Tracking water dimers in ambient nanocapsules by vibrational spectroscopy.

Nanoconfined few-molecule water clusters are invaluable systems to study fundamental aspects of hydrogen bonding. Unfortunately, most experiments on water clusters must be performed at cryogenic temperatures. Probing water clusters in noncryogenic systems is however crucial to understand the behavior of confined water in atmospheric or biological settings, but such systems usually require either complex synthesis and/or introduce many confounding external bonds to the clusters. Here, we show that combining Raman spectroscopy with the molecular nanocapsule cucurbituril is a powerful technique to sequester and analyze water clusters in ambient conditions. We observe sharp peaks in vibrational spectra arising from a single rigid confined water dimer. The high resolution and rich information in these vibrational spectra allow us to track specific isotopic exchanges inside the water dimer, verified with density-functional theory and kinetic population modeling. We showcase the versatility of such molecular nanocapsules by tracking water cluster vibrations through systematic changes in confinement size, in temperatures up to 120° C, and in their chemical environment.

Highly compressible glass-like supramolecular polymer networks.

Supramolecular polymer networks are non-covalently crosslinked soft materials that exhibit unique mechanical features such as self-healing, high toughness and stretchability. Previous studies have focused on optimizing such properties using fast-dissociative crosslinks (that is, for an aqueous system, dissociation rate constant kd > 10 s-1). Herein, we describe non-covalent crosslinkers with slow, tuneable dissociation kinetics (kd < 1 s-1) that enable high compressibility to supramolecular polymer networks. The resultant glass-like supramolecular networks have compressive strengths up to 100 MPa with no fracture, even when compressed at 93% strain over 12 cycles of compression and relaxation. Notably, these networks show a fast, room-temperature self-recovery (< 120 s), which may be useful for the design of high-performance soft materials. Retarding the dissociation kinetics of non-covalent crosslinks through structural control enables access of such glass-like supramolecular materials, holding substantial promise in applications including soft robotics, tissue engineering and wearable bioelectronics.

Deconvoluting the Optical Response of Biocompatible Photonic Pigments.

To unlock the widespread use of block copolymers as photonic pigments, there is an urgent need to consider their environmental impact (cf. microplastic pollution). Here we show how an inverse photonic glass architecture can enable the use of biocompatible bottlebrush block copolymers (BBCPs), which otherwise lack the refractive index contrast needed for a strong photonic response. A library of photonic pigments is produced from poly(norbornene-graft-polycaprolactone)-block-poly(norbornene-graft-polyethylene glycol), with the color tuned via either the BBCP molecular weight or the processing temperature upon microparticle fabrication. The structure-optic relationship between the 3D porous morphology of the microparticles and their complex optical response is revealed by both an analytical scattering model and 3D finite-difference time domain (FDTD) simulations. Combined, this allows for strategies to enhance the color purity to be proposed and realized with our biocompatible BBCP system.

Formulation of Metal-Organic Framework-Based Drug Carriers by Controlled Coordination of Methoxy PEG Phosphate: Boosting Colloidal Stability and Redispersibility.

Metal-organic framework nanoparticles (nanoMOFs) have been widely studied in biomedical applications. Although substantial efforts have been devoted to the development of biocompatible approaches, the requirement of tedious synthetic steps, toxic reagents, and limitations on the shelf life of nanoparticles in solution are still significant barriers to their translation to clinical use. In this work, we propose a new postsynthetic modification of nanoMOFs with phosphate-functionalized methoxy polyethylene glycol (mPEG-PO3) groups which, when combined with lyophilization, leads to the formation of redispersible solid materials. This approach can serve as a facile and general formulation method for the storage of bare or drug-loaded nanoMOFs. The obtained PEGylated nanoMOFs show stable hydrodynamic diameters, improved colloidal stability, and delayed drug-release kinetics compared to their parent nanoMOFs. Ex situ characterization and computational studies reveal that PEGylation of PCN-222 proceeds in a two-step fashion. Most importantly, the lyophilized, PEGylated nanoMOFs can be completely redispersed in water, avoiding common aggregation issues that have limited the use of MOFs in the biomedical field to the wet form-a critical limitation for their translation to clinical use as these materials can now be stored as dried samples. The in vitro performance of the addition of mPEG-PO3 was confirmed by the improved intracellular stability and delayed drug-release capability, including lower cytotoxicity compared with that of the bare nanoMOFs. Furthermore, z-stack confocal microscopy images reveal the colocalization of bare and PEGylated nanoMOFs. This research highlights a facile PEGylation method with mPEG-PO3, providing new insights into the design of promising nanocarriers for drug delivery.

Dynamic Interfacial Adhesion through Cucurbit[n]uril Molecular Recognition.

Supramolecular building blocks, such as cucurbit[n]uril (CB[n])-based host-guest complexes, have been extensively studied at the nano- and microscale as adhesion promoters. Herein, we exploit a new class of CB[n]-threaded highly branched polyrotaxanes (HBP-CB[n]) as aqueous adhesives to macroscopically bond two wet surfaces, including biological tissue, through the formation of CB[8] heteroternary complexes. The dynamic nature of these complexes gives rise to adhesion with remarkable toughness, displaying recovery and reversible adhesion upon mechanical failure at the interface. Incorporation of functional guests, such as azobenzene moieties, allows for stimuli-activated on-demand adhesion/de-adhesion. Macroscopic interfacial adhesion through dynamic host-guest molecular recognition represents an innovative strategy for designing the next generation of functional interfaces, biomedical devices, tissue adhesives, and wound dressings.

Light-Regulated Molecular Trafficking in a Synthetic Water-Soluble Host.

Cucurbit[8]uril (CB[8])-mediated complexation of a dicationic azobenzene in water allows for the light-controlled encapsulation of a variety of second guest compounds, including amino acids, dyes, and fragrance molecules. Such controlled guest sequestration inside the cavity of CB[8] enables the regulation of the thermally induced phase transition of poly(N-isopropylacrylamide)-which is not photosensitive-thus demonstrating the robustness and relevancy of the light-regulated CB[8] complexation.

Supramolecular chemistry at interfaces: host-guest interactions for fabricating multifunctional biointerfaces.

CONSPECTUS: Host-guest chemistry can greatly improve the selectivity of biomolecule-ligand binding on account of recognition-directed interactions. In addition, functional structures and the actuation of supramolecular assemblies in molecular systems can be controlled efficiently through various host-guest chemistry. Together, these highly selective, strong yet dynamic interactions can be exploited as an alternative methodology for applications in the field of programmable and controllable engineering of supramolecular soft materials through the reversible binding between complementary components. Many processes in living systems such as biotransformation, transportation of matter, and energy transduction begin with interfacial molecular recognition, which is greatly influenced by various external stimuli at biointerfaces. Detailed investigations about the molecular recognition at interfaces can result in a better understanding of life science, and further guide us in developing new biomaterials and medicines. In order to mimic complicated molecular-recognition systems observed in nature that adapt to changes in their environment, combining host-guest chemistry and surface science is critical for fabricating the next generation of multifunctional biointerfaces with efficient stimuli-responsiveness and good biocompatibility. In this Account, we will summarize some recent progress on multifunctional stimuli-responsive biointerfaces and biosurfaces fabricated by cyclodextrin- or cucurbituril-based host-guest chemistry and highlight their potential applications including drug delivery, bioelectrocatalysis, and reversible adsorption and resistance of peptides, proteins, and cells. In addition, these biointerfaces and biosurfaces demonstrate efficient response toward various external stimuli, such as UV light, pH, redox chemistry, and competitive guests. All of these external stimuli can aid in mimicking the biological stimuli evident in complex biological environments. We begin by reviewing the current state of stimuli-responsive supramolecular assemblies formed by host-guest interactions, discussing how to transfer host-guest chemistry from solution onto surfaces required for fabricating multifunctional biosurfaces and biointerfaces. Then, we present different stimuli-responsive biosurfaces and biointerfaces, which have been prepared through a combination of cyclodextrin- or cucurbituril-based host-guest chemistry and various surface technologies such as self-assembled monolayers or layer-by-layer assembly. Moreover, we discuss the applications of these biointerfaces and biosurfaces in the fields of drug release, reversible adsorption and release of some organic molecules, peptides, proteins, and cells, and photoswitchable bioelectrocatalysis. In addition, we summarize the merits and current limitations of these methods for fabricating multifunctional stimuli-responsive biointerfaces in a dynamic noncovalent manner. Finally, we present possible strategies for future designs of stimuli-responsive multifunctional biointerfaces and biosurfaces by combining host-guest chemistry with surface science, which will lead to further critical development of supramolecular chemistry at interfaces.

Efficient host-guest energy transfer in polycationic cyclophane-perylene diimide complexes in water.

We report the self-assembly of a series of highly charged supramolecular complexes in aqueous media composed of cyclobis(4,4'-(1,4-phenylene)bispyridine-p-phenylene)tetrakis(chloride) (ExBox) and three dicationic perylene diimides (PDIs). Efficient energy transfer (ET) is observed between the host and guests. Additionally, we show that our hexacationic complexes are capable of further complexation with neutral cucurbit[7]uril (CB[7]), producing a 3-polypseudorotaxane via the self-assembly of orthogonal recognition moieties. ExBox serves as the central ring, complexing to the PDI core, while two CB[7]s behave as supramolecular stoppers, binding to the two outer quaternary ammonium motifs. The formation of the 3-polypseudorotaxane results in far superior photophysical properties of the central PDI unit relative to the binary complexes at stoichiometric ratios. Lastly, we also demonstrate the ability of our binary complexes to act as a highly selective chemosensing ensemble for the neurotransmitter melatonin.

Electrokinetic assembly of one-dimensional nanoparticle chains with cucurbit[7]uril controlled subnanometer junctions.

One-dimensional (1D) nanoparticle chains with defined nanojunctions are of strong interest due to their plasmonic and electronic properties. A strategy is presented for the assembly of 1D gold-nanoparticle chains with fixed and rigid cucurbit[n]uril-nanojunctions of 9 Å. The process is electrokinetically accomplished using a nanoporous polycarbonate membrane and controlled by the applied voltage, the nanoparticle/CB[n] concentration ratio, time and temperature. The spatial structure and time-resolved analysis of chain plasmonics confirm a growth mechanism at the membrane nanopores.

Improved Imaging Surface for Quantitative Single-Molecule Microscopy.

Preventing nonspecific binding is essential for sensitive surface-based quantitative single-molecule microscopy. Here we report a much-simplified RainX-F127 (RF-127) surface with improved passivation. This surface achieves up to 100-fold less nonspecific binding from protein aggregates compared to commonly used polyethylene glycol (PEG) surfaces. The method is compatible with common single-molecule techniques including single-molecule pull-down (SiMPull), super-resolution imaging, antibody-binding screening and single exosome visualization. This method is also able to specifically detect alpha-synuclein (α-syn) and tau aggregates from a wide range of biofluids including human serum, brain extracts, cerebrospinal fluid (CSF) and saliva. The simplicity of this method further allows the functionalization of microplates for robot-assisted high-throughput single-molecule experiments. Overall, this simple but improved surface offers a versatile platform for quantitative single-molecule microscopy without the need for specialized equipment or personnel.

A facile route to viologen functional macromolecules through azide-alkyne [3+2] cycloaddition.

Viologen end and side-chain functional macromolecules are synthesized through a high-yielding, copper-mediated azide-alkyne [3+2] cycloaddition reaction. Specifically, poly(ethylene glycol) (PEG) and the C-terminus of a model oligopeptide are quantitatively end-coupled to a viologen moiety as confirmed by (1) H NMR, gel permeation chromatography (GPC), and mass spectrometry (MS). Side-chain functionalization of a styrene backbone is also readily achieved forming a polyelectrolyte species and demonstrating the applicability of this method across a range of macromolecular species. It is found that viologen itself slows the reaction and that careful choice of counter ions, the specific chelating ligand for the copper-mediated reaction, solvent, as well as the amount of copper also play major roles in the time to completion of the reaction and hence the yield. Macromolecules formed through this route bind effectively with supramolecular host molecule cucurbit[8]uril allowing for controlled solution-phase self-assembly, for example of a supramolecular star polymer.

Tissue-Mimetic Supramolecular Polymer Networks for Bioelectronics.

Addressing the mechanical mismatch between biological tissue and traditional electronic materials remains a major challenge in bioelectronics. While rigidity of such materials limits biocompatibility, supramolecular polymer networks can harmoniously interface with biological tissues as they are soft, wet, and stretchable. Here, an electrically conductive supramolecular polymer network that simultaneously exhibits both electronic and ionic conductivity while maintaining tissue-mimetic mechanical properties, providing an ideal electronic interface with the human body, is introduced. Rational design of an ultrahigh affinity host-guest ternary complex led to binding affinities (>1013  M-2 ) of over an order of magnitude greater than previous reports. Embedding these complexes as dynamic cross-links, coupled with in situ synthesis of a conducting polymer, resulted in electrically conductive supramolecular polymer networks with tissue-mimetic Young's moduli (<5 kPa), high stretchability (>500%), rapid self-recovery and high water content (>84%). Achieving such properties enabled fabrication of intrinsically-stretchable stand-alone bioelectrodes, capable of accurately monitoring electromyography signals, free from any rigid materials.

Triply triggered doxorubicin release from supramolecular nanocontainers.

The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers.

X-Ray Markers for Thin Film Implants.

Implantable electronic medical devices are used in functional mapping of the brain before surgery and to deliver neuromodulation for the treatment of neurological and neuropsychiatric disorders. Their electrode arrays are assembled by hand, and this leads to bulky form factors with limited flexibility and low electrode counts. Thin film implants, made using microfabrication techniques, are emerging as an attractive alternative, as they offer dramatically improved conformability and enable high density recording and stimulation. A major limitation of these devices, however, is that they are invisible to fluoroscopy, the most common method used to monitor the insertion of implantable electrodes. Here, the development of mechanically flexible X-ray markers using bismuth- and barium-infused elastomers is reported. Their X-ray attenuation properties in human cadavers are explored and it is shown that they are biocompatible in cell cultures. It is further shown that they do not distort magnetic resonance imaging images and their integration with thin film implants is demonstrated. This work removes a key barrier for the adoption of thin film implants in brain mapping and in neuromodulation.

Chemical complexity--supramolecular self-assembly of synthetic and biological building blocks in water.

Aqueous supramolecular chemistry, the non-covalent assembly of simple building blocks into higher ordered architectures in water has received much focus recently. Biological systems are able to form complex, and well-defined microstructures essential to cellular function, and supramolecular chemistry has demonstrated its utility in assembling molecules to form increasingly complex assemblies. This tutorial review will summarise non-covalent building blocks based on both synthetic and biological systems in an aqueous environment, emphasising the complexity of the assemblies formed. Examples of higher ordered assemblies will be highlighted, from supramolecular plastics to spider silks, towards more compartmentalised protocell precursors.

Mechanical Characterization of Human Brain Tissue and Soft Dynamic Gels Exhibiting Electromechanical Neuro-Mimicry.

Synthetic hydrogels are an important class of materials in tissue engineering, drug delivery, and other biomedical fields. Their mechanical and electrical properties can be tuned to match those of biological tissues. In this work, hydrogels that exhibit both mechanical and electrical biomimicry are reported. The presented dual networks consist of supramolecular networks formed from 2:1 homoternary complexes of imidazolium-based guest molecules in cucubit[8]uril and covalent networks of oligoethylene glycol-(di)methacrylate. The viscoelastic properties of human brain tissues are also investigated. The mechanical properties of the dual network gels are benchmarked against the human tissue, and it is found that they both are neuro-mimetic and exhibit cytocompatibility in a neural stem cell model.

Microfluidic Droplet-Facilitated Hierarchical Assembly for Dual Cargo Loading and Synergistic Delivery.

Bottom-up hierarchical assembly has emerged as an elaborate and energy-efficient strategy for the fabrication of smart materials. Herein, we present a hierarchical assembly process, whereby linear amphiphilic block copolymers are self-assembled into micelles, which in turn are accommodated at the interface of microfluidic droplets via cucurbit[8]uril-mediated host-guest chemistry to form supramolecular microcapsules. The monodisperse microcapsules can be used for simultaneous carriage of both organic (Nile Red) and aqueous-soluble (fluorescein isothiocyanate-dextran) cargo. Furthermore, the well-defined compartmentalized structure benefits from the dynamic nature of the supramolecular interaction and offers synergistic delivery of cargos with triggered release or through photocontrolled porosity. This demonstration of premeditated hierarchical assembly, where interactions from the molecular to microscale are designed, illustrates the power of this route toward accessing the next generation of functional materials and encapsulation strategies.

Supramolecular polymeric peptide amphiphile vesicles for the encapsulation of basic fibroblast growth factor.

The synthesis of a supramolecular double hydrophilic peptide-conjugated polymer held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent temperature triggered self-assembly into vesicles are described. Basic fibroblast growth factor can be easily loaded into the vesicles under benign conditions and their bioactivities can be preserved without the need for excipients such as heparin.

The control of cargo release from physically crosslinked hydrogels by crosslink dynamics.

Controlled release of drugs and other cargo from hydrogels has been an important target for the development of next generation therapies. Despite the increasingly strong focus in this area of research, very little of the published literature has sought to develop a fundamental understanding of the role of molecular parameters in determining the mechanism and rate of cargo release. Herein, a series of physically crosslinked hydrogels have been prepared utilizing host-guest binding interactions of cucurbit[8]uril that are identical in strength (plateau modulus), concentration and structure, yet exhibit varying network dynamics on account of the use of different guests for supramolecular crosslinking. The diffusion of molecular cargo through the hydrogel matrix and the release characteristics from these hydrogels were investigated. It was determined that the release processes of the hydrogels could be directly correlated with the dynamics of the physical interactions responsible for crosslinking and corresponding time-dependent mesh size. These observations highlight that network dynamics play an indispensable role in determining the release mechanism of therapeutic cargo from a hydrogel, identifying that fine-tuning of the release characteristics can be gained through rational design of the molecular processes responsible for crosslinking in the carrier hydrogels.