Supramolecular Co-assembly Research Articles

A directed co-assembly of herbal small molecules into carrier-free nanodrugs for enhanced synergistic antitumor efficacy.

Carrier-free nanomedicines without structural modification are attractive for the development of natural small molecules (NSMs) and biomedical applications. Moreover, the combination of NSMs is expected to obtain nanomedicines with high efficacy and low side effects due to their inherent pharmacological activities and health benefits. However, poor water solubility and low bioavailability of NSMs limit their wider biomedical and clinical applications. In this study, we revealed the co-assembly properties of pentacyclic triterpenoids and constructed a series of carrier-free nanodrugs, which are co-assembled nanoparticles (NPs) formed by the combination of two NSMs via a supramolecular assembly strategy. Experimental work and simulation studies were combined to reveal the co-assembly mechanism of non-covalent interactions between NSMs. Not only do co-assembled NPs have rapid cellular uptake ability and passive targeting tumor ability based on the EPR effect, but also their constituent units could arrest the cell cycle at different stages of tumor cells and induce apoptosis, showing synergistic anti-tumor effects (CI < 0.7). Compared with self-assembled NPs and positive control, co-assembled NPs show the strongest therapeutic effect in vivo. Importantly, the co-assembled NPs highlight the unique advantages of NSMs in terms of biosafety and health benefits, and systemic toxicity and histological examination confirm that co-assembled NPs have reliable biosafety, and no side effects and nano toxicity risks were observed.

Co-Assembly between Fmoc Diphenylalanine and Diphenylalanine within a 3D Fibrous Viscous Network Confers Atypical Curvature and Branching.

Supramolecular polymer co-assembly is a useful approach to modulate peptide nanostructures. However, the co-assembly scenario where one of the peptide building blocks simultaneously forms a hydrogel is yet to be studied. Herein, we investigate the co-assembly formation of diphenylalanine (FF), and Fmoc-diphenylalanine (FmocFF) within the 3D network of FmocFF hydrogel. The overlapping peptide sequence between the two building blocks leads to their co-assembly within the gel state modulating the nature of the FF crystals. We observe the formation of branched microcrystalline aggregates with an atypical curvature, in contrast to the FF assemblies obtained from aqueous solution. Optical microscopy reveal the sigmoidal kinetic growth profile of these aggregates. Microfluidics and ToF-SIMS experiments exhibit the presence of co-assembled structures of FF and FmocFF in the crystalline aggregates. Molecular dynamics simulation was used to decipher the mechanism of co-assembly formation.

Impact of Molecular Size and Shape on the Supramolecular Co-Assembly of Chiral Tricarboxamides: A Comparative Study.

A comparative investigation of the chiral amplification features of a series of three families of C3 -symmetric tricarboxamides, 1,3,5-triphenylbenzenetricarboxamides (TPBAs), benzenetricarboxamides (BTAs) and oligo(phenylene ethynylene) tricarboxamides (OPE-TAs), is here reported. As previously observed for BTAs and OPE-TAs, a similar dichroic response is obtained for TPBAs decorated with one, two or three chiral side chains bearing stereogenic centers, thus confirming the efficient transfer of point chirality to the supramolecular helical aggregates. Unlike BTAs and OPE-TAs, the chiral amplification ability of TPBAs in majority rules experiments shows a negligible dependence on the number of chiral centers per monomeric unit, and stands the largest among the series of tricarboxamides. Detailed experimental and theoretical studies demonstrate that the rotation angle between the TPBA units in the helical stack is intermediate to that observed for BTAs and OPE-TAs. This feature strongly conditions the steric interactions between vicinal molecules in the stack and the final chiral amplification outcome. Furthermore, theoretical calculations show that achiral side chains favor the interdigitation of the helical aggregates and thereby the formation of bundle superstructures.

Bioactive Natural Small Molecule-Tuned Coassembly of Photosensitive Drugs for Highly Efficient Synergistic and Enhanced Type I Photochemotherapy.

Self-assembling natural small molecules (NSMs) with favorable anticancer activity are of increasing interest as novel drug delivery platforms without structural modification for biomedical applications. However, a lack of knowledge and practicability of NSMs as drug carriers limited their current biomedical application. Here, via a green and facile supramolecular coassembly strategy, we report and develop a series of carrier-free terpenoid natural small molecule-mediated coassembled photosensitive drugs for enhanced and synergistic chemo/photodynamic therapy. After screening 17 terpenoid NSMs, we identified 11 compounds that could form coassembled NSMs-Ce6 NPs with regulatable drug sizes. Analysis of the representative betulonic acid (BC)-mediated nano-coassemblies (BC-Ce6 NPs) reveals the high efficiency of the coassembly strategy and highlights the tremendous potential of NSMs as novel drug delivery platforms. Through molecular dynamics simulation and theoretical calculations, we elucidate the mystery of the coassembly process, indicating that the linear coplanar arrangement of BC dimeric units is primarily responsible for the formation of rod-like or spherical morphology. Meanwhile, we demonstrated that the reduced energy gap between the singlet and triplet excited states (ΔEST) facilitates efficient reactive oxygen species generation by promoting ·OH generation via a type I photoreaction mechanism. The assembled nanodrugs exhibit multiple favorable therapeutic features, ensuring a remarkably enhanced, synergistic, and secure combinatorial anticancer efficacy of 93.6% with highly efficient tumor ablation. This work not only expands the possibility of natural biodegradable materials for wide biological applications but also provides a new perspective for the construction of NSM-mediated nano-coassemblies for precision therapy.

Ultralong-Circulating and Self-Targeting "Watson-Crick A = T"-Inspired Supramolecular Nanotheranostics for NIR-II Imaging-Guided Photochemotherapy.

A carrier-free theranostic nanodrug directly coassembled using a NIR probe and a chemotherapeutic drug is a promising alternative for cancer theranostics. Nevertheless, this nanodrug still faces the limitations of short blood circulation and inefficient tumor accumulation/tumoral cellular uptake in vivo. Meanwhile, most exogenous targeting ligands and poly(ethylene glycol) have no therapeutic effect. Herein, we designed an ultralong-circulating and self-targeting nanodrug by an ordered supramolecular coassembly of indocyanine green (ICG), methotrexate (MTX, chemotherapeutic drug and cancer-cell-specific ligand), and clofarabine (CA). Notably, CA, as a surfactant-like chemotherapeutic drug, was introduced into the initial ICG-MTX coassembly by "Watson-Crick A = T-inspired" hydrogen-bond-driven sequential assembly with MTX. This carrier-free theranostic nanodrug with exceptionally high drug payload (100 wt %) not only showed superior serum stabilities but also displayed ultralong blood circulation (>7 days), enabling efficient accumulation at tumor sites. Moreover, our nanodrugs could be self-recognized by cancer cells and release the drugs on demand through lysosomal acidity and external laser stimulus. Under NIR-II imaging guidance, high-efficiency tumor ablation via synergistic photothermal-chemotherapy could be achieved in one treatment cycle while preventing the tumor recurrence. Our ultralong-circulating and self-recognizing carrier-free theranostic nanodrug based on the "drug-delivering-drug" strategy might have the potential for clinical theranostic application.

Interfacial Self-Assembly to Spatially Organize Graphene Oxide Into Hierarchical and Bioactive Structures

Multicomponent self-assembly holds great promise for the generation of complex and functional biomaterials with hierarchical microstructure. Here, we describe the use of supramolecular co-assembly between an elastin-like recombinamer (ELR5) and a peptide amphiphile (PA) to organise graphene oxide (GO) flakes into bioactive structures across multiple scales. The process takes advantage of a reaction – diffusion mechanism to enable the incorporation and spatial organization of GO within multiple ELR5/PA layers. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), and ImageJ software were used to demonstrate the hierarchical organisation of GO flakes within the ELR5/PA layers and the distribution profiles of GO throughout the ELR5/PA membranes. Furthermore,atomic force microscopy (AFM) revealed improved Young’s moduli of the ELR5/PA/GOmembranes compared to the ELR5/PA membranes. Lastly, we investigated biocompatibility of the ELR5/PA/GO membrane via various cell culture methods.

Supramolecular Co-assembly of the Ti8L12 Cube with [Ti(DMF)6] Species and Ti12-Oxo Cluster.

Titanium-based coordination cages are fascinating in the field of supramolecular and photophysical chemistry. Herein, we address the unprecedented supramolecular co-assembly arrangement of a cubic Ti8L12 cage with [Ti(DMF)6] species and Ti12-oxo cluster, contributing to the cocrystals of {Ti8L12 + Ti(DMF)6} (PTC-116) and {Ti8L12 + Ti12-oxo} (PTC-117). The ESI-MS and 1H NMR measurements reveal their stability in solution. The photophysical properties of these supramolecular complexes in solution, including light absorption and photoluminescent behaviors, were further investigated.

Coassembly-Induced Transformation of Dipeptide Amyloid-Like Structures into Stimuli-Responsive Supramolecular Materials.

Conformational transition of proteins and peptides into highly stable, β-sheet-rich structures is observed in many amyloid-associated neurodegenerative disorders, yet the precise mechanism of amyloid formation at the molecular level remains poorly understood due to the complex molecular structures. Short peptides provide simplified models for studying the molecular basis of the assembly mechanism that governs β-sheet fibrillation processes underlying the formation and inhibition of amyloid-like structures. Herein, we report a supramolecular coassembly strategy for the inhibition and transformation of stable β-sheet-rich amyloid-derived dipeptide self-assemblies into adaptable secondary structural fibrillar assemblies by mixing with bipyridine derivatives. The interplay between the type and mixing ratio of bipyridine derivatives allowed the variable coassembly process with stimuli-responsive functional properties, studied by various experimental characterizations and computational methods. Furthermore, the resulting coassemblies showed functional redox- and photoresponsive properties, making them promising candidates for controllable drug release and fluorescent imprint. This work presents a coassembly strategy not only to explore the mechanism of amyloid-like structure formation and inhibition at the molecular level but also to manipulate amyloid-like structures into responsive supramolecular coassemblies for material science and biotechnology applications.

Supramolecular Assemblies of Heterogeneous Mesoporous Silica Nanoparticles to Co-deliver Antimicrobial Peptides and Antibiotics for Synergistic Eradication of Pathogenic Biofilms.

Pathogenic biofilms protected by extracellular polymeric substances frequently compromise the efficiency of antibacterial drugs and severely threaten human health. In this study, we designed a multi-stimuli-responsive magnetic supramolecular nanoplatform to co-deliver large and low molecular weight drugs for synergistic eradication of pathogenic biofilms. This co-delivery platform was composed of mesoporous silica nanoparticles (MSNs) with large pores (MSNLP) capped by β-cyclodextrin (β-CD)-modified polyethylenimine (PEICD) and adamantane (ADA)-decorated MSNs containing a magnetic core (MagNP@MSNA) capped by cucurbit[6]uril (CB[6]). The host MSNs (H, MSNLP@PEICD) and the guest MSNs (G, MagNP@MSNA-CB[6]) spontaneously form coassemblies (H+G), based on the host-guest interactions between β-CD and ADA. Under the stimulus of pathogen cells together with heating by an alternating magnetic field (AMF), the supramolecular coassemblies released both the large molecular weight antimicrobial peptide melittin (MEL) and the low molecular weight antibiotic ofloxacin (OFL) with high efficiency. As compared to free drugs (MEL and OFL) or unattached MSNs (H or G), the drug-loading H+G coassemblies (H-MEL+G-OFL) exhibited much higher capacity for biofilm eradication, thoroughly removing biofilm biomass and killing the pathogenic cells, and displaying no obvious toxicity to mammalian cells. This strong antibiofilm capacity was severely decreased when the host and guest components were prevented from coassembling but administered simultaneously, revealing the critical role of the supramolecular assembly in biofilm removal. Moreover, an in vivo implantation model showed that the coassemblies eradicated the pathogenic biofilms from the implants, preventing host tissue damage and inflammation. Therefore, the co-delivering and multi-stimuli-responsive nanocarriers could overcome the anti-infection difficulties during treatment of infections because of protective biofilms.

An Efficient Near-Infrared Emissive Artificial Supramolecular Light-Harvesting System for Imaging in the Golgi Apparatus.

Light-harvesting systems are an important way for capturing, transferring and utilizing light energy. It remains a key challenge to develop highly efficient artificial light-harvesting systems. Herein, we report a supramolecular co-assembly based on lower-rim dodecyl-modified sulfonatocalix[4]arene (SC4AD) and naphthyl-1,8-diphenyl pyridinium derivative (NPS) as a light-harvesting platform. NPS as a donor shows significant aggregation induced emission enhancement (AIEE) after assembling with SC4AD. Upon introduction of Nile blue (NiB) as an acceptor into the NPS-SC4AD co-assembly, the light-harvesting system becomes near-infrared (NIR) emissive (675 nm). Importantly, the NIR emitting NPS-SC4AD-NiB system exhibits an ultrahigh antenna effect (33.1) at a high donor/acceptor ratio (250:1). By co-staining PC-3 cells with a Golgi staining reagent, NBD C6 -ceramide, NIR imaging in the Golgi apparatus has been demonstrated using these NIR emissive nanoparticles.

InVivo Bioengineering of Fluorescent Conductive Protein-Dye Microfibers.

SummaryEngineering protein-based biomaterials is extremely challenging in bioelectronics, medicine, and materials science, as mechanical, electrical, and optical properties need to be merged to biocompatibility and resistance to biodegradation. An effective strategy is the engineering of physiological processes in situ, by addition of new properties to endogenous components. Here we show that a green fluorescent semiconducting thiophene dye, DTTO, promotes, in vivo, the biogenesis of fluorescent conductive protein microfibers via metabolic pathways. By challenging the simple freshwater polyp Hydra vulgaris with DTTO, we demonstrate the stable incorporation of the dye into supramolecular protein-dye co-assembled microfibers without signs of toxicity. An integrated multilevel analysis including morphological, optical, spectroscopical, and electrical characterization shows electrical conductivity of biofibers, opening the door to new opportunities for augmenting electronic functionalities within living tissue, which may be exploited for the regulation of cell and animal physiology, or in pathological contexts to enhance bioelectrical signaling.

Fluorescent Imprintable Hydrogels via Organic/Inorganic Supramolecular Coassembly.

Photoresponsive hydrogels with on/off luminescence show a promising application potential in writable information recording and display materials. However, it still remains a tremendous challenge to fabricate such hydrogels on account of the intrinsic fluorescence quenching effect and the lack of suitable responsive groups. Herein, we present fluorescent imprintable hydrogels constructed via organic/inorganic supramolecular coassembly. A photoisomeric cyanostilbene conjugated cationic surfactant exhibited an aggregation-induced emission behavior upon clay (laponite) complexation, along with excellent thixotropism brought by laponite. Macrocyclic cucurbituril[7] and β-cyclodextrin rings capable of forming host-guest complexes with the surfactant were utilized to give ternary hybrid hydrogels with luminescence and photoresponsive properties. On the account of trans-cis photoisomerization of the cyanostilbene unit, the fluorescence of the multicomponent hydrogels could undergo rapid quenching within a short irradiation period under UV light and be recovered when subjected to an annealing process. According to these properties, the imprinted fluorescent patterns using the hybrid hydrogels were erasable and rewritable. Thus, this research successfully integrates host-guest complexation and supramolecular coassembly into the fabrication of fluorescent imprintable hydrogels.

Visible-to-UV photon upconversion in air-saturated water by multicomponent co-assembly

Visible-to-UV TTA-based photon upconversion in aerated water is achieved for the first time by utilizing oxygen blocking ability of dense multicomponent supramolecular co-assemblies.

Acceptor-induced cooperative supramolecular co-assembly with emissive charge-transfer for advanced supramolecular encryption.

A novel acceptor-induced cooperative supramolecular co-assembly based on a dendritic electron donor and 1,2,4,5-tetracyanobenzene acceptor has been successfully developed. The resulting co-assembly is capable of displaying emissive charge transfer properties and intriguing vapo-fluorochromic behaviors, which can be used for supramolecular encryption applications with reversible authentication.

Precursor-Mediated Synthesis of Shape-Controlled Colloidal CsPbBr3 Perovskite Nanocrystals and Their Nanofiber-Directed Self-Assembly

Shape control is often necessary to tune the optical and electronic properties of nanocrystals (NCs) and is mostly achieved through manipulation of surface ligands and processing conditions. Here we present a versatile synthesis of colloidal CsPbBr3 perovskite NCs of various shapes (nanorods, nanocubes, and nanoplatelets) from an inexpensive steroidal Cs precursor: cesium cholate (CsCh). Cesium cholate has several advantages over the most commonly used Cs precursor (cesium oleate or Cs2CO3 or CsOAc) such as low cost, nonhygroscopicity, and better reproducibility in the perovskite synthesis. Due to the solubility of this Cs precursor in polar solvents such as methanol, a miniscule polar environment is created during the nucleation and growth of the nanocrystals leading to the serendipitous formation of nanorods at 180 °C, whereas using a biphasic mixture of 1-octadecene and methanol, the morphology changes to nanocubes. By lowering the reaction temperature (90 °C), nanoplatelets with 8–9 monolayers thicknesses are formed. These colloidal NCs of a variety of shapes are strongly luminescent with a green emission having narrow emission line widths (16–17 nm) and high quantum yields (96% for nanocubes, 94% for nanoplatelets). Furthermore, hybrid materials of nanocubes and organogel of a dimeric bile acid-derived ester gelator are obtained through coassembly in which nanocubes arrange along nanofibers with stable, sharp, and bright green emission. This enables spatial ordering of nanocubes ranging from micrometer to centimeter scale in thin films, which is crucial for advanced optoelectronic applications. To date, there is no report in the literature on the anisotropic organization of perovskite CsPbBr3 nanocubes triggered by supramolecular coassembly involving organogel nanofibers.

Aqueous phase and amorphous state room temperature phosphorescence from a small aromatic carbonyl derivative

Harvesting triplet excitons via room temperature phosphorescence (RTP) in solution or amorphous state from purely organic chromophores is a formidable challenge. Supramolecular hybrid co-assembly between a brominated aromatic carbonyl derivative (BrPhS) and laponite clay (LP) particles is shown to result in remarkable triplet stabilization to result room temperature phosphorescence (RTP) in aqueous solution as well as in amorphous thin films. This remarkable feature is realized by means of highly organized, rigid molecular network of the dye molecules on the inorganic scaffold which reduces the vibrational dissipations as well as limits the oxygen diffusion to facilitate the triplet harvesting under ambient conditions. The water soluble phosphor, BrPhS is also shown to be an excellent triplet emitter in other amorphous polymer matrices like polyvinyl alcohol (PVA) and sodium polystyrene sulphonate (PSS) with phosphorescence quantum yield over 30% in air.

Crystallization of a Supramolecular Coassembly of an Atomically Precise Nanoparticle with a Crown Ether

We report the crystal structure of a supramolecular coassembly of a red luminescent silver cluster, [Ag29(BDT)12(TPP)4]3– (referred to as Ag29) (BDT, 1,3-benzene dithiol; TPP, triphenyl phosphine),...

Coassembly of Complementary Peptide Nucleic Acid into Crystalline Structures by Microfluidics

AbstractThe self‐assembly of simple units into well‐ordered supramolecular polymeric structures may give rise to a broad range of desirable attributes. In the field of bionanotechnology, there are two main classes commonly used as building blocks for self‐assembly—amino acids and nucleobases. While protein, peptide, and amino acid building blocks propose broad chemical versatility, the specific Watson–Crick base pairings of nucleic acids allow rational design and precise control over the assembly process. Specifically, artificially synthesized peptide nucleic acids (PNA), short DNA mimics that have an amide backbone, can present a unique set of properties while preserving the specific base pairing of the nucleic acids. The use of complementary building blocks allows the study of supramolecular polymer coassemblies. Here, the coassembly of two paired di‐PNA building blocks provides a new layer of control, as both building blocks are required for the spontaneous assembly to occur. Utilizing a microfluidic system, the growth of the well‐ordered structure can be regulated and monitored. The crystal structure of the formed assemblies display Watson–Crick base pairing with similar distances as those found in typical DNA double helices. Moreover, the crystals exhibit intriguing optical properties that may be implemented in various materials science and nanotechnological applications.

Stoichiometry-controlled secondary structure transition of amyloid-derived supramolecular dipeptide co-assemblies

Conformational transitions of secondary structures are a crucial factor in many protein misfolding diseases. However, the actual transition of folded proteins into β-sheet-rich structures is not fully understood. Inhibition of aggregate formation, mediated by the β-sheet conformation, and control of the secondary structural transition of proteins and peptides could potentially attenuate the development of amyloid-associated diseases. Here we describe a stoichiometry-controlled secondary structure transition of amyloid-derived dipeptide assemblies from a β-sheet to supramolecular helix conformation through co-assembly with a bipyridine derivative. The transition is mainly mediated by the intermolecular hydrogen bonds and π-π interactions between the two components, which induce the altered stacking and conformation of the co-assemblies, as confirmed by experimental results and computational simulations. This work not only exemplifies a feasible strategy to disrupt the β-sheet conformation, underlying amyloid-like fibril formation, but also provides a conceptual basis for the future utilization of the helical nanostructures in various biological applications.

Dual Engineering Interface-Driven Complementary Graphene Oxide-Protein Dimer Supramolecular Architecture Enables Nucleus Imaging and Therapy.

Seeking a versatile nanoplatform for multimodal nucleus imaging and therapy is a challenging task. General complementary bottom-up bionanotechnology for controlling a 3D supramolecular coassembly is proposed. The dual engineering interface proof-of-concept of the supramolecular architecture can be demonstrated via a genetically engineered protein dimer and plasmonically engineered graphene oxide (GO). Incorporation of anisotropic plasmonic nanoparticles as an intercalation layer among the GO 3D supramolecular architecture can provide covalent conjugation sites and simultaneously endow tunable optical properties of GO, ranging from the ultraviolet-to-near-infrared region. Interestingly, the precise design of a specific two-site mutation of the plasmid is favorable for giving an organized coassembly instead of random networks of GO, which contributes to giving continuous distinguishable enhanced Raman imaging for tracking cancer cells. Unexpectedly, penetration into the cell nucleus via the submicro 3D supramolecular coassembly exhibits an excellent nucleus therapeutic potential of cancer cells.