Engineering living cells with cucurbit[7]uril-based supramolecular polymer chemistry: from cell surface engineering to manipulation of subcellular organelles

Supramolecular polymer chemistry, which closely integrates noncovalent interactions with polymeric structures, is a promising toolbox for living cell engineering. Here, we report our recent progress in exploring the applications of cucurbit[7]uril (CB[7])-based supramolecular polymer chemistry for engineering living cells. First, a modular polymer-analogous approach was established to prepare multifunctional polymers that contain CB[7]-based supramolecular recognition motifs. The supramolecular polymeric systems were successfully applied to cell surface engineering and subcellular organelle manipulation. By anchoring polymers on the cell membranes, cell–cell interactions were established by CB[7]-based host–guest recognition, which further facilitated heterogeneous cell fusion. In addition to cell surface engineering, placing the multifunctional polymers on specific subcellular organelles, including the mitochondria and endoplasmic reticulum, has led to enhanced physical contact between subcellular organelles. It is highly anticipated that the CB[7]-based supramolecular polymer chemistry will provide a new strategy for living cell engineering to advance the development of cell-based therapeutic materials.

Cucurbit[7]uril-based supramolecular polymer chemistry, which closely integrates host–guest recognition with multifunctional polymeric structures, is a promising toolbox for living cell engineering.     

Spatiotemporal dynamics of supramolecular polymers by in situ quantitative catalyst-free hydroamination

Implementing chemical reactivity into synthetic supramolecular polymers based on π-conjugated molecules has been of great interest to create functional materials with spatiotemporal dynamic properties. However, the development of an in situ chemical reaction within supramolecular polymers is still in its infancy, because one needs to design optimal π-conjugated monomers having excellent reactivity under mild conditions possibly without byproducts or a catalyst. Herein we report the synthesis of a supramolecular polymer based on ethynyl core-substituted naphthalenediimide (S-NDI2) molecules that react with various amines quantitatively in a nonpolar solvent, without a catalyst, at 298 K. Most interestingly, the in situ reaction of the S-NDI2 supramolecular polymer with a linear aliphatic diamine proceeded much faster than the homogeneous reaction of a monomeric naphthalenediimide with the same diamine, affording diamine-linked S-NDI2 oligomers and polymers. The acceleration of in situ hydroamination was presumably due to rapid intra-supramolecular cross-linking between ethynyl and amino groups fixed in close proximity within the supramolecular polymer. Such intra-supramolecular cross-linking did not occur efficiently with an incompatible diamine. The systematic kinetic studies of in situ catalyst-free hydroamination within supramolecular polymers provide us with a useful, facile and versatile tool kit for designing dynamic supramolecular polymeric materials based on electron-deficient π-conjugated monomers.

A supramolecular polymer based on ethynyl core-substituted naphthalenediimides reacted with various amines quantitatively without a catalyst, exhibiting unconventional reaction kinetics and products.     

Recent progress and future challenges in the supramolecular polymerization of metal-containing monomers

The self-assembly of discrete molecular entities into functional nanomaterials has become a major research area in the past decades. The library of investigated compounds has diversified significantly, while the field as a whole has matured. The incorporation of metal ions in the molecular design of the (supra-)molecular building blocks greatly expands the potential applications, while also offering a promising approach to control molecular recognition and attractive and/or repulsive intermolecular binding events. Hence, supramolecular polymerization of metal-containing monomers has emerged as a major research focus in the field. In this perspective article, we highlight recent significant advances in supramolecular polymerization of metal-containing monomers and discuss their implications for future research. Additionally, we also outline some major challenges that metallosupramolecular chemists (will) have to face to produce metallosupramolecular polymers (MSPs) with advanced applications and functionalities.

In this perspective article, we highlight recent significant advances in the self-assembly of metal-containing monomers and discuss their implications for future research.     

Depolymerization of supramolecular polymers by a covalent reaction; transforming an intercalator into a sequestrator

Controlling the reciprocity between chemical reactivity and supramolecular structure is a topic of great interest in the emergence of molecular complexity. In this work, we investigate the effect of a covalent reaction as a trigger to depolymerize a supramolecular assembly. We focus on the impact of an in situ thiol–ene reaction on the (co)polymerization of three derivatives of benzene-1,3,5-tricarboxamide (BTA) monomers functionalized with cysteine, hexylcysteine, and alkyl side chains: Cys-BTA, HexCys-BTA, and a-BTA. Long supramolecular polymers of Cys-BTA can be depolymerized into short dimeric aggregates of HexCys-BTAvia the in situ thiol–ene reaction. Analysis of the system by time-resolved spectroscopy and light scattering unravels the fast dynamicity of the structures and the mechanism of depolymerization. Moreover, by intercalating the reactive Cys-BTA monomer into an unreactive inert polymer, the in situ thiol–ene reaction transforms the intercalator into a sequestrator and induces the depolymerization of the unreactive polymer. This work shows that the implementation of reactivity into supramolecular assemblies enables temporal control of depolymerization processes, which can bring us one step closer to understanding the interplay between non-covalent and covalent chemistry.

We report on the controlled depolymerization of supramolecular 1D polymers into well-defined dimers triggered by a covalent reaction on the side chains of the monomer.     

Supramolecular interactions between ethylene-bridged oligoureas: nanorings and chains formed by cooperative positive allostery

Ethylene-bridged oligoureas are dynamic foldamers in which the polarity of a coherent chain of intramolecular hydrogen bonds may be controlled by intra- or intermolecular interactions with hydrogen-bond donors or acceptors. In this paper, we describe the way that supramolecular interactions between ethylene-bridged oligoureas bearing a 3,5-bis(trifluoromethyl)phenylurea (BTMP) terminus leads to higher-order structures both in the crystalline state and in solution. The oligoureas self-assemble by head-to-tail hydrogen bonding interactions to form either supramolecular ‘nanorings’ with cyclic hydrogen bond chain directionality, or supramolecular helical chains of hydrogen bonds. The self-assembly process features a cascade of cooperative positive allostery, in which each intermolecular hydrogen bond formation at the BTMP terminus switches the native hydrogen bond chain directionality of monomers, favouring further assembly. Monomers with a benzyl urea terminus self-assemble into nanorings, whereas monomers with a N-ethyl urea terminus form helical chains. In the crystal state, parallel helices have identical handedness and polarity, whereas antiparallel helices have opposite handedness. The overall dipole moment of crystals is zero due to the antiparallel arrangements of local dipoles in the crystal packing. Supramolecular interactions in solution were also examined by VT and DOSY NMR spectroscopy, up to the point of crystal formation. The size of higher aggregates in dichloromethane was estimated by their hydrodynamic radius. The relative orientation of the monomers within the aggregates, determined by 2D ROESY NMR, was the same as in the crystals, where syn-orientations lead to the formation of rings and anti-orientations result in chains. Overall, the switch of hydrogen bond polarity propagates intermolecularly in crystal and solution states, constituting an example of intermolecular communication within supramolecular polymers.

Hydrogen-bonded urea oligomers form supramolecular aggregates in the crystalline state. Intermolecular hydrogen bonding generates nano-rings or chains, according to the length and substitution pattern of the oligomers.     

Synthesis of degradable and chemically recyclable polymers using 4,4-disubstituted five-membered cyclic ketene hemiacetal ester (CKHE) monomers

Novel degradable and chemically recyclable polymers were synthesized using five-membered cyclic ketene hemiacetal ester (CKHE) monomers. The studied monomers were 4,4-dimethyl-2-methylene-1,3-dioxolan-5-one (DMDL) and 5-methyl-2-methylene-5-phenyl-1,3-dioxolan-4-one (PhDL). The two monomers were synthesized in high yields (80–90%), which is an attractive feature. DMDL afforded its homopolymer with a relatively high molecular weight (M_n >100 000, where M_n is the number-average molecular weight). DMDL and PhDL were copolymerized with various families of vinyl monomers, i.e., methacrylates, acrylates, styrene, acrylonitrile, vinyl pyrrolidinone, and acrylamide, and various functional methacrylates and acrylate. Such a wide scope of the accessible polymers is highly useful for material design. The obtained homopolymers and random copolymers of DMDL degraded in basic conditions (in the presence of a hydroxide or an amine) at relatively mild temperatures (room temperature to 65 °C). The degradation of the DMDL homopolymer generated 2-hydroxyisobutyric acid (HIBA). The generated HIBA was recovered and used as an ingredient to re-synthesize DMDL monomer, and this monomer was further used to re-synthesize the DMDL polymer, demonstrating the chemical recycling of the DMDL polymer. Such degradability and chemical recyclability of the DMDL polymer may contribute to the circular materials economy.

Novel degradable and chemically recyclable polymers were synthesized using five-membered cyclic ketene hemiacetal ester (CKHE) monomers.     

Diaryliodonium salts facilitate metal-free mechanoredox free radical polymerizations

Mechanically-induced redox processes offer a promising alternative to more conventional thermal and photochemical synthetic methods. For macromolecule synthesis, current methods utilize sensitive transition metal additives and suffer from background reactivity. Alternative methodology will offer exquisite control over these stimuli-induced mechanoredox reactions to couple force with redox-driven chemical transformations. Herein, we present the iodonium-initiated free-radical polymerization of (meth)acrylate monomers under ultrasonic irradiation and ball-milling conditions. We explore the kinetic and structural consequences of these complementary mechanical inputs to access high molecular weight polymers. This methodology will undoubtedly find broad utility across stimuli-controlled polymerization reactions and adaptive material design.

Mechanically-induced redox processes offer a promising alternative to more conventional thermal and photochemical synthetic methods.     

Mechanochemical ring-opening metathesis polymerization: development,scope, and mechano-exclusive polymer synthesis

Ruthenium-alkylidene initiated ring-opening metathesis polymerization has been realized under solid-state conditions by employing a mechanochemical ball milling method. This method promotes greenness and broadens the scope to include mechano-exclusive products. The carbene- and pyridine-based Grubbs 3^rd-generation complex outperformed other catalysts and maintained similar mechanistic features of solution-phase reactions. High-speed ball milling provides sufficient mixing and energy to the solid reaction mixture, which is composed of an initiator and monomers, to minimize or eliminate the use of solvents. Therefore, the solubility and miscibility of monomers and Ru-initiators are not limiting factors in solid-state ball milling. A wide variety of solid monomers, including ionomers, fluorous monomers, and macromonomers, were successfully polymerized under ball milling conditions. Importantly, direct copolymerization of immiscible (ionic/hydrophobic) monomers exemplifies the synthesis of mechano-exclusive polymers that are difficult to make using traditional solution procedures. Finally, the addition of a small amount of a liquid additive (i.e., liquid-assisted grinding) minimized chain-degradation, enabling high-molecular-weight polymer synthesis.

Mechanochemical ball-milling ring-opening metathesis polymerization minimized solvent use and produced previously inaccessible polymers in solution.     

Isomeric anthracene diimide polymers

N-type semiconducting polymers are attractive for organic electronics, but desirable electron-deficient units for synthesizing such polymers are still lacking. As a cousin of rylene diimides such as naphthalene diimide (NDI) and perylene diimide (PDI), anthracene diimide (ADI) is a promising candidate; its polymers, however, have not been achieved yet because of synthetic challenges for its polymerizable monomers. Herein, we present ingenious synthesis of two dibromide ADI monomers with dibromination at differently symmetrical positions of the ADI core, which are further employed to construct ADI polymers. More interestingly, the two obtained ADI polymers possess the same main-chain and alkyl-chain structures but different backbone conformations owing to varied linking positions between repeating units. This feature enables their different optoelectronic properties and film-state packing behavior. The ADI polymers offer first examples of conjugated polymer conformational isomers and are highly promising as a new class of n-type semiconductors for various organic electronics applications.

Two anthracene diimide (ADI) polymers with the backbone conformational isomerism, new members of aromatic diimide polymers family, have been synthesized as a class of highly promising n-type semiconductors for organic electronics.     

Water-soluble supramolecular polymers constructed by macrocycle-based host-guest interactions

Water soluble supramolecular polymers are especially important due to their superior biocompatibility and environmental adaptation, which determined they have wide applications in various areas, such as drug delivery, self-healing, shape memory. On the other hand, macrocyclic compounds are the most used building blocks in the preparation of supramolecular polymers. Macrocycle-based supramolecular polymers, which introduce the host-guest interaction in the system, endow these polymers with interesting and smart physicalchemical properties. In this review, we summarized recent studies about supramolecular polymers in aqueous solution based on macrocyclic compounds.     

Bottom-up supramolecular assembly in two dimensions

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. Attracted by the interesting properties of two-dimensional inorganic analogues, monomers of different chemical natures are being explored for the assembly of dynamic 2D systems. Although many important discoveries have been already achieved, great challenges are still to be addressed in this field. Hierarchical multicomponent assembly, directional non-covalent growth and internal structural control are a just a few of the examples that will be discussed in this perspective about the exciting present and the bright future of two-dimensional supramolecular assemblies.

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. This perspective discusses the main strategies to direct the supramolecular self-assembly of organic monomers in 2D.     

A graph representation of molecular ensembles for polymer property prediction

Synthetic polymers are versatile and widely used materials. Similar to small organic molecules, a large chemical space of such materials is hypothetically accessible. Computational property prediction and virtual screening can accelerate polymer design by prioritizing candidates expected to have favorable properties. However, in contrast to organic molecules, polymers are often not well-defined single structures but an ensemble of similar molecules, which poses unique challenges to traditional chemical representations and machine learning approaches. Here, we introduce a graph representation of molecular ensembles and an associated graph neural network architecture that is tailored to polymer property prediction. We demonstrate that this approach captures critical features of polymeric materials, like chain architecture, monomer stoichiometry, and degree of polymerization, and achieves superior accuracy to off-the-shelf cheminformatics methodologies. While doing so, we built a dataset of simulated electron affinity and ionization potential values for >40k polymers with varying monomer composition, stoichiometry, and chain architecture, which may be used in the development of other tailored machine learning approaches. The dataset and machine learning models presented in this work pave the path toward new classes of algorithms for polymer informatics and, more broadly, introduce a framework for the modeling of molecular ensembles.

A graph representation that captures critical features of polymeric materials and an associated graph neural network achieve superior accuracy to off-the-shelf cheminformatics methodologies.     

Fluorescent supramolecular polymers of barbiturate dyes with thiophene-cored twisted π-systems

Because supramolecular polymerization of emissive π-conjugated molecules depends strongly on π–π stacking interaction, the formation of well-defined one-dimensional nanostructures often results in a decrease or only a small increase of emission efficiency. This is also true for our barbiturate-based supramolecular polymers wherein hydrogen-bonded rosettes of barbiturates stack quasi-one-dimensionally through π–π stacking interaction. Herein we report supramolecular polymerization-induced emission of two regioisomeric 2,3-diphenylthiophene derivatives functionalized with barbituric acid and tri(dodecyloxy)benzyl wedge units. In CHCl₃, both compounds are molecularly dissolved and accordingly poorly emissive due to a torsion-induced non-radiative decay. In methylcyclohexane-rich conditions, these barbiturates self-assemble to form crystalline nanofibers and exhibit strongly enhanced emission through supramolecular polymerization driven by hydrogen-bonding. Our structural analysis suggests that the barbiturates form a tape-like hydrogen-bonding motif, which is rationalized by considering that the twisted geometries of 2,3-diphenylthiophene cores prevend the competing rosettes from stacking into columnar supramolecular polymers. We also found that a small difference in the molecular polarity originating from the substitutional position of the thiophene core influences interchain association of the supramolecular polymers, affording different luminescent soft materials, gel and nanosheet.

Two barbiturate dyes with regioisomeric thiophene-cored twisted π-systems show strongly enhanced emission through supramolecular polymerization. The supramolecular polymers thus formed exhibit distinct emission colors and degree of agglomeration.     

Single-crystal-to-single-crystal synthesis of a pseudostarch via topochemical azide–alkyne cycloaddition polymerization

There is high demand for polysaccharide-mimics as enzyme-stable substitutes for polysaccharides for various applications. Circumventing the problems associated with the solution-phase synthesis of such polymers, we report here the synthesis of a crystalline polysaccharide-mimic by topochemical polymerization. By crystal engineering, we designed a topochemically reactive crystal of a glucose-mimicking monomer decorated with azide and alkyne units. In the crystal, the monomers arrange in head-to-tail fashion with their azide and alkyne groups in a ready-to-react antiparallel geometry, suitable for their topochemical azide–alkyne cycloaddition (TAAC) reaction. On heating the crystals, these pre-organized monomer molecules undergo regiospecific TAAC polymerization, yielding 1,4-triazolyl-linked pseudopolysaccharide (pseudostarch) in a single-crystal-to-single-crystal manner. This crystalline pseudostarch shows better thermal stability than its amorphous form and many natural polysaccharides.

Prudent crystal engineering allows head-to-tail arrangement of inositol monomer molecules pre-organizing azide and alkyne units of adjacent monomers in a ready-to-react manner. On heating regiospecific SCSC polymerization yields a starch-like polymer.     

Synthesis and gas transport properties of new aromatic 3F polymers

New aromatic 3F polymers were obtained from condensations of 2,2,2-trifluoroacetophenone (1) with biphenyl (a), terphenyl (b), a mixture of biphenyl with terphenyl (ab), phenyl ether (c) and diphenoxybenzophenone (d). The reactions were performed at room temperature in the Brønsted superacid trifluoromethanesulfonic acid (TFSA) and in a mixture of TFSA with dichloromethane. The polymers show high glass transition temperatures >170 °C, excellent thermal stability (decomposition temperatures ≥475 °C) and good solubility in chlorinated solvents and strong acids. The 3F polymer structures based on biphenyl and terphenyl show attractive permeability coefficients for CO₂ (∼200 Barrers) and H₂ (∼120 Barrers), whereas the 3F polymers that contain ether linkages have permeability coefficients in the typical range of regular polysulfone and polycarbonate. However, in sharp contrast to polysulfone and polycarbonate families, new 3F polymers possess high chemical stability and they have advantages since their reactions, based on commercially available monomers, can be carried out in one-pot at room temperature and offer a large variety of structures not possible to prepare by other synthetic methods.     

Exhaustive Baeyer–Villiger oxidation: a tailor-made post-polymerization modification to access challenging poly(vinyl acetate) copolymers

The discovery of exhaustive (nearly quantitative) post-polymerization modifications (PPM) relies heavily on the efficiency of their corresponding small-molecule protocols. However, the direct translation of existing small-molecule protocols into PPM methods has never been guaranteed due to the intrinsic differences between small-molecule substrates and polymers. Herein, we introduce the direct optimization on polymers (DOP) as a complementary approach to developing exhaustive PPM reactions. As proof of the DOP concept, we present an exhaustive Baeyer–Villiger (BV) post-modification which cannot be accessed by conventional approaches. This user-friendly methodology provides general access to synthetically challenging copolymers of vinyl acetate and more activated monomers (MAMs) including both statistical and narrow-dispersed block copolymers. Furthermore, a scalable one-pot copolymerization/exhaustive BV post-modification procedure was developed to produce such materials showing improved performance over regular PVAc.

Exhaustive Baeyer–Villiger (BV) oxidation, which was developed by a direct optimization on polymers (DOP) approach, provides a general solution for preparing synthetically challenging poly(vinyl acetate) statistical and block copolymers.     

Albumin-mediated “Unlocking” of supramolecular prodrug-like nanozymes toward selective imaging-guided phototherapy

Construction of an activatable photosensitizer and integration into an adaptive nanozyme during phototherapy without producing off-target toxicity remains a challenge. Herein, we have fabricated a prodrug-like supramolecular nanozyme based on a metallic-curcumin and cyanine co-assembly. The albumin-mediated phenol AOH group transformation of nanozyme changes its adjustable oxygen stress from negative superoxide dismutase-like activity of ROS-scavenging to positive photo oxidase activity with an ROS-amplifying capacity. It further increases the depth penetration of a nanozyme in a tumor spheroid, selectively targeting tumorous phototherapy. It also triggers a signal in targeted tumor cells and helps increase cancer cell ablation. This work suggests new options for development of activatable supramolecular nanozymes and provides a synergetic prodrug-like nanozyme strategy for early diagnosis and preclinical phototherapeutics.

An adaptive nanozyme without producing off-target toxicity has been successfully applied in phototherapy.     

Direct growth of crystalline triazine-based graphdiyne using surface-assisted deprotection–polymerisation

Graphdiyne polymers have interesting electronic properties due to their π-conjugated structure and modular composition. Most of the known synthetic pathways for graphdiyne polymers yield amorphous solids because the irreversible formation of carbon–carbon bonds proceeds under kinetic control and because of defects introduced by the inherent chemical lability of terminal alkyne bonds in the monomers. Here, we present a one-pot surface-assisted deprotection/polymerisation protocol for the synthesis of crystalline graphdiynes over a copper surface starting with stable trimethylsilylated alkyne monomers. In comparison to conventional polymerisation protocols, our method yields large-area crystalline thin graphdiyne films and, at the same time, minimises detrimental effects on the monomers like oxidation or cyclotrimerisation side reactions typically associated with terminal alkynes. A detailed study of the reaction mechanism reveals that the deprotection and polymerisation of the monomer is promoted by Cu(ii) oxide/hydroxide species on the as-received copper surface. These findings pave the way for the scalable synthesis of crystalline graphdiyne-based materials as cohesive thin films.

We present a one-pot deprotection/polymerisation protocol for the synthesis of crystalline graphdiynes on top of a copper surface starting with stable trimethylsilylated alkyne monomers.      

Coils,Rods and Rings in Hydrogen‐Bonded Supramolecular Polymers

The article discusses the development and properties of supramolecular polymers based on quadruple hydrogen bonds between self‐complementary ureidotriazine (UTr) and ureidopyrimidinone (UPy) functional groups. The high association constant with which these groups dimerize leads to polymers with a high degree of polymerization in isotropic solution. Application of these units for the functionalization of telechelic polymers results in new materials with mechanical properties approaching those of covalent polymers, but with a much stronger temperature‐dependent behavior. Solvophobic interactions between the hydrogen bonding moieties may be used to obtain supramolecular polymers with a well defined helical columnar architecture. Another consequence of the high dimerization constant of the UPy group is the phenomenon of a critical concentration in solutions of many bifunctional monomers. Below this concentration, only cycles are present, while above the critical concentration, the amount of cycles remains constant, and a polymer is formed. Conformational properties of the linker units are used to control the equilibrium between polymers and cycles, and are proposed to form a promising strategy toward tunable materials.

Supramolecular polymer material with elastomeric properties resulting from functionalization with UPy groups. (Reproduced with permission. © John Wiley & Sons, Inc.)     

Unexpected chirality transition and inversion mediated by dissolution–aggregation and the odd–even effect

The evolution of hierarchical chirality at macromolecular and supramolecular levels in biological systems is ubiquitous; however, achieving precise control over transitions between them in polymer systems is still challenging. Here, we reported multiple chiroptical transitions and inversion phenomena in side-chain azobenzene (Azo) polymers, PAzo-l/d-m (m = 3, 6, 7, 8, 9, and 10, where m is the total number of atoms from the chiral stereocenter to the Azo unit), with different distances from the chiral stereocenter to the Azo unit. In the case of m = 3, an unexpected macromolecular-to-supramolecular chirality transition and inversion occurred in situ when the Azo-polymer underwent from a macromolecular-dissolved state to a supramolecular-aggregated state. To our surprise, an exciton-coupling induced multiple chiroptical inversion was observed upon the heating-assisted reassembly treatment, which was demonstrated to be driven by H- to J-aggregation transition. Furthermore, the odd–even effect was first established to regulate the supramolecular helical orientations (left- or right-handedness) in side-chain Azo-polymer assemblies.

Unexpected chirality transition and inversion at molecular, macromolecular and supramolecular levels were realized by dissolution–aggregation and the odd–even effect, which is helpful for the design of advanced chirality-controllable materials.