n]arene derivatives. The rhomboidal metallacycle G2 with four nitrile units was firstly constructed through coordination-driven self-assembly. Subsequently, the cross-linked supramolecular polymers H₂⊃G2 were then generated through host-guest interactions. It should be noted that the obtained supramolecular polymer displayed interesting AIE properties due to the restriction of TPE intramolecular motions within the polymeric network. More importantly, by taking advantages of dynamic nature of both coordination bonds and host-guest interactions, the resultant supramolecular polymer displayed dual stimuli-responsive fluorescent transitions under different stimuli such as the competitive guest and halide anion.     

SELF-ASSEMBLY OF BOLA AMPHIPHILES

A bola amphiphile is composed of two polar head groups attached to the ends of a hydrophobic tail. In this paper, the principles of molecular self-assembly of bola amphiphiles are quantitatively established by applying thermodynamic and geometric considerations developed earlier for the more common one-headed amphiphiles. Bola amphiphiles are found to aggregate into spheres, small spherocylinders, large cylinders, small and large discs and vesicles. Inside these aggregates, the hydrophobic tail is expected to assume both a folded and a fully stretched conformation. In general, the presence of the second polar group in a bola amphiphile causes an increase in the aqueous solubility of the amphiphile, an increase in the cmc and a decrease in the aggregation number when compared to the corresponding one-headed amphiphile. The quantitative principles of self-assembly established here can aid in deciding which bola amphiphiles should be synthesized in order to generate desired organized assemblies.     

Polymer Gels Constructed Through Metal–Ligand Coordination

In the past few years, combining supramolecular and macromolecular chemistries has become of great interest to yield dynamic and responsive assemblies with self-restructuring abilities. Among them, polymer networks, that are held together by one or a combination of supramolecular interactions, offer new possibilities to scientists for the creation of artificial materials with self-healing properties. In particular, incorporating coordination complexes into polymeric architectures opens up the possibility of imparting the physicochemical properties of both partners to the resulting material. Here, recent achievements in the field of supramolecular gels that are formed via self-assembly of oligo- and polymeric units through reversible metal–ligand interactions are reviewed. The different strategies and routes for the elaboration of those materials are reported as well as the properties that the coordination centers confer to the supramolecular assemblies.     

pH-Responsive Self-Assembly of Designer Aromatic Peptide Amphiphiles and Enzymatic Post-Modification of Assembled Structures

Supramolecular fibrous materials in biological systems play important structural and functional roles, and therefore, there is a growing interest in synthetic materials that mimic such fibrils, especially those bearing enzymatic reactivity. In this study, we investigated the self-assembly and enzymatic post-modification of short aromatic peptide amphiphiles (PAs), Fmoc-L_nQG (n = 2 or 3), which contain an LQG recognition unit for microbial transglutaminase (MTG). These aromatic PAs self-assemble into fibrous structures via π-π stacking interactions between the Fmoc groups and hydrogen bonds between the peptides. The intermolecular interactions and morphologies of the assemblies were influenced by the solution pH because of the change in the ionization states of the C-terminal carboxy group of the peptides. Moreover, MTG-catalyzed post-modification of a small fluorescent molecule bearing an amine group also showed pH dependency, where the enzymatic reaction rate was increased at higher pH, which may be because of the higher nucleophilicity of the amine group and the electrostatic interaction between MTG and the self-assembled Fmoc-L_nQG. Finally, the accumulation of the fluorescent molecule on these assembled materials was directly observed by confocal fluorescence images. Our study provides a method to accumulate functional molecules on supramolecular structures enzymatically with the morphology control.     

Mannose‐Decorated Multicomponent Supramolecular Polymers Trigger Effective Uptake into Antigen‐Presenting Cells

A modular route to prepare functional self‐assembling dendritic peptide amphiphiles decorated with mannosides, to effectively target antigen‐presenting cells, such as macrophages, is reported. The monomeric building blocks were equipped with tetra(ethylene glycol)s (TEGs) or labeled with a Cy3 fluorescent probe. Experiments on the uptake of the multifunctional supramolecular particles into murine macrophages (Mφs) were monitored by confocal microscopy and fluorescence‐activated cell sorting. Mannose‐decorated supramolecular polymers trigger a significantly higher cellular uptake and distribution, relative to TEG carrying bare polymers. No cytotoxicity or negative impact on cytokine production of the treated Mφs was observed, which emphasized their biocompatibility. The modular nature of the multicomponent supramolecular polymer coassembly protocol is a promising platform to develop fully synthetic multifunctional vaccines, for example, in cancer immunotherapy.