Oren A. Scherman

One-Step Fabrication of Supramolecular Microcapsules from Microfluidic Droplets

Be My Guests For a range of applications, including medical diagnostics or drug delivery, it is necessary to encapsulate one or more components into a microcapsule. While there are many methods that can do this, most either produce a range of capsule size or are not easily scalable for making large quantities. J. Zhang et al. (p. 690) developed a microfluidic-based system for making capsules using host-guest chemistry. Cucurbit[8]uril, which readily forms complexes in water, was used as the host molecule and could accommodate two different guest molecules. Rapid complexation was observed of methyl viologen–modified gold nanoparticles and a naphthol-containing copolymer. A molecular host that binds two guests directs scalable fabrication of hollow polymer/gold nanoparticle hybrid structures. Although many techniques exist for preparing microcapsules, it is still challenging to fabricate them in an efficient and scalable process without compromising functionality and encapsulation efficiency. We demonstrated a simple one-step approach that exploits a versatile host-guest system and uses microfluidic droplets to generate porous microcapsules with easily customizable functionality. The capsules comprise a polymer-gold nanoparticle composite held together by cucurbit[8]uril ternary complexes. The dynamic yet highly stable micrometer-sized structures can be loaded in one step during capsule formation and are amenable to on-demand encapsulant release. The internal chemical environment can be probed with surface enhanced Raman spectroscopy.

Ultrahigh-Water-Content Supramolecular Hydrogels Exhibiting Multistimuli Responsiveness

Hydrogels are three-dimensional networked materials that are similar to soft biological tissues and have highly variable mechanical properties, making them increasingly important in a variety of biomedical and industrial applications. Herein we report the preparation of extremely high water content hydrogels (up to 99.7% water by weight) driven by strong host-guest complexation with cucurbit[8]uril (CB[8]). Cellulosic derivatives and commodity polymers such as poly(vinyl alcohol) were modified with strongly binding guests for CB[8] ternary complex formation (K(eq) = 10(12) M(-2)). When these polymers were mixed in the presence of CB[8], whereby the overall solid content was 90% cellulosic, a lightly colored, transparent hydrogel was formed instantaneously. The supramolecular nature of these hydrogels affords them with highly tunable mechanical properties, and the dynamics of the CB[8] ternary complex cross-links allows for rapid self-healing of the materials after damage caused by deformation. Moreover, these hydrogels display responsivity to a multitude of external stimuli, including temperature, chemical potential, and competing guests. These materials are easily processed, and the simplicity of their preparation, their availability from inexpensive renewable resources, and the tunability of their properties are distinguishing features for many important water-based applications.

Single-molecule strong coupling at room temperature in plasmonic nanocavities

Photon emitters placed in an optical cavity experience an environment that changes how they are coupled to the surrounding light field. In the weak-coupling regime, the extraction of light from the emitter is enhanced. But more profound effects emerge when single-emitter strong coupling occurs: mixed states are produced that are part light, part matter, forming building blocks for quantum information systems and for ultralow-power switches and lasers. Such cavity quantum electrodynamics has until now been the preserve of low temperatures and complicated fabrication methods, compromising its use. Here, by scaling the cavity volume to less than 40 cubic nanometres and using host–guest chemistry to align one to ten protectively isolated methylene-blue molecules, we reach the strong-coupling regime at room temperature and in ambient conditions. Dispersion curves from more than 50 such plasmonic nanocavities display characteristic light–matter mixing, with Rabi frequencies of 300 millielectronvolts for ten methylene-blue molecules, decreasing to 90 millielectronvolts for single molecules—matching quantitative models. Statistical analysis of vibrational spectroscopy time series and dark-field scattering spectra provides evidence of single-molecule strong coupling. This dressing of molecules with light can modify photochemistry, opening up the exploration of complex natural processes such as photosynthesis and the possibility of manipulating chemical bonds.

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.

Photocontrol over Cucurbit[8]uril Complexes: Stoichiometry and Supramolecular Polymers

Herein we report the photocontrol of cucurbit[8]uril (CB[8])-mediated supramolecular polymerization of azobenzene-containing monomers. The CB[8] polymers were characterized both in solution and in the solid state. These host-guest complexes can be reversibly switched between highly thermostable photostationary states. Moreover, a remarkable stabilization of Z-azobenzene was achieved by CB[8] complexation, allowing for structural characterization in the solid state.

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.

Supramolecular Polymerization Promoted and Controlled through Self‐Sorting

A new method in which supramolecular polymerization is promoted and controlled through self-sorting is reported. The bifunctional monomer containing p-phenylene and naphthalene moieties was prepared. Supramolecular polymerization is promoted by selective recognition between the p-phenylene group and cucurbit[7]uril (CB[7]), and 2:1 complexation of the naphthalene groups with cucurbit[8]uril (CB[8]). The process can be controlled by tuning the CB[7] content. This development will enrich the field of supramolecular polymers with important advances towards the realization of molecular-weight and structural control.

Supramolecular Peptide Amphiphile Vesicles through Host–Guest Complexation†

Single-tail peptide amphiphiles, have been explored as a new class of biomaterials in many fields including nanotechnology and tissue engineering. A typical peptide amphiphile molecule is linked through a covalent amide bond between a hydrophilic peptide sequence and a hydrophobic lipid of variable length. In an aqueous environment, these peptide amphiphiles undergo self-assembly into structures such as vesicles, both spherical and cylindrical micelles or nanotubes, and have been successfully applied in the biomedical sciences for biomaterial conjugation and as bioactive scaffolds for tissue engineering. Although covalent attachment of two components to form peptide amphiphiles has been extremely successful, the synthetic versatility and the ability to respond to external triggers remains limited. A supramolecular approach to form the peptide amphiphile by connecting two building blocks through a non-covalent interaction would represent a major advance, especially in designing stimuliresponsive systems capable of being targeted by specific triggers. Cucurbit[n]urils (CB[n]) are a family of macrocyclic hosts known to form inclusion complexes with selectivity and high binding affinity in aqueous media. One of the larger macrocycles in this family, CB[8], can be used as a “molecular handcuff” to join two molecules together in a non-covalent fashion, and has been applied to form biomaterials such as polymer–protein conjugation and protein dimerization. Additionally, CB[n] hosts have found great utility in “switch on/switch off” fluorescence assays by supramolecular complexation with various fluorescent guests. Pyrene and its derivatives have been widely used as fluorescence probes in a large number of complex systems, on account of their high fluorescence quantum yields, long excited state lifetimes and the ability to form excimers. Herein, we utilize a functional pyrene bearing an imidazolium group both as a fluorescence sensor and as a guest for CB[8] and linked it to a simple peptide sequence (1). Pyrene-functionalized peptide 1 is able to form the supramolecular peptide amphiphile complex 3 with viologen lipid 2 through CB[8] conjugation, as shown in Figure 1a. During the

Strongly Fluorescent, Switchable Perylene Bis(diimide) Host–Guest Complexes with Cucurbit[8]uril In Water†

Supramolecular complexation of perylene bis(diimide) (PDI) dyes with the macrocyclic host cucurbit[8]uril (CB[8]) prevents self-aggregation of the dye molecules and enables their use as highly (photo)chemically stable, strongly-emitting fluorophores in water. The complexes are stimuli-responsive to binders and can be electrochemically cycled, leading to reversible on-off fluorescence switching and access to noncovalent formation of higher-order architectures in water.

Formation of Single‐Chain Polymer Nanoparticles in Water through Host–Guest Interactions

The dynamic three-dimensional structures of enzymes are dictated by secondary bonding interactions and play a crucial role in both molecular recognition and allosteric regulation. Controlled crosslinking of single polymer chains in isolation, that can be seen as a mimic of the self-organization of enzymes, has previously been realized in organic solvents through crosslinking of multivalent polymer chains under highly dilute conditions. 2] In this instance, crosslinking must be specifically intramolecular to form these “self-collapsed” single-chain polymeric entities, which have been reported as discrete, spherical nanoparticulate structures. Whilst a few of the above systems are documented in the literature, where novel applications for such systems have been realized, only a small number are shown to be reversible and only one example exists in water. Moreover, the controlled folding and unfolding of a single polymer chain in water has not yet been realized. A completely reversible form of this system would be beneficial for many reasons, especially in light of one notable property of these nanoparticles (NPs), which is their ability to produce non-Einsteinian reductions in viscosity. Supramolecular crosslinking motifs exploit well-established non-covalent interactions and their incorporation into molecular constructs has led to the formation of materials with novel properties. Notable examples of such materials predominantly include gelating entities where intermolecular crosslinking leads to gel formation. This strategy has been particularly successful for systems that consist of polymeric subunits which are able to gel through multivalent functionality. Cucurbit[8]uril (CB[8]), a macrocylic host molecule capable of binding two aromatic guest molecules simultaneously, is a suitable candidate for such reversible crosslinking on account of the variety of guests available for binding. This allows for the use of guests with a range of orthogonal stimuli where guest binding can be controlled through simple external conditions (e.g. temperature, pH, light, competing guests), thus allowing for reversibility to be easily achieved. As a result, a variety of systems have already been produced bearing this reversible CB[8]-based crosslinking motif. Herein we document a CB[8]-mediated system for the preparation of metastable single-chain polymer nanoparticles. These nanoparticles are shown to form rapidly, are highly tunable and reversible and do not require protection chemistries (Figure 1).