The ability of styrene maleic acid copolymers to dissolve lipid membranes into nanosized lipid particles is a facile method of obtaining membrane proteins in solubilized lipid discs while conserving part of their native lipid environment. While the currently used copolymers can readily extract membrane proteins in native nanodiscs, their highly disperse composition is likely to influence the dispersity of the discs as well as the extraction efficiency. In this study, reversible addition–fragmentation chain transfer was used to control the polymer architecture and dispersity of molecular weights with a high-precision. Based on Monte Carlo simulations of the polymerizations, the monomer composition was predicted and allowed a structure–function analysis of the polymer architecture, in relation to their ability to assemble into lipid nanoparticles. We show that a higher degree of control of the polymer architecture generates more homogeneous samples. We hypothesize that low dispersity copolymers, with control of polymer architecture are an ideal framework for the rational design of polymers for customized isolation and characterization of integral membrane proteins in native lipid bilayer systems.

Ligand-functionalized, multivalent nanoparticles have been extensively studied for biomedical applications from imaging agents to drug delivery vehicles. However, the ligand cluster size is usually heterogeneous and the local valency is ill-defined. Here, we present a mixed micelle platform hierarchically self-assembled from a mixture of two amphiphilic 3-helix and 4-helix peptide-polyethylene glycol (PEG)-lipid hybrid conjugates. We demonstrate that the local multivalent ligand cluster size on the micelle surface can be controlled based on the coiled-coil oligomeric state. The oligomeric states of mixed peptide bundles were found to be in their individual native states. Similarly, mixed micelles indicate the orthogonal self-association of coiled-coil amphiphiles. Using differential scanning calorimetry, fluorescence recovery spectroscopy, and coarse-grained molecular dynamics simulation, we studied the distribution of coiled-coil bundles within the mixed micelles and observed migration of coiled-coils into nanodomains within the sub-20 nm mixed micelle. This report provides important insights into the assembly and formation of nanophase-separated micelles with precise control over the local multivalent state of ligands on the micelle surface.

A subtle but highly pertinent factor in the self-assembly of hierarchical nanostructures is the kinetic landscape. Self-assembly of a hierarchical multicomponent system requires the intricate balance of noncovalent interactions on a similar energy scale that can result in several self-assembly processes occurring at different time scales. We seek to understand the hierarchical assemblies within an amphiphilic 3-helix peptide-PEG-lipid conjugate system in the formation process of highly stable 3-helix micelles (3HMs). 3HM self-assembles through multiple parallel processes: helix folding, coiled-coil formation, micelle assembly, and packing of alkyl chains. Our results show that the kinetic pathway of 3HM formation is mainly governed by two confounding factors: lateral diffusion of amphiphiles to form coiled-coils within the micelle corona and packing of alkyl tails within the hydrophobic micelle core. 3HM has exhibited highly desirable attributes as a drug delivery nanocarrier; understanding the role of individual components in the kinetic pathway of 3HM formation will allow us to exert better control over the kinetic pathway, as well as to enhance future design and eventually manipulate the kinetic intermediates for potential drug delivery applications.

A monolayer 2D capping layer with high Young's modulus is shown to be able to effectively suppress the dewetting of underlying thin films of small organic semiconductor molecule, polymer, and polycrystalline metal, respectively. To verify the universality of this capping layer approach, the dewetting experiments are performed for single-layer graphene transferred onto polystyrene (PS), semiconducting thienoazacoronene (EH-TAC), gold, and also MoS2 on PS. Thermodynamic modeling indicates that the exceptionally high Young's modulus and surface conformity of 2D capping layers such as graphene and MoS2 substantially suppress surface fluctuations and thus dewetting. As long as the uncovered area is smaller than the fluctuation wavelength of the thin film in a dewetting process via spinodal decomposition, the dewetting should be suppressed. The 2D monolayer-capping approach opens up exciting new possibilities to enhance the thermal stability and expands the processing parameters for thin film materials without significantly altering their physical properties.

Block copolymer (BCP)-based supramolecules provide a versatile strategy to generate functional materials using noncovalent bond between small molecules and BCPs. Here, we report supramolecules composed of phenol-containing ionic liquids (ILs) hydrogen bonded to BCP, polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP). IL-containing supramolecules exhibit ordered structures in a wide range of IL loading and chemistry. Rheological behaviors and nanostructures of IL-containing supramolecules can be tuned by controlling the IL loading without losing ordered structure. The hydrogen bonds and nanostructures can be retained in a wide range of temperatures with different IL chemistry. Supramolecules provide a diverse platform toward IL materials with ordered structure and tunable properties with high tolerance of thermal treatment and processing.

Nanorods (NRs) have unique anisotropic properties that are desirable for various applications. Block copolymer-based supramolecules present unique opportunities to control inter-rod ordering and macroscopic alignment of NRs to fully take advantage of their unique anisotropic properties. Here, we studied the effects of NR aspect ratio where the NR length is in the range of 20–180 nm on the assemblies of NRs in supramolecular framework. At a moderate loading (∼3 vol %), well-ordered assemblies of 37–90 nm NRs embedded in the supramolecular framework were formed. Shorter NRs (∼22 nm) coassemble with the supramolecule but were not well-ordered and displayed little orientational control within the microdomains. In contrast, longer NRs (∼180 nm) formed kinetically trapped states that restricted the formation of well-ordered coassemblies in NR/supramolecule blends. Additionally, the NRs are shown to be capable of kinetically trapping the system after normally reversible morphological transitions triggered by the thermal dissociation of the supramolecule, arresting the system away from a stable morphology. These studies shed light on the effects of NR-induced kinetic arrest on the self-assembly of a supramolecular nanocomposite.

Coiled-coil peptide–polymer conjugates are an emerging class of biomaterials. Fundamental understanding of the coiled-coil oligomeric state and assembly process of these hybrid building blocks is necessary to exert control over their assembly into well-defined structures. Here, we studied the effect of peptide structure and PEGylation on the self-assembly process and oligomeric state of a Langmuir monolayer of amphiphilic coiled-coil peptide–polymer conjugates using X-ray reflectivity (XR) and grazing-incidence X-ray diffraction (GIXD). Our results show that the oligomeric state of PEGylated amphiphiles based on 3-helix bundle-forming peptide is surface pressure dependent, a mixture of dimers and trimers was formed at intermediate surface pressure but transitions into trimers completely upon increasing surface pressure. Moreover, the interhelical distance within the coiled-coil bundle of 3-helix peptide-PEG conjugate amphiphiles was not perturbed under high surface pressure. Present studies provide valuable insights into the self-assembly process of hybrid peptide–polymer conjugates and guidance to develop biomaterials with controlled multivalency of ligand presentation.

Block copolymer (BCP)-based supramolecular systems provide a versatile approach to manipulate functional structures spanning several nanometers to macroscopic length scales. Most studies to date focused on supramolecules containing asymmetrically end-functionalized small molecules, and it remains challenging to obtain molecular control over small molecule ordering within the BCP microdomain. Here we designed symmetrically end-functionalized bis-phenol quarterthiophene (BP4T) small molecules and systematically investigated how the end-group chemistry of the small molecules affects the supramolecular assembly process and the resulting morphology. Bifunctionalized small molecules can bridge two adjacent polymer blocks and lead to macroscopically aligned hierarchical assemblies at much higher degree of ordering than previously observed for asymmetrically functionalized small molecule analogues. The supramolecular morphology is very sensitive to the stoichiometry between the BP4T and polymer repeat unit because of the specific molecular organization within BCP microdomain. Furthermore, similar thermoresponsiveness of supramolecule, i.e., ∼40% change in the supramolecular periodicity during the heating and cooling cycles, can be obtained at BP4T loading stoichiometry of 0.5, much smaller than that of asymmetrically functionalized small molecule. These results clearly demonstrate that supramolecular assemblies can be readily manipulated by engineering the small molecule chemistry. Present studies provide basic design principles and an effective route to fabricate well-defined hierarchical assemblies for functional and stimuli-responsive nanomaterials.

Small molecules (SMs) with unique optical or electronic properties provide an opportunity to incorporate functionality into block copolymer (BCP)-based supramolecules. However, the assembly of supramolecules based on these highly crystalline molecules differs from their less crystalline counterparts. Here, two families of organic semiconductor SMs are investigated, where the composition of the crystalline core, the location (side- vs end-functionalization) of the alkyl solubilizing groups, and the constitution (branched vs linear) of the alkyl groups are varied. With these SMs, we present a systematic study of how the phase behavior of the SMs affects the overall assembly of these organic semiconductor-based supramolecules. The incorporation of SMs has a large effect on the interfacial curvature, the supramolecular periodicity, and the overall supramolecular morphology. The crystal packing of the SM within the supramolecule does not necessarily lead to the assembly of the comb block within the BCP microdomains, as is normally observed for alkyl-containing supramolecules. An unusual lamellar morphology with a wavy interface between the microdomains is observed due to changes in the packing structure of the small molecule within BCP microdomains. Since the supramolecular approach is modular and small molecules can be readily switched out, present studies provide useful guidance toward access supramolecular assemblies over several length scales using optically active and semiconducting small molecules.

3-Helix micelles (3HM) formed by self-assembly of peptide–polymer conjugate amphiphiles have shown promise as a nanocarrier platform due to their long-circulation, deep tumor penetration, selective accumulation in tumor, and ability to cross the blood-brain barrier (BBB) for glioblastoma therapy. There is a need to understand the structural contribution to the high in vivo stability and performance of 3HM. Using selective deuteration, the contrast variation technique in small-angle neutron scattering, and coarse-grained molecular dynamics simulation, we determined the spatial distribution of each component within 3HM. Our results show a slightly deformed polyethylene glycol (PEG) conformation within the micelle that is radially offset from its conjugation site toward the exterior of the micelle and a highly solvated shell. Surprisingly, ∼85 v/v % of 3HM is water, unusually higher than any micellar nanocarrier based on our knowledge. The result will provide important structural insights for future studies to uncover the molecular origin of 3HM’s in vivo performance, and development of the nanocarriers.

Using organic semiconductor-containing supramolecule, this study investigates how the small molecule (SM) phase behavior as well as the loading rate and size of the NPs can affect their coassembly in supramolecular frameworks containing strongly interacting molecules. The NPs can be incorporated into the supramolecular microdomains even from a macrophase-separated state. However, the assembly of nanocomposites based on strongly interacting SMs is found to be distinct from both supramolecular nanocomposites based on simple alkyls and supramolecules based on strongly interacting SMs without NPs. The strong crystallization of the SMs tends to force the NPs into less crystalline domains of the comb block, where the SMs are less abundant. The larger NPs favor assembly in the center of the comb domains, parallel to the BCP lamellar axis, to minimize the entropic penalty of deforming the polymer chain, while the smaller particles assemble into rows in between the comb lamellae, perpendicular to the axis of the BCP lamellae. These studies present a versatile method for the coassembly of strongly interacting, functional SMs with NPs for the fabrication of nanocomposite devices.

The phase behavior of supramolecular nanocomposite thin films was systematically investigated as a function of nanoparticle (NP) loading from 1 to >50 wt %. The coassembly of NP and supramolecule can be divided into five regimes, from a supramolecule-guided assembly to a NP governing assembly process, depending on the energetic contributions from the surface energy, NP-supramolecule interaction, and the kinetic pathway of the assembly process. A range of morphologies such as 1D NP chains, 2D sheets, 3D NP assemblies, and NP solids can be readily obtained, providing opportunities to meet structural control in nanocomposites for a wide range of applications.

Directed co-assembly of polymer-conjugated cyclic peptide nanotubes (CPNs) and block copolymers in thin films is a viable approach to fabricate sub-nanometer porous membranes without synthesizing nanotubes with identical length and vertical alignment. Here we show that the process is pathway dependent and successful co-assembly requires eliminating CPNs larger than 100 nm in solution. Optimizing polymer–solvent interactions can improve conjugate dispersion to a certain extent, but this limits thin film fabrication. Introduction of a trace amount of hydrogen-bond blockers, such as trifluoroacetic acid by vapor absorption, is more effective to reduce CPN aggregation in solution and circumvents issues of solvent immiscibility. This study provides critical insights into guided assemblies within nanoscopic frameworks toward sub-nanometer porous membranes.

Nanoparticles, 10–30 nm in size, have shown great prospects as nanocarriers for drug delivery. We designed amphiphiles based on 3-helix peptide-PEG conjugate forming 15 nm micelles (defined as “3-helix micelles”) with good in vivo stability. Here, we investigated the effect of the site of PEG conjugation on the kinetic stability and showed that the conjugation site affects the PEG chain conformation and the overall molecular architecture of the subunit. Compared to the original design where the PEG chain is located in the middle of the 3-helix bundle, micelle kinetic stability was reduced when the PEG chain was attached near the N-terminus (t1/2 = 35 h) but was enhanced when the PEG chain was attached near the C-terminus (t1/2 = 80 h). Quantitative structural and kinetic analysis suggest that the kinetic stability was largely dictated by the combined effects of entropic repulsion associated with PEG chain conformation and the geometric packing of the trimeric subunits. The modular design approach coupled with a variety of well-defined protein stucture and functional polymers will significantly expand the utility of these materials as nanocarriers to meet current demands in nanomedine.

•Developed strategies and recent advances in the self-assembly of anisotropic nanomaterials are extensively reviewed.•Potential applications of assembled anisotropic nanomaterials in chemical and biological sensing, and energy harvesting and transport are thoroughly explored.•Based on recent research developments, we provide perspectives and future research opportunities in anisotropic nanomaterial assembly.Anisotropic nanoparticles are ideal building blocks for a variety of functional materials due to their unique and anisotropic optical, electronic, magnetic and mechanical properties. Precise control over the orientation and spatial arrangement of these nanomaterials is often requisite to achieve coupling between nanoparticles and thereby translate the properties of individual nanoparticles to macroscopic material properties. The physics and thermodynamics involved in the self-assembly are inherently more complex than isotropic nanoparticles due to the anisotropy within the system. However, the anisotropy also introduces anisotropic nanoparticle surface chemistry and stronger interparticle interactions which could be leveraged to achieve self-assembly. To address these challenges and opportunities, a plethora of strategies have been conceived and developed to induce the self-assembly of anisotropic nanoparticles into desired nanostructures over macroscopic areas and volumes. These strategies involve manipulation of interparticle physical interactions, modification of nanoparticle surface chemistry, application of external fields, and utilization of physically or chemically patterned templates to achieve the required level of spatial and orientational control over the assembly of anisotropic nanoparticles. The resulting ordered anisotropic nanoparticle assemblies display strong plasmonic, electronic, and excitonic coupling, which render these assemblies as ideal materials for chemical and biological sensing, energy harvesting, and many other technological applications. Considering the rapid advancement in this field of research, this review aims to provide an overview of the assembly, applications, and opportunities of anisotropic nanomaterials.

Nanopatterning and functionalizing of graphene is often required to tune or enhance its unique physical properties. However, complex processes are needed to overcome the chemical incompatibilities between the patterning template, the functional small molecules or nanoparticles, and the underlying graphene. We present a block copolymer (BCP)-based supramolecular thin film as a versatile platform for the generation of periodic patterns of small molecules and ordered assemblies of nanoparticles on top of a graphene substrate without chemical modification of any components. The present approach opens opportunities to readily pattern and functionalize graphene, and to investigate the structure–property correlations of graphene/nanoparticle and graphene/small molecule composite materials.

Nanostructured dielectric composites can be obtained by dispersing high permittivity fillers, barium titanate (BTO) nanocubes, within a supramolecular framework. Thin films of BTO supramolecular nanocomposites exhibit a dielectric permittivity (εr) as high as 15 and a relatively low dielectric loss of ∼0.1 at 1 kHz. These results demonstrate a new route to control the dispersion of high permittivity fillers toward high permittivity dielectric nanocomposites with low loss. Furthermore, the present study shows that the size distribution of nanofillers plays a key role in their spatial distribution and local ordering and alignment within supramolecular nanostructures.

3-Helix micelles have demonstrated excellent in vitro and in vivo stability. Previous studies showed that the unique design of the peptide–polymer conjugate based on protein tertiary structure as the headgroup is the main design factor to achieve high kinetic stability. In this contribution, using amphiphiles with different alkyl tails, namely, C16 and C18, we quantified the effect of alkyl length on the stability of 3-helix micelles to delineate the contribution of the micellar core and shell on the micelle stability. Both amphiphiles form well-defined micelles, <20 nm in size, and show good stability, which can be attributed to the headgroup design. C18-micelles exhibit slightly higher kinetic stability in the presence of serum proteins at 37 °C, where the rate constant of subunit exchange is 0.20 h–1 for C18-micelles vs 0.22 h–1 for C16-micelles. The diffusion constant for drug release from C18-micelles is approximately half of that for C16-micelles. The differences between the two micelles are significantly more pronounced in terms of in vivo stability and extent of tumor accumulation. C18-micelles exhibit significantly longer blood circulation time of 29.5 h, whereas C16-micelles have a circulation time of 16.1 h. The extent of tumor accumulation at 48 h after injection is ∼43% higher for C18-micelles. The present studies underscore the importance of core composition on the biological behavior of 3-helix micelles. The quantification of the effect of this key design parameter on the stability of 3-helix micelles provides important guidelines for carrier selection and use in complex environment.

Nanocomposites, composed of organic and inorganic building blocks, can combine the properties from the parent constituents and generate new properties to meet current and future demands in functional materials. Recent developments in nanoparticle synthesis provide a plethora of inorganic building blocks, building the foundation for constructing hybrid nanocomposites with unlimited possibilities. The properties of nanocomposite materials depend not only on those of individual building blocks but also on their spatial organization at different length scales. Block copolymers, which microphase separate into various nanostructures, have shown their potential for organizing inorganic nanoparticles in bulk/thin films. Block copolymer-based supramolecules further provide more versatile routes to control spatial arrangement of the nanoparticles over multiple length scales. This review provides an overview of recent efforts to control the hierarchical assemblies in block copolymer-based hybrid nanocomposites.

A simple approach to obtain end-to-end assemblies of nanorods over macroscopic distances in thin films is described. Nanorods with aspect ratio of 8–12 can be aligned parallel to the surface in an end-to-end fashion by imposing geometric confinement via block copolymer-based supramolecular assemblies. Successful control over the orientation and location of nanorods requires a balance of particle–particle interactions and entropy associated with geometric confinement from the supramolecular framework, as well as consideration of the kinetics of assembly.

Hybrid nanoparticle (NP) arrays based on particles of different sizes and chemistries are highly desirable to obtain tunable properties for nanodevices. A simple approach to control the spatial organization of NP mixtures within supramolecular frameworks based on NP size has been developed. By varying the ratio of the NP size to the periodicity of the block-copolymer-based supramolecule, a range of hybrid NP assemblies in thin films, ranging from 1D chains to 2D lattices and 3D arrays and networks of NPs, can be readily generated.

As a new family of soft materials, peptide/protein–polymer conjugates can lead to a wide range of potential biological and nonbiological applications. The performance of these materials depends on the protein structure and phase behavior arising from a balance between the enthalpic interactions of the components and surrounding media as well as the entropic contribution associated with polymer chain deformation. There is a great need to perform structural studies in solution that systematically investigate the polymer chain conformation upon linkage to a peptide or protein so as to evaluate how polymers affect the protein structure of the biomolecule and, consequently, its functionality. Combinations of a range of factors including low contrast, weak scattering signals in dilute solutions as well as difficulties in separating the component scattering contributions, pose significant challenges to structural characterization. Here we present a synchrotron small-angle X-ray scattering (SAXS) study of two model helix bundle forming peptide–polymer conjugates and show that with analytical modeling of the scattering intensity detailed structural information on both peptide structure and polymer conformation can be extracted. The peptide–poly(ethylene glycol) (PEG) conjugates are based on peptides that self-associate to form well-defined 3- or 4-helix bundles and the PEG chain is covalently linked either to the end or the side of the peptide (i.e. end- or side-conjugation). Using a simplified analytical geometrical body form factor model, where the peptide–polymer bundles are modeled as parallel cylinders with attached Gaussian chains, a quantitative description of the scattering behavior can be reached. On the basis of the simplified structural model, the protein tertiary structures, i.e., the α-helix bundle, remains largely intact and maintains its oligomeric state but exhibits slight swelling in solution with respect to the crystal structure. The PEG chain conformation appears to slightly depend on the conjugate architecture. In terms of the chain dimension represented by Rg, the end-conjugated PEG exhibit similar value as compared to free PEG for the molecular weight studied (2 kDa). For the side-conjugates our simple scattering model seems to indicate a systematically slightly lower values for Rg, i.e., a slight compression, in particular for the highest molecular weight (5 kDa). However, considering the limitations of the model and experimental uncertainties, further investigations, such as neutron scattering, is needed to illustrate detailed chain conformation. The present studies can be extended to other peptide–polymer or protein–polymer hybrid systems to extract information on both protein structure and polymer chain conformation. This work will thus provide valuable guidance to understand their structure and phase behavior using X-ray and neutron scattering.

Block copolymer (BCP)-based supramolecules represent a versatile platform to generate functional nanostructures without the need for complex synthesis. The noncovalent bonding between the BCP and small molecules further opens opportunities to access thermal responsive assemblies. A BCP supramolecule containing cholesteric liquid crystal (LC) small molecules is observed to undergo thermally induced, nonreversible order–order transitions (OOTs), resulting in several well-defined morphologies readily tunable by annealing temperature. The nonreversible OOTs highlight the importance of small molecule phase transitions and intermolecular interactions on the overall phase behavior of the supramolecule. The present system also provides a route to manipulate local nanostructures via heating.

Designing stable drug nanocarriers, 10–30 nm in size, would have significant impact on their transport in circulation, tumor penetration, and therapeutic efficacy. In the present study, biological properties of 3-helix micelles loaded with 8 wt % doxorubicin (DOX), ∼15 nm in size, were characterized to validate their potential as a nanocarrier platform. DOX-loaded micelles exhibited high stability in terms of size and drug retention in concentrated protein environments similar to conditions after intravenous injections. DOX-loaded micelles were cytotoxic to PPC-1 and 4T1 cancer cells at levels comparable to free DOX. 3-Helix micelles can be disassembled by proteolytic degradation of peptide shell to enable drug release and clearance to minimize long-term accumulation. Local administration to normal rat striatum by convection enhanced delivery (CED) showed greater extent of drug distribution and reduced toxicity relative to free drug. Intravenous administration of DOX-loaded 3-helix micelles demonstrated improved tumor half-life and reduced toxicity to healthy tissues in comparison to free DOX. In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics.

Developing routes to control the organization of one-dimensional nanomaterials, such as nanorods, with high precision is critical to generate functional materials since the collective properties depend on their spatial arrangements, interparticle ordering, and macroscopic alignment. We have systematically investigated the coassemblies of nanorods and block copolymer (BCP)-based supramolecules and showed that the energetic contributions from nanorod ligand–polymer interactions, polymer chain deformation, and rod–rod interactions are comparable and can be tailored to disperse nanorods with control over inter-rod ordering and the alignment of nanorods within BCP microdomains. By varying the supramolecular morphology and chemical nature of the nanorods, two highly sought-after morphologies, that is, nanoscopic networks of nanorods and nanorod arrays parallel to cylindrical BCP microdomains can be obtained. The supramolecular approach can be applied to achieve morphological control in nanorod-containing nanocomposites toward fabrication of optical and electronic nanodevices.

We demonstrated a versatile approach to obtain layered nanoparticle sheets with in-plane hexagonal order and 3-D ordered arrays of single nanoparticle chains in thin films upon blending nanoparticles with block copolymer (BCP)-based supramolecules. Basic understanding on the thermodynamic and kinetic aspects of the assembly process paved a path to manipulate these assemblies to meet demands in nanoparticle-based device fabrication and understand structure–property correlations.

Despite increasing demands to employ amphiphilic micelles as nanocarriers and nanoreactors, it remains a significant challenge to simultaneously reduce the particle size and enhance the particle stability. Complementary to covalent chemical bonding and attractive intermolecular interactions, entropic repulsion can be incorporated by rational design in the headgroup of an amphiphile to generate small micelles with enhanced stability. A new family of amphiphilic peptide–polymer conjugates is presented where the hydrophilic headgroup is composed of a 3-helix coiled coil with poly(ethylene glycol) attached to the exterior of the helix bundle. When micelles form, the PEG chains are confined in close proximity and are compressed to act as a spring to generate lateral pressure. The formation of 3-helix bundles determines the location and the directionalities of the force vector of each PEG elastic spring so as to slow down amphiphile desorption. Since each component of the amphiphile can be readily tailored, these micelles provide numerous opportunities to meet current demands for organic nanocarriers with tunable stability in life science and energy science. Furthermore, present studies open new avenues to use energy arising from entropic polymer chain deformation to self-assemble energetically stable, single nanoscopic objects, much like repulsion that stabilizes bulk assemblies of colloidal particles.

Generating stable, multifunctional organic nanocarriers will have a significant impact on drug formulation. However, it remains a significant challenge to generate organic nanocarriers with a long circulation half-life, effective tumor penetration, and efficient clearance of metabolites. We have advanced this goal by designing a new family of amphiphiles based on coiled-coil 3-helix bundle forming peptide–poly(ethylene glycol) conjugates. The amphiphiles self-assemble into monodisperse micellar nanoparticles, 15 nm in diameter. Using the 3-helix micelles, a drug loading of ∼8 wt % was obtained using doxorubicin and the micelles showed minimal cargo leakage after 12 h of incubation with serum proteins at 37 °C. In vivo pharmacokinetics studies using positron emission tomography showed a circulation half-life of 29.5 h and minimal accumulation in the liver and spleen. The demonstrated strategy, by incorporating unique protein tertiary structure in the headgroup of an amphiphile, opens new avenues to generate organic nanoparticles with tunable stability, ligand clustering, and controlled disassembly to meet current demands in nanomedicine.Keywords: 3-helix micelle; helix bundle; nanocarriers; peptide−polymer conjugate; stability

Small organic molecules with strong intermolecular interactions have a wide range of desirable optical and electronic properties and rich phase behaviors. Incorporating them into block copolymer (BCP)-based supramolecules opens new routes to generate functional responsive materials. Using oligothiophene-containing supramolecules, we present systematic studies of critical thermodynamic parameters and kinetic pathway that govern the coassemblies of BCP and strongly interacting small molecules. A number of potentially useful morphologies for optoelectronic materials, including a nanoscopic network of oligothiophene and nanoscopic crystalline lamellae, were obtained by varying the assembly pathway. Hierarchical coassemblies of oligothiophene and BCP, rather than macrophase separation, can be obtained. Crystallization of the oligothiophene not only induces chain stretching of the BCP block the oligothiophene is hydrogen bonded to but also changes the conformation of the other BCP coil block. This leads to an over 70% change in the BCP periodicity (e.g., from 31 to 53 nm) as the oligothiophene changes from a melt to a crystalline state, which provides access to a large BCP periodicity using fairly low molecular weight BCP. The present studies have demonstrated the experimental feasibility of generating thermoresponsive materials that convert heat into mechanical energy. Incorporating strongly interacting small molecules into BCP supramolecules effectively increases the BCP periodicity and may also open new opportunities to tailor their optical properties without the need for high molecular weight BCP.

Detailed structural characterization of protein–polymer conjugates and understanding of the interactions between covalently attached polymers and biomolecules will build a foundation to design and synthesize hybrid biomaterials. Conjugates based on simple protein structures are ideal model system to achieve these ends. Here we present a systematic structural study of coiled-coil peptide–poly(ethylene glycol) (PEG) side-conjugates in solution, using circular dichroism, dynamic light scattering, and small-angle X-ray scattering, to determine the conformation of conjugated PEG chains. The overall size and shape of side-conjugates were determined using a cylindrical form factor model. Detailed structural information of the covalently attached PEG chains was extracted using a newly developed model where each peptide–PEG conjugate was modeled as a Gaussian chain attached to a cylinder, which was further arranged in a bundle-like configuration of three or four cylinders. The peptide–polymer side-conjugates were found to retain helix bundle structure, with the polymers slightly compressed in comparison with the conformation of free polymers in solution. Such detailed structural characterization of the peptide–polymer conjugates, which elucidates the conformation of conjugated PEG around the peptide and assesses the effect of PEG on peptide structure, will contribute to the rational design of this new family of soft materials.

A facile route to generate cyclic peptide nanotubes with tunable interiors is presented. By incorporating 3-amino-2-methylbenzoic acid in the d,l-alternating primary sequence of a cyclic peptide, a functional group can be presented in the interior of the nanotubes without compromising the formation of high aspect ratio nanotubes. The new design of such a cyclic peptide also enables one to modulate the nanotube growth process to be compatible with the polymer processing window without compromising the formation of high aspect ratio nanotubes, thus opening a viable approach toward molecularly defined porous membranes.

Directed co-assembly of block copolymers and proteins/peptides may lead to hierarchically structured functional biomolecular materials. However, this requires one to synergistically direct multiple self-assembly processes. Retaining proper cofactor binding is essential to utilize many bio-motifs for catalytic reactions and sensing. Here, by using a heme-binding helix bundle peptide-polymer conjugate and a holomyoglobin-polymer conjugate as examples, we show that the simultaneous, macroscopic assembly of heme-binding proteins and diblock copolymers can be achieved in thin films without compromising protein structures, cofactor binding and enzymatic activities. To our knowledge, this is the first example of a protein/cofactor complex formed upon being co-assembled with an amphiphilic block copolymer in thin films. Molecular assemblyvia a combination of biomolecular recognition and polymer phase separation in this fashion will lead to hybrid materials combining properties of both synthetic and biological building blocks.

The macroscopic alignment of hierarchical assemblies of block copolymer- (BCP-) based supramolecules in thin films is investigated as a function of interfacial interaction and film thickness. We specifically focus on how these two parameters affect the longevity of supramolecular morphology where BCP microdomains are oriented normal to the surface. As the film thickness increases above one equilibrium period of supramolecular assembly, hierarchical assemblies with vertically aligned BCP microdomains can be long-lived metastable state when the volume fraction of the comb block is higher than 0.5. The perpendicular-to-parallel reorientation process strongly depends on the strength of the surface field, the chemical nature of the surface, and the film thickness. The longevity of the vertically aligned assemblies can be attributed to two reasons. One is the spatial distribution of small molecules that mediate the interactions between each BCP block with the underlying substrate and the other is the comb–coil architecture of the supramolecule. These studies provide critical guidance to manipulate assemblies of supramolecules in thin films and access transient nanostructures.

Porous thin films containing subnanometer channels oriented normal to the surface exhibit unique transport and separation properties and can serve as selective membranes for separation and protective coatings. While molecularly defined nanoporous inorganic and organic materials abound, generating flexible nanoporous thin films with highly aligned channels over large areas has been elusive. Here, we developed a new approach where the growth of cyclic peptide nanotubes can be directed in a structural framework set by the self-assembly of block copolymers. By conjugating polymers to cyclic peptides, the subunit of an organic nanotube can be selectively solubilized in one copolymer microdomain. The conjugated polymers also mediate the interactions between nanotube and local medium and guide the growth of nanotubes in a confined geometry. This led to subnanometer porous membranes containing high-density arrays of through channels. This new strategy takes full advantage of nanoscopic assembly of BCPs and the reversibility of organic nanotube growth and circumvents impediments associated with aligning and organizing high aspect ratio nano-objects normal to the surface. Furthermore, the hierarchical coassembly strategy described demonstrates the feasibility of synchronizing multiple self-assembly processes to achieve hierarchically structured soft materials with molecular level control.Keywords (keywords): block copolymer; cyclic peptide−polymer conjugate; nanotube; subnanometer porous membrane

Some of the recent progress in generating hierarchically structured hybrid materials using peptide–polymer conjugates is presented. In particular, we review some of the developments in de novo designed coiled-coil helix bundles and their synthetic polymer conjugates from a materials point of view. As one of the most important motifs underlying many of the functionalities found in natural proteins, coiled-coil helix bundles present unique opportunities to generate functional materials with structures and functionalities similar to those seen in nature. As we utilize peptide tertiary structures stabilized by non-covalent interactions, the principles governing the assembly process at multiple length scales become more complicated. Some challenges, as well as the critical areas that require further study for the advancement of this burgeoning field, are discussed. Further investigation will not only improve our fundamental understanding of multi-length scale assembly in multi-component systems, but may also lead to very unique functional biomolecular materials.

Amphiphilic peptide−polymer conjugates can lead to hierarchically structured, biomolecular materials. Because the peptide structure determines the size, shape, and intermolecular interactions of these building blocks, systematic understanding of how the peptide structure and functionality are affected upon implementing hydrophobicity is required to direct their assemblies in solution and in the solid state. However, depending on the peptide sequence and native structure, previous studies have shown that the hydrophobic moieties affect peptide structures differently. Here, we present a solution study of amphiphilic peptide−polymer conjugates, where a hydrophobic polymer, polystyrene, is covalently linked to the N-terminus of a coiled-coil helix bundle-forming peptide. The effect of conjugated hydrophobic polymers on the peptide secondary and tertiary structures was examined using two types of model, coiled-coil helix bundles. In particular, the integrity of the binding pocket within the helix bundle upon hydrophobic polymer conjugation was evaluated. Upon attachment of polystyrene to the peptide N-terminus, the coiled-coil helices partially unfolded and functionality within the bundle core was inhibited. These observations are attributed to favorable interactions between hydrophobic residues with the PS block at the peptide−polymer interface that lead to rearrangement of peptide residues and consequently, unfolding of peptide structures. Thus, the hydrophobicity of the covalently linked polymers modifies the conjugates’ architecture, size, and shape and may be used to tailor the assembly and disassembly process. Furthermore, the hydrophobicity of the covalently linked polymer needs to be taken into consideration to maintain the built-in functionalities of protein motifs when constructing amphiphilic peptide−polymer conjugates.

Organic small molecule semiconductors have many advantages over their polymer analogues. However, to fabricate organic semiconductor-based devices using solution processing, it is requisite to eliminate dewetting to ensure film uniformity and desirable to assemble nanoscopic features with tailored macroscopic alignment without compromising their electronic properties. To this end, we present a modular supramolecular approach. A quaterthiophene organic semiconductor is attached to the side chains of poly(4-vinylpyridine) via noncovalent hydrogen bonds to form supramolecular assemblies that act as p-type semiconductors in field-effect transistors. In thin films, the quaterthiophenes can be readily assembled into microdomains, tens of nanometers in size, oriented normal to the surface. The supramolecules exhibited the same field-effect mobilities as that of the quaterthiophene alone (10−4 cm2/(V·s)). Since the organic semiconductors can be readily substituted, this modular supramolecular approach is a viable method for the fabrication of functional, nanostructured organic semiconductor films using solution processing.Keywords: charge mobility; organic semiconductor; supramolecular assembly; thin film

Abstract

Generating laterally ordered, ultradense, macroscopic arrays of nanoscopic elements will revolutionize the microelectronic and storage industries. We used faceted surfaces of commercially available sapphire wafers to guide the self-assembly of block copolymer microdomains into oriented arrays with quasi–long-range crystalline order over arbitrarily large wafer surfaces. Ordered arrays of cylindrical microdomains 3 nanometers in diameter, with areal densities in excess of 10 terabits per square inch, were produced. The sawtoothed substrate topography provides directional guidance to the self-assembly of the block copolymer, which is tolerant of surface defects, such as dislocations. The lateral ordering and lattice orientation of the single-grain arrays of microdomains are maintained over the entire surface. The approach described is parallel, applicable to different substrates and block copolymers, and opens a versatile route toward ultrahigh-density systems.

We report a simple route to generate nonequilibrium nanostructures combining two known block copolymer (BCP) morphologies by first templating the spatial arrangement of BCP in thin films using a supramolecule. The BCP subsequently assembles within the morphological framework established by the supramolecule, leading to a templated, nonequilibrium nanostructures not accessible by the BCP alone. Thin films with hexagonally packed cylindrical domains oriented normal to the surface were formed initially by the self-assembly of the diblock copolymer-based supramolecules, comprised of symmetric polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) with 3-pentadecylphenol (PDP) hydrogen-bonded to the 4VP. After selective removal of ∼90% of the PDP and a brief solvent annealing in a chloroform atmosphere, symmetric PS-b-P4VP, containing a trace amount of PDP, self-assembled forming polygonal (dominantly hexagonal) microdomains oriented normal to the surface. This process reported should be applicable to the large library of copolymer-based supramolecules and enables the generation of novel nonequilibrium nanostructured morphologies. It also provides a new platform to study the pathway-dependent self-assembly in polymer thin films.

The hierarchical assemblies of supramolecules, which consisted of polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) with 3-pentadecylphenol (PDP) hydrogen-bonded to the 4VP, were investigated in thin films after solvent annealing in a chloroform atmosphere. The synergistic coassembly of PS-b-P4VP and PDP was utilized to generate oriented hierarchical structures in thin films. Hierarchical assemblies, including lamellae-within-lamellae and cylinders-within-lamellae, were simultaneously ordered and oriented from a few to several tens of nanometers over macroscopic length scales. The macroscopic orientation of supramolecular assembly depends on the P4VP(PDP) fraction and can be tailored by varying the PDP to P4VP ratio without interfering with the supramolecular morphologies. The lamellar and cylindrical microdomains, with a periodicity of ∼40 nm, could be oriented normal to the surface, while the assembly of comb blocks, P4VP(PDP), with a periodicity of ∼4 nm, were oriented parallel to the surface. Furthermore, using one PS-b-P4VP copolymer, thin films with different hierarchical structures, i.e., lamellae-within-lamellae and cylinders-within-lamellae, were obtained by varying the ratio of PDP to 4VP units. The concepts described in these studies can be potentially applied to other BCP-based supramolecular thin films, thus creating an avenue to functional, hierarchically ordered thin films.

We present a new design of peptide−polymer conjugates where a polymer chain is covalently linked to the side chain of a helix bundle-forming peptide. The effect of conjugated polymer chains on the peptide structure was examined using a de novo designed three-helix bundle and a photoactive four-helix bundle. Upon attachment of poly(ethylene glycol) to the exterior of the coiled-coil helix bundle, the peptide secondary structure was stabilized and the tertiary structure, that is, the coiled-coil helix bundle, was retained. When a heme-binding peptide as an example is used, the new peptide−polymer conjugate architecture also preserves the built-in functionalities within the interior of the helix bundle. It is expected that the conjugated polymer chains act to mediate the interactions between the helix bundle and its external environment. Thus, this new peptide−polymer conjugate design strategy may open new avenues to macroscopically assemble the helix bundles and may enable them to function in nonbiological environments.

Nanocomposites, composed of organic and inorganic building blocks, can combine the properties from the parent constituents and generate new properties to meet current and future demands in functional materials. Recent developments in nanoparticle synthesis provide a plethora of inorganic building blocks, building the foundation for constructing hybrid nanocomposites with unlimited possibilities. The properties of nanocomposite materials depend not only on those of individual building blocks but also on their spatial organization at different length scales. Block copolymers, which microphase separate into various nanostructures, have shown their potential for organizing inorganic nanoparticles in bulk/thin films. Block copolymer-based supramolecules further provide more versatile routes to control spatial arrangement of the nanoparticles over multiple length scales. This review provides an overview of recent efforts to control the hierarchical assemblies in block copolymer-based hybrid nanocomposites.