Supramolecular Assembly Process Research Articles

Carrier‐Free Disulfiram Based Nanomedicine for Enhanced Cancer Therapy

Numerous nanomedicines have been developed to improve the efficiency and safety of conventional anticancer drugs. However, the carrier materials and intricate nature of multifunctional design always hindered the clinical transformation of nanomedicines. Herein, a novel carrier‐free anticancer nanomedicine (CFDC) with tailored morphologies including nanodots, nanorod and nanosheet were prepared using the clinically approved anti‐alcoholism drug disulfiram (DSF) via supramolecular assembly process. Our study reveals that CFDC induces the production of reactive oxygen species and activates the downstream apoptosis‐related c‐Jun N‐terminal kinase (JNK) and p‐38 pathway. In addition, the CFDC effectively counteract the inhibitory effect of NF‐κB expression on ROS‐induced cellular cytotoxicity, ultimately resulting in enhanced cell apoptosis, which is not achievable by pure DSF and the simply mixing of DSF and Cu2+ (DSF + Cu). Notably, the CFDC exhibits 3.1‐, 3.0‐ folds increased on cancer cell DNA damage compared with the DSF, and DSF + Cu groups. In vivo experiments conducted on breast‐ or prostate‐bearing mice modals demonstrated that the CFDC exhibits a higher efficacy in suppressing the tumor growth. The remarkable drug delivery efficiency and better anticancer effect of CFDC nanodrug provide promising prospects for the clinical transformation of DSF based nanodrug in cancer therapy.

Cation Triggered Self-Assembly of α-Lactalbumin Nanotubes.

Metal ions play a dual role in biological systems. Although they actively participate in vital life processes, they may contribute to protein aggregation and misfolding and thus contribute to development of diseases and other pathologies. In nanofabrication, metal ions mediate the formation of nanostructures with diverse properties. Here, we investigated the self-assembly of α-lactalbumin into nanotubes induced by coordination with metal ions, screened among the series Mn2+, Co2+, Ni2+, Zn2+, Cd2+, and Au3+. Our results revealed that the affinity of metal ions toward hydrolyzed α-lactalbumin peptides not only impacts the kinetics of nanotube formation but also influences their length and rigidity. These findings expand our understanding of supramolecular assembly processes in protein-based materials and pave the way for designing novel materials such as metallogels in biochip and biosensor applications.

Spontaneous Multi-scale Supramolecular Assembly Driven by Noncovalent Interactions Coupled with the Continuous Marangoni Effect.

Reported herein is the multi-scale supramolecular assembly (MSSA) process along with redox reactions driven by supramolecular interactions coupled with the spontaneous Marangoni effect in ionic liquid (IL)-based extraction systems. The black powder, the single sphere with a black exterior, and the single colorless sphere were formed step by step at the interface when an aqueous solution of KMnO4 was mixed with the IL phase 1-(2-hydroxyethyl)-3-methylimidazolium bis(trifluoromethylsulfonyl) imide (C2OHmimNTf2) bearing octyl(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide (CMPO). The mechanism of the whole process was studied systematically. The phenomena were related closely to the change in the valence state of Mn. The MnO4- ion could be reduced quickly to δ-MnO2 and further to Mn2+ slowly by the hydroxyl-functionalized IL C2OHmimNTf2. Based on Mn2+, Mn(CMPO)32+, elementary building blocks (EBBs), and [EBB]n clusters were generated step by step. The [EBB]n clusters with the large enough size that were transferred to the interface, together with the remaining δ-MnO2, assembled into the single sphere with a black exterior, driven by supramolecular interactions coupled with the spontaneous Marangoni effect. When the remaining δ-MnO2 was used up, the mixed single sphere turned completely colorless. It was found that the reaction site of C2OHmim+ with Mn(VII) and Mn(IV) was distributed mainly at the side chain with a hydroxyl group. The MSSA process presents unique spontaneous phase changes. This work paves the way for the practical application of the MSSA-based separation method developed recently. The process also provides a convenient way to observe in situ and characterize directly the continuous Marangoni effect.

Revealing Pathway Complexity and Helical Inversion in Supramolecular Assemblies Through Solvent-Induced Radical Disparities.

New insights are raised to interpret pathway complexity in the supramolecular assembly of chiral triarylamine tris-amide (TATA) monomer. In cosolvent systems, the monomer undergoes entirely different assembly processes depending on the chemical feature of the two solvents. Specifically, 1,2-dichloroethane (DCE) and methylcyclohexane (MCH) cosolvent trigger the cooperative growth of monomers with M helical arrangement, and hierarchical thin nanobelts are further formed. But in DCE and hexane (HE) combination, a different pathway occurs where monomers go through isodesmic growth to generate twisted nanofibers with P helical arrangement. Moreover, the two distinct assemblies exhibit opposite excited-state chirality. The driving force for both assemblies is the formation of intermolecular hydrogen bonds between amide moieties. However, the mechanistic investigation indicates that radical and neutral triarylamine species go through distinct assembly phases by changing solvent structures. The neutralization of radicals in MCH plays a critical role in pathway complexity, which significantly impacts the overall supramolecular assembly process, giving rise to inversed supramolecular helicity and distinct morphologies. This differentiation in pathways affected by radicals provides a new approach to manipulate chiral supramolecular assembly process by facile solvent-solute interactions.

Tailored Polypyrrole Nanofibers as Ion-to-Electron Transduction Membranes for Wearable K+ Sensors.

Conductive polymers are recognized as ideal candidates for the development of noninvasive and wearable sensors for real-time monitoring of potassium ions (K+ ) in sweat to ensure the health of life. However, the low ion-to-electron transduction efficiency and limited active surface area hamper the development of high-performance sensors for low-concentration K+ detection in the sweat. Herein, a wearable K+ sensor is developed by tailoring the nanostructure of polypyrrole (PPy), serving as an ion-to-electron transduction layer, for accurately and stably tracing the K+ fluctuation in human sweat. The PPy nanostructures can be tailored from nanospheres to nanofibers by controlling the supramolecular assembly process during PPy polymerization. Resultantly, the ion-to-electron transduction efficiency (17-fold increase in conductivity) and active surface area (1.3-fold enhancement) are significantly enhanced, accompanied by minimized water layer formation. The optimal PPy nanofibers-based K+ sensor achieved a high sensitivity of 62mVdecade-1 , good selectivity, and solid stability. After being integrated with a temperature sensor, the manufactured wearable sensor realized accurate monitoring of K+ fluctuation in the human sweat.

Recent progress in quantitative analysis of self‐assembled peptides

AbstractSelf‐assembled peptides have been among the important biomaterials due to its excellent biocompatibility and diverse functions. Over the past decades, substantial progress and breakthroughs have been made in designing self‐assembled peptides with multifaceted biomedical applications. The techniques for quantitative analysis, including imaging‐based quantitative techniques, chromatographic technique and computational approach (molecular dynamics simulation), are becoming powerful tools for exploring the structure, properties, biomedical applications, and even supramolecular assembly processes of self‐assembled peptides. However, a comprehensive review concerning these quantitative techniques remains scarce. In this review, recent progress in techniques for quantitative investigation of biostability, cellular uptake, biodistribution, self‐assembly behaviors of self‐assembled peptide etc., are summarized. Specific applications and roles of these techniques are highlighted in detail. Finally, challenges and outlook in this field are concluded. It is believed that this review will provide technical guidance for researchers in the field of peptide‐based materials and pharmaceuticals, and facilitate related research for newcomers in this field.

Construction of Oligorotaxanes with Hydrogen-Bonded Aramide Macrocycles through Threaded Host-Guest Complexation.

The development of efficient and selective organic synthetic approaches for complex molecules has garnered significant attention due to the need for precise control over molecular structures and functions. Rotaxanes, a type of mechanically interlocked molecules (MIMs), have shown promising applications in various fields including sensing, catalysis, and material science. However, the highly selective synthesis of oligo[n]rotaxanes (mostly n≥3) through controlling host-guest complexation and supramolecular threading assembly process still remains an ongoing challenge. In particular, the utilization of two-dimensional (2D) macrocycles with structural shape-persistency for the synthesis of oligo[n]rotaxanes is rare. In this concept, research on cooperatively threaded host-guest complexation with hydrogen-bonded (H-bonded) aramide macrocycles and selective synthetic protocols of oligo[n]rotaxanes has been summarized. The high efficiency and selectivity in synthesis are ascribed to the synergistic interplay of multiple non-covalent bonding interactions such as hydrogen bonding and intermolecular π-π stacking of macrocycles within the unique supramolecular structure of threaded host-guest complexes. This review focuses on the latest progress in the concepts, synthesis, and properties of H-bonded aramide macrocycle-based oligorotaxanes, and presents an in-depth outlook on challenges in this emerging field.

Automated Structural Activity Screening of β‐Diketonate Assemblies with High‐Throughput Ion Mobility‐Mass Spectrometry

AbstractEmbracing complexity in design, metallo‐supramolecular self‐assembly presents an opportunity for fabricating materials of economic significance. The array of accessible supramolecules is alluring, along with favourable energy requirements. Implementation is hampered by an inability to efficiently characterise complex mixtures. The stoichiometry, size, shape, guest binding properties and reactivity of individual components and combinations thereof are inherently challenging to resolve. A large combinatorial library of four transition metals (Fe, Cu, Ni and Zn), and six β‐diketonate ligands at different molar ratios and pH was robotically prepared and directly analysed over multiple timepoints with electrospray ionisation travelling wave ion mobility‐mass spectrometry. The dataset was parsed for self‐assembling activity without first attempting to structurally assign individual species. Self‐assembling systems were readily categorised without manual data‐handling, allowing efficient screening of self‐assembly activity. This workflow clarifies solution phase supramolecular assembly processes without manual, bottom‐up processing. The complex behaviour of the self‐assembling systems was reduced to simpler qualities, which could be automatically processed.

Automated Structural Activity Screening of β-Diketonate Assemblies with High-Throughput Ion Mobility-Mass Spectrometry.

Embracing complexity in design, metallo-supramolecular self-assembly presents an opportunity for fabricating materials of economic significance. The array of accessible supramolecules is alluring, along with favourable energy requirements. Implementation is hampered by an inability to efficiently characterise complex mixtures. The stoichiometry, size, shape, guest binding properties and reactivity of individual components and combinations thereof are inherently challenging to resolve. A large combinatorial library of four transition metals (Fe, Cu, Ni and Zn), and six β-diketonate ligands at different molar ratios and pH was robotically prepared and directly analysed over multiple timepoints with electrospray ionisation travelling wave ion mobility-mass spectrometry. The dataset was parsed for self-assembling activity without first attempting to structurally assign individual species. Self-assembling systems were readily categorised without manual data-handling, allowing efficient screening of self-assembly activity. This workflow clarifies solution phase supramolecular assembly processes without manual, bottom-up processing. The complex behaviour of the self-assembling systems was reduced to simpler qualities, which could be automatically processed.

Spatiotemporal Studies of Soluble Inorganic Nanostructures with X-rays and Neutrons.

This Review addresses the use of X-ray and neutron scattering as well as X-ray absorption to describe how inorganic nanostructured materials assemble, evolve, and function in solution. We first provide an overview of techniques and instrumentation (both large user facilities and benchtop). We review recent studies of soluble inorganic nanostructure assembly, covering the disciplines of materials synthesis, processes in nature, nuclear materials, and the widely applicable fundamental processes of hydrophobic interactions and ion pairing. Reviewed studies cover size regimes and length scales ranging from sub-Ångström (coordination chemistry and ion pairing) to several nanometers (molecular clusters, i.e. polyoxometalates, polyoxocations, and metal-organic polyhedra), to the mesoscale (supramolecular assembly processes). Reviewed studies predominantly exploit 1) SAXS/WAXS/SANS (small- and wide-angle X-ray or neutron scattering), 2) PDF (pair-distribution function analysis of X-ray total scattering), and 3) XANES and EXAFS (X-ray absorption near-edge structure and extended X-ray absorption fine structure, respectively). While the scattering techniques provide structural information, X-ray absorption yields the oxidation state in addition to the local coordination. Our goal for this Review is to provide information and inspiration for the inorganic/materials science communities that may benefit from elucidating the role of solution speciation in natural and synthetic processes.

Spatiotemporal Studies of Soluble Inorganic Nanostructures with X‐rays and Neutrons

AbstractThis Review addresses the use of X‐ray and neutron scattering as well as X‐ray absorption to describe how inorganic nanostructured materials assemble, evolve, and function in solution. We first provide an overview of techniques and instrumentation (both large user facilities and benchtop). We review recent studies of soluble inorganic nanostructure assembly, covering the disciplines of materials synthesis, processes in nature, nuclear materials, and the widely applicable fundamental processes of hydrophobic interactions and ion pairing. Reviewed studies cover size regimes and length scales ranging from sub‐Ångström (coordination chemistry and ion pairing) to several nanometers (molecular clusters, i.e. polyoxometalates, polyoxocations, and metal‐organic polyhedra), to the mesoscale (supramolecular assembly processes). Reviewed studies predominantly exploit 1) SAXS/WAXS/SANS (small‐ and wide‐angle X‐ray or neutron scattering), 2) PDF (pair‐distribution function analysis of X‐ray total scattering), and 3) XANES and EXAFS (X‐ray absorption near‐edge structure and extended X‐ray absorption fine structure, respectively). While the scattering techniques provide structural information, X‐ray absorption yields the oxidation state in addition to the local coordination. Our goal for this Review is to provide information and inspiration for the inorganic/materials science communities that may benefit from elucidating the role of solution speciation in natural and synthetic processes.

Controlled, supramolecular polymer formulation to engineer hydrogels with tunable mechanical and dynamic properties

AbstractNature uses combined covalent (chemical bonds) and non‐covalent (physical bonds) synthesis in a highly, controlled multi‐step fashion to create functional materials with different mechanical and dynamic properties out of similar building blocks. Surprisingly, this control in fully synthetic systems remains elusive, even though the effects of formulation pathways on the assembly processes have been emphasized—highlighting the importance of and relationship between energy landscapes and function in synthetic systems. Here, we control multiple, coherent supramolecular assembly processes (fiber formation and crosslinking) to formulate hydrogels with tunable mechanical and dynamic properties. Hydrogels are prepared via two different formulation methods using similar building blocks (monofunctional and bifunctional supramolecular monomers), including (1) the mixing of the supramolecular monomers under basic conditions (Fbasic) and (2) the mixing of the supramolecular monomers under neutral conditions (Fneutral). In Fbasic, network formation is induced via simultaneous fiber formation and crosslinking, yielding homogeneously mixed networks which are dense, stiff (~10 kPa) and robust. In Fneutral, network formation is induced through sequential fiber formation and crosslinking, yielding heterogenous, soft (~2 kPa) and dynamic networks. With these results, we advance towards the controlled, multistep, non‐covalent synthesis to create larger hierarchical, functional structures, similar to nature.

Pathway Control of π‐Conjugated Supramolecular Polymers by Incorporating Donor‐Acceptor Functionality

AbstractControlling the nanoscale orientation of π‐conjugated systems remains challenging due to the complexity of multiple energy landscapes involved in the supramolecular assembly process. In this study, we have developed an effective strategy for programming the pathways of π‐conjugated supramolecular polymers, by incorporating both electron‐rich methoxy‐ or methanthiol‐benzene as donor unit and electron‐poor cyano‐vinylenes as acceptor units on the monomeric structure. It leads to the formation of parallel‐stacked supramolecular polymers as the metastable species through homomeric donor/acceptor packing, which convert to slip‐stacked supramolecular polymers as the thermodynamically stable species facilitated by heteromeric donor‐acceptor packing. By further investigating the external seed‐induced kinetic‐to‐thermodynamic transformation behaviors, our findings suggest that the donor‐acceptor functionality on the seed structure is crucial for accelerating pathway conversion. This is achieved by eliminating the initial lag phase in the supramolecular polymerization process. Overall, this study provides valuable insights into designing molecular structures that control aggregation pathways of π‐conjugated nanostructures.

Pathway Control of π-Conjugated Supramolecular Polymers by Incorporating Donor-Acceptor Functionality.

Controlling the nanoscale orientation of π-conjugated systems remains challenging due to the complexity of multiple energy landscapes involved in the supramolecular assembly process. In this study, we have developed an effective strategy for programming the pathways of π-conjugated supramolecular polymers, by incorporating both electron-rich methoxy- or methanthiol-benzene as donor unit and electron-poor cyano-vinylenes as acceptor units on the monomeric structure. It leads to the formation of parallel-stacked supramolecular polymers as the metastable species through homomeric donor/acceptor packing, which convert to slip-stacked supramolecular polymers as the thermodynamically stable species facilitated by heteromeric donor-acceptor packing. By further investigating the external seed-induced kinetic-to-thermodynamic transformation behaviors, our findings suggest that the donor-acceptor functionality on the seed structure is crucial for accelerating pathway conversion. This is achieved by eliminating the initial lag phase in the supramolecular polymerization process. Overall, this study provides valuable insights into designing molecular structures that control aggregation pathways of π-conjugated nanostructures.

Highly Synergistic Properties of Multicomponent Hydrogels Thanks to Cooperative Nucleopeptide Assemblies

Supramolecular materials have drawn much attention in the past years, particularly because of their great versatility in terms of structures, organization, and types of nano-objects they can form. Among them, amino acid and peptide derivatives are biomolecules extensively used thanks to their inherent properties and applicability for biological and health applications. Their exceptional abilities to self-assemble have been harnessed to create a myriad of objects and materials, including hydrogels. However, the use of one and only one molecule (i.e., monocomponent) is the widely reported approach which is of great interest in terms of simplicity of use, but it has numerous limitations in terms of properties. To tackle these issues, the multicomponent approach is a promising strategy, even if challenging, for designing low-molecular-weight molecules able to interact with each other to create new assemblies and new properties not achievable with a single compound. In this context, we report herein on the design, synthesis, and multiscale analysis of an original series of nucleopeptides, i.e., comprising both peptide and DNA-nucleobase moieties linked covalently. Thanks to their dual nature, these nucleopeptides are able to co-assemble when complementary nucleobase moieties interact intermolecularly via hydrogen bonding and π-stacking interactions, leading to impressive synergistic effects, which result in mechanical properties improved by more than 270,000% (with stiffness up to >700 kPa) and self-assembly abilities by ∼280%. To decipher the structure/property relationships, a comprehensive multiscale analysis approach (including rheology, fluorescence, cryo-scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, circular dichroism, nuclear magnetic resonance, and high-resolution magic angle spinning) has been carried out to understand the impact of nucleobases on the supramolecular assembly process and the subsequent formation of nanoobjects, three-dimensional architectures of the hydrogel scaffold, and the resulting physicochemical and mechanical properties of these highly synergistic nucleopeptide assemblies.

Carbodiimide‐Fueled Assembly of π‐Conjugated Peptides Regulated byElectrostatic Interactions

AbstractThe front cover artwork is provided by Herdeline Ardoña and co‐workers at UC Irvine and BioPACIFIC MIP. The image illustrates a workflow for supramolecular assembly and disassembly processes accessed through a carbodiimide‐fueled approach that instructs the self‐assembly and hydrolysis‐induced disassembly of peptides bearing optoelectronically active units. Read the full text of the Research Article at 10.1002/syst.202300003.

Frontispiece: Induced CPL‐Active Materials Based on Chiral Supramolecular Co‐Assemblies

Circularly polarized luminescence (CPL) has attracted much interest due to its potential applications on chiral photonic techniques and optoelectronic materials science. Chiral supramolecular assembly processes can be accompanied by chirality transfer and induction mechanism, which can promote the amplification effect on the induced CPL of achiral dyes. More information can be found in the Review article by W. Zheng, Y. Cheng and co-workers. (DOI: 10.1002/chem.202204039).

Induced CPL-Active Materials Based on Chiral Supramolecular Co-Assemblies.

Circularly polarized luminescence (CPL) has attracted much interest due to its potential applications on chiral photonic techniques and optoelectronic materials science. As known, dissymmetry factor (gem ) of CPL is one essential factor for evaluating the features of CPL-active materials. Much attention has focused on how to increase the gem value, which is one of the most important issues for CPL practical applications. Recently, more and more works have demonstrated that chiral supramolecular could provide the significant strategy to improve the gem value through the orderly helical superstructure of chiral building blocks. Normally, this kind of chiral supramolecular assembly process can be accompanied by chirality transfer and induction mechanism, which can promote the amplification effect on the induced CPL of achiral dyes. In this review, we fully summarized recent advances on the induced CPL-active materials of chiral supramolecular co-assemblies, their applications in circularly polarized organic light-emitting diodes (CP-OLEDs) and current challenges.

Visualization of supramolecular assembly by aggregation‐induced emission

AbstractSupramolecular architectures are constructed by the self‐assembly of small building blocks via the use of metal‐ligand coordination, π–π stacking interactions, hydrogen bonding, host‐guest interactions, and other noncovalent driving forces, which confer unique dynamic reversibility and stimulus responsiveness to the supramolecular materials and also lead to the demand of expensive and complex equipment for the characterization of supramolecular assembly processes. Fortunately, the self‐assembly processes bring the monomeric chromophores together, offering possibilities to establish ties between the supramolecular assembly and aggregation‐induced emission (AIE) techniques. Compared to conventional luminescent molecules, AIE luminogens (AIEgens) exhibit significant fluorescence enhancement upon the restriction of molecular motions, thus displaying the advantages of signal amplification and low background noises. Given the above, the real‐time, sensitive, and in situ visualization of the formation of self‐assemblies and their stimuli responsiveness based on AIE becomes accessible. Here, we review recent works that encompass the visualization of supramolecular assembly‐related behaviors by means of AIE characteristics of chromophores. The organization of this review will be by different types of supramolecular architectures, including metallacycles/cages, micelles/vesicles, supramolecular polymers, and supramolecular gels. An overview of future opportunities and challenges for the real‐time monitoring of supramolecular assembly by AIE is also provided.

Non-specificity as the sticky problem in therapeutic antibody development.

Antibodies are highly potent therapeutic scaffolds with more than a hundreddifferent products approved on the market. Successful development of antibody-based drugs requires a trade-off between high target specificity and target binding affinity. In order to better understand this problem, we here review non-specific interactions and explore their fundamental physicochemical origins. We discuss the role of surface patches - clusters of surface-exposed amino acid residues with similar physicochemical properties - as inducers of non-specific interactions. These patches collectively drive interactions including dipole-dipole, π-stacking and hydrophobic interactions to complementary moieties. We elucidate links between these supramolecular assembly processes and macroscopic development issues, such as decreased physical stability and poor in vivo half-life. Finally, we highlight challenges and opportunities for optimizing protein binding specificity and minimizing non-specificity for future generations of therapeutics.