Supramolecular Vesicles Research Articles

PH-Responsive supramolecular vesicles for imaging-guided drug delivery: Harnessing aggregation-induced emission.

The water-soluble tribenzotriquinacene-based hexacarboxylic acid ammonium salt, TBTQ-C 6 , acts as the host component (H) forming host-guest complexes with tetraphenylethylene (TPE)-functionalized monotopic and tetratopic quaternary ammonium derivatives, G1 and G2, to yield supra-amphiphiles. These supra-amphiphiles self-assemble to form pH-responsive fluorescent vesicles, which have allowed us to capitalize on the aggregation-induced emission (AIE) effect for imaging-guided drug delivery systems. These systems exhibit efficient drug loading and pH-responsive delivery capabilities. Upon encapsulation of the anticancer drug doxorubicin (DOX), both the TPE and DOX chromophores undergo dual-fluorescence deactivation due to the energy transfer relay (ETR) effect. Under acidic conditions, the release of DOX interrupts the ETR effect, resulting in the fluorescence recovery of TPE fluorogens and DOX, allowing for real-time visual monitoring of the drug release process. Cytotoxicity experiments confirmed the low toxicity of the unloaded vectors to normal cells, while the DOX-loaded vectors were found to significantly enhance the anticancer activity of DOX against cancer cells in vitro. The AIE-featured supramolecular vesicles presented in this research hold great potential for imaging-guided drug delivery systems.

Liquid-Liquid Phase Separation Mediated Formation of Chiral 2D Crystalline Nanosheets of a Co-Assembled System.

The role of macromolecule-macromolecule and macromolecule-H2O interactions and the resulting perturbation of the H-bonded network of H2O in the liquid-liquid phase separation (LLPS) process of biopolymers are well-known. However, the potential of the hydrated state of supramolecular structures (non-covalent analogs of macromolecules) of synthetic molecules is not widely recognized for playing a similar role in the LLPS process. Herein, LLPS occurred during the co-assembly of hydrated supramolecular vesicles (bolaamphiphile, BA1) with a net positive charge (zeta potential, ζ = +60 ± 2mV) and a dianionic chiral molecule (disodium l-[+]-tartrate) is reported. As inferred from cryo-transmission electron microscopy (TEM), the LLPS-formed droplets serve as the nucleation precursors, dictating the structure and properties of the co-assembly. The co-assembled structure formed by LLPS effectively integrates the counter anion's asymmetry, resulting in the formation of ultrathin free-standing, chiral 2D crystalline sheets. The significance of the hydrated state of supramolecular structures in influencing LLPS is unraveled through studies extended to a less hydrated supramolecular structure of a comparable system (BA2). The role of LLPS in modulating the hydrophobic interaction in water paves the way for the creation of advanced functional materials in an aqueous environment.

The Intramolecular Charge Transfer Mechanism by Which Chiral Self-Assembled H8-BINOL Vesicles Enantioselectively Recognize Amino Alcohols.

The chiral H8-BINOL derivatives R-1 and R-2 were efficiently synthesized via a Suzuki coupling reaction, and they can be used as novel dialdehyde fluorescent probes for the enantioselective recognition of R/S-2-amino-1-phenylethanol. In addition, R-1 is much more effective than R-2. Scanning electron microscope images and X-ray analyses show that R-1 can form supramolecular vesicles through the self-assembly effect of the π-π force and strong hydrogen bonding. As determined via analysis, the fluorescence of the probe was significantly enhanced by mixing a small amount of S-2-amino-1-phenylethanol into R-1, with a redshift of 38 nm, whereas no significant fluorescence response was observed in R-2-amino-1-phenylethanol. The enantioselective identification of S-2-amino-1-phenylethanol by the probe R-1 was further investigated through nuclear magnetic titration and fluorescence kinetic experiments and DFT calculations. The results showed that this mechanism was not only a simple reactive probe but also realized object recognition through an ICT mechanism. As the intramolecular hydrogen bond activated the carbonyl group on the probe R-1, the carbonyl carbon atom became positively charged. As a strong nucleophile, the amino group of S-2-amino-1-phenylethanol first transferred the amino electrons to a carbonyl carbocation, resulting in a significantly enhanced fluorescence of the probe R-1 and a 38 nm redshift. Similarly, S-2-amino-1-phenylethanol alone caused severe damage to the self-assembled vesicle structure of the probe molecule itself due to its spatial structure, which made R-1 highly enantioselective towards it.

Supramolecular prodrug vesicles for selective antimicrobial therapy employing a chemo-photodynamic strategy

Supramolecular prodrug vesicles for selective antimicrobial therapy employing a chemo-photodynamic strategy

Designer pseudopeptides: autofluorescent polygonal tubes via Phe-zipper and triple helix.

Chemists are increasingly turning to biology for inspiration to develop novel and superior synthetic materials. Here, we present an innovative peptide design strategy for tubular assembly. In this simple design, a phenylene urea unit is introduced as an aglet at the N-terminus of the peptide. When α-amino isobutyric acid (Aib) is the first residue and phenylalanine (Phe) is the second residue from the phenylene urea entity, it induces an edge-to-face π-π interaction resulting in a turn conformation. The peptides with a unique reverse turn conformation associate to form polygonal peptide tubes via a Phe-zipper arrangement, as evidenced by microscopic and single crystal X-ray studies. Ultra-microscopic imaging revealed that the tubular assembly is hexagonal, square, and triangular in shape. This hierarchical assembly reveals the interplay between π-π interactions and hydrogen bonding. In another design, pseudopeptide 5, wherein a Phe-Phe (FF) unit is linked to phenylene urea, formed polygonal tubes via a triple helical arrangement. Interestingly, the extension of this design to the bis-urea core resulted in vesicular assembly. These supramolecular polygonal tubes and vesicles showed autofluorescence, which allowed confocal imaging. The observed fluorescence is an additional advantage for applications in biological and medical sciences.

Modeling the origin of cells

Protocells (dividing supramolecular vesicles harboring unlinked genetic replicators) are thought to have played an important role in the origin and early evolution of life. Under what scenario did such reproducers come into play? New work by Babajanyan et al. provides theoretical insight into the symbiosis between replicators and reproducing compartments.

Multifunctional Supramolecular Vesicles as Zn2+ -Triggered Microglial Modulator Alleviates Alzheimer's Disease.

Zn2+ -induced β-amyloid protein (Aβ) aggregation and microglia activation are the predominant contributors in Alzheimer's disease (AD). Regulating intracephalic excessive Zn2+ is a promising therapeutic strategy for AD treatment. However, only inhibition of Zn2+ is hardly to repair continuous damages caused by activated microglia. Herein, an intelligent resveratrol-loaded supramolecular vesicles (RES-loaded vesicles) with zinc ion chelation function and responsive release capability are constructed to alleviate Aβ fibrillation, oxidative stress, and microglial dysfunction. The resveratrol encapsulation efficiency and drug loading efficiency are calculated to be 49.67% and 7.87%, respectively. In vitro studies demonstrate that the RES-loaded vesicles can modulate Zn2+ -dependent Aβ aggregation. More importantly, the cargoes will be released in zinc environment and further reprograms microglia from proinflammatory M1 phenotype toward anti-inflammatory M2 phenotype, which prevents spontaneous neuroinflammation and alleviates cytotoxicity of cultured cells from 29% to 12%. With the stereotactic or intranasal administration, RES-loaded vesicles can overcome the blood brain barrier, alleviate neuronal apoptosis, neuroinflammation, and ultimately ameliorate cognitive impairment in two AD mouse models. This work provides a new sight for taking advantage of Zn2+ to treat CNS disorders.

P-sulfonatocalix[8]arene and chitosan based vesicle formation studies by spectroscopic and thermal methods

p-sulfonatocalix [8]arene and chitosan based supramolecular amphiphilic vesicles were formed by electrostatic interaction between anionic character of calixarene and cationic chitosan molecules. UV–visible, fluorescence, dynamic light scattering and thermogravimetric analysis were performed for the characterization of p-SCX8 with chitosan. Increase in absorption and enhancement of fluorescence emission intensity attributed to vesicle formation between both calixarene and chitosan in aqueous media. Results obtained from size distribution curve of dynamic light scattering experiment gives clear evidence for vesicle formation at pH 4.98. Positive zeta potential values obtained from dynamic light scattering experiment gives the evidence for vesicle formation. Thermogravimetric analysis gives quantitative results for purity and stability of the vesicles. From overall studies we can conclude that degree of deacetylation as well as pH 4.98 of the solutions and anionic nature of pSCX8 plays important role in electrostatic interaction of vesicle formation.

Supramolecular vesicle engineering by regulating the assembly of shape-persistent aromatic-hydrazone macrocycles

The size of supramolecular vesicles is manipulated by regulating the assembly of macrocycles with different mono- or bi-pyridinium salts.

Suprasomes Based on Host-Guest Molecular Recognition: An Excellent Alternative to Liposomes in Cancer Theranostics.

Liposomes and polymersomes, typical vesicular drug delivery systems (DDSs), have faced some limitations in cancer theranostics. Suprasomes, supramolecular vesicles assembled from amphiphiles linked by noncovalent interactions, show potential as new generation of vesicular DDSs. We construct suprasomes based on host-guest recognition, by which the desired functions can be integrated into carriers without tedious synthesis. Photothermally active host-guest complex is formed between a functional guest and pillar[5]arene, which further self-assembles into hollow suprasomes. A supramolecular nanomedicine is developed by encapsulating cisplatin in the suprasomes. The obtained cisplatin@Suprasomes achieve excellent anticancer efficacy and anti-metastasis combining chemotherapy and photothermal therapy, which ablate the tumors without relapse and metastasis. This work demonstrates the facile functionalization of suprasomes, holding promise as alternatives to liposomes and polymersomes.

Suprasomes Based on Host–Guest Molecular Recognition: An Excellent Alternative to Liposomes in Cancer Theranostics

AbstractLiposomes and polymersomes, typical vesicular drug delivery systems (DDSs), have faced some limitations in cancer theranostics. Suprasomes, supramolecular vesicles assembled from amphiphiles linked by noncovalent interactions, show potential as new generation of vesicular DDSs. We construct suprasomes based on host–guest recognition, by which the desired functions can be integrated into carriers without tedious synthesis. Photothermally active host–guest complex is formed between a functional guest and pillar[5]arene, which further self‐assembles into hollow suprasomes. A supramolecular nanomedicine is developed by encapsulating cisplatin in the suprasomes. The obtained cisplatin@Suprasomes achieve excellent anticancer efficacy and anti‐metastasis combining chemotherapy and photothermal therapy, which ablate the tumors without relapse and metastasis. This work demonstrates the facile functionalization of suprasomes, holding promise as alternatives to liposomes and polymersomes.

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery.

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host-guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.

Temporally Controlled Multienzyme Catalysis Using a Dissipative Supramolecular Nanozyme.

The development of superior functional enzyme mimics (nanozymes) is essential for practical applications, including point-of-care diagnostics, biotechnological applications, biofuels, and environmental remediation. Nanozymes with the ability to control their catalytic activity in response to external fuels offer functionally valuable platforms mimicking nonequilibrium systems in nature. Herein, we fabricated a supramolecular coordination bonding-based dynamic vesicle that exhibits multienzymatic activity. The supramolecular nanozyme shows effective laccase-like catalytic activity with a KM value better than the native enzyme and higher stability in harsh conditions. Besides, the nanostructure demonstrates an efficient peroxidase-like activity with NADH peroxidase-like properties. Generation of luminescence from luminol and oxidation of dopamine are efficiently catalyzed by the nanozyme with high sensitivity, which is useful for point-of-care detections. Notably, the active nanozyme exhibits dynamic laccase-mimetic activity in response to pH variation, which has never been explored before. While a neutral/high pH leads to the self-assembly, a low pH disintegrates the assembled nanostructures and consequently turns off the nanozyme activity. Altogether, the self-assembled Cu2+-based vesicular nanostructure presents a pH-fueled dissipative system demonstrating effective temporally controlled multienzymatic activity.

Anticancer pH-Responsive Supramolecular Vesicles Fabricated Using Water-Soluble Pillar[5]arene and Curcumin Derivative

A pH-responsive curcuminoid delivery system based on supramolecular vesicles was fabricated via a novel host–guest inclusion complex between water-soluble pillar[5]arene (WP5) and hydrophobic bisdemethoxycurcumin (BDMC). This WP5 and BDMC (WP5 ⊃ BDMC) inclusion complex was studied using 1H NMR, UV–vis, and fluorescence spectroscopy. This resulting inclusion complex could self-assemble into well-defined supramolecular vesicles by host–guest interactions and presented a significant pH-responsive behavior, which was investigated using dynamic laser scattering, transmission electron microscopy, and UV–vis spectroscopy. The suitable preservation time for WP5 ⊃ BDMC and the construction ratio between host/guest molecules were both of great significance for the aggregated morphology of supramolecular vesicles. Furthermore, the BDMC complexes showed good anticancer ability in vitro, as they could inhibit HepG2 cell proliferation and migration. Therefore, the curcuminoid vesicles could provide a promising platform for drug delivery or food packaging utilization.

Supramolecular engineering of cell membrane vesicles for cancer immunotherapy

The clinical translation of nanomedicines has been strongly hampered by the limitations of delivery vehicles, promoting scientists to search for novel nanocarriers. Although cell membrane-based delivery systems have attracted extensive attention, further functionalizations are urgently desired to augment their theranostic functions. We propose a cell-friendly supramolecular strategy to engineer cell membranes utilizing cyclodextrin-based host–guest molecular recognitions to fix the defects arising from chemical and genetic modifications. In this study, the supramolecular cell membrane vesicles (SCMVs) specifically accumulate in tumors, benefiting from tumor-homing capability and the enhanced permeability and retention effect. SCMVs co-delivering indocyanine green and an indoleamine 2,3-dioxygenase inhibitor effectively ablate tumors combining photodynamic therapy and immunotherapy. Driven by host–guest inclusion complexation, SCMVs successfully encapsulate resiquimod to repolarize tumor-associated macrophages into M1 phenotype, synergizing with immune checkpoint blockade therapy. This supramolecular engineering methodology based on noncovalent interactions presents a generalizable and cell-friendly tactic to develop living cell–originated nanomaterials for precise cancer therapy.

Supramolecular Assembly‐Induced Emission Enhancement Vesicles Regulated by Pincer‐Like Hosts Containing Pillar[5]arenes

AbstractSupramolecular assembly‐induced emission enhancement (SAIEE) systems have been proved to be a highly efficient approach for the fabrication of luminescent nanoparticles with uniform morphology. Herein, fluorescent supramolecular vesicles are constructed from tetraphenylethene‐based cyano‐alkane tetramer (TPE‐(CN)4) and pincer‐like hosts containing two pillar[5]arene units (B‐(TAP[5]A)2) through a synergistic effect of host–guest interactions and hydrophobic interactions. Notably, the emission intensity of supramolecular vesicles can be remarkably enhanced with quantum yield determined to be 37.69%, whereas that of TPE‐(CN)4 is only 18.93% in mixture solvent. Furthermore, the supramolecular vesicles can retard the photocyclization reaction of TPE‐(CN)4 under UV light and exhibit considerable emission intensity at high temperature. Enthused by the above results, artificial light‐harvesting systems with high antenna effect of 18.7 are facilely established by introducing cyano‐vinyl derivatives (CV‐CN) as donor, demonstrating the adjustable emission wavelength through Förster resonance energy transfer in the present SAIEE systems. Taking advantage of the tunable emission colors, fluorescent ink based on supramolecular vesicles is successfully prepared, setting the basis for potential application in security painting. As a proof‐of‐concept study, the pincer‐like host facilitates the optical performance of chromophores with aggregation‐induced emission feature, and unlocks more possibilities for the establishment of SAIEE systems in aqueous.

A Pd2L4 Metallacage‐Cored Supramolecular Amphiphile and Its Application in Dual‐Responsive Controllable Release†

Comprehensive SummaryThe construction of multi‐responsive supramolecular systems for drug delivery is a challenging task. In this work, a Pd2L4 metallacage 1·([BF4]−)4 with four pyrene units was first designed and synthesized through coordination‐driven self‐assembly. After the introduction of γ‐CD, a supramolecular amphiphile 1–γ‐CD was successfully constructed based on the host–guest molecular recognition between γ‐CD and the pyrene unit of 1·([BF4]−)4, which further self‐assembled into dual‐responsive supramolecular vesicles in aqueous solution. DOX·HCl was used as a model molecule to study the drug encapsulation and release behavior of the supramolecular vesicles. By adjusting the pH of the solution to acidic condition or adding a certain amount of α‐amylase, the vesicle structure was destroyed to achieve rapid and effective release of the drug molecules. This study provides an example for the rational design of efficient dual‐responsive supramolecular nanocarriers, which have potential application value in the field of controlled drug delivery.

Orthogonal Design of Supramolecular Prodrug Vesicles via Water-Soluble Pillar[5]arene and Betulinic Acid Derivative for Dual Chemotherapy

Supramolecular prodrug vesicles with efficient property for dual chemotherapy have been successfully constructed based on the orthogonal self-assembly between a water-soluble pillar[5]arene host (WP5) and a betulinic acid guest (BA-D) as well as doxorubicin (DOX). Under the acidic microenvironment of cancer cells, both the encapsulated anticancer drug DOX and prodrug BA-D can be effectively released from DOX-loaded WP5⊃BA-D prodrug vesicles for combinational chemotherapy. Furthermore, bioexperiments indicate that DOX-loaded prodrug vesicles can obviously enhance the anticancer efficiency based on the cooperative effect of DOX and BA-D, while remarkably reducing the systematic toxicity in tumor-mice, displaying great potential applications in combinational chemotherapy for cancer treatments.

Recognition and discrimination of citric acid isomers by luminescent nanointerface self‐assembled from amphiphilic Eu(III) complexes

Recognition and discrimination of citrate and its isomer, isocitrate, are important but challenging for monitoring the energy metabolism process in clinical conditions, since they have similar chemical and physical properties. In this work, we constructed a luminescent supramolecular vesicle with novel amphiphilic Eu3+ complex (EuL+). Highly selective detection and discrimination of citrate and isocitrate at micromolar analyte concentration were realized via cooperative interaction between luminescent vesicular interface and the isomers, representing the most sensitive sensing system for the isomers. Interestingly, EuL+ vesicles showed different degrees of enhancement in luminescence intensity in the presence of citrate (5.1-fold) or isocitrate (1.7-fold) due to their imparity in the coordination with EuL+. Moreover, EuL+ vesicles displayed high selectivity towards citrate even in the presence of other carboxylates and anions. Based on this, the as-prepared luminescent vesicles were successfully employed to track the conversion process between citrate and isocitrate.

Naphthalimide-Based Azo-Functionalized Supramolecular Vesicle in Hypoxia-Responsive Drug Delivery.

Supramolecular materials that respond to external triggers are being extensively utilized in developing spatiotemporal control in biomedical applications ranging from drug delivery to diagnostics. The present article describes the development of self-assembled vesicles in 1:9 (v/v), tetrahydrofuran (THF)-water by naphthalimide-based azo moiety containing amphiphile (NI-Azo) where azo moiety would act as the stimuli-responsive junction. The self-assembly of NI-Azo took place through H-type of aggregation. Microscopic and spectroscopic analyses confirmed the formation of supramolecular vesicles with a dimension of 200-250 nm. Azo (-N═N-) moiety is known to get reduced to amine derivatives in the presence of the azoreductase enzyme, which is overexpressed in the hypoxic microenvironment. The absorbance intensity of this characteristic azo (-N═N-) moiety of NI-Azo (1:9 (v/v), THF-water) at 458 nm got diminished in the presence of both extracellular and intracellular bacterial azoreductase extracted from Escherichia coli bacteria. The same observation was noted in the presence of sodium dithionite (mimic of azoreductase), indicating that azoreductase/sodium dithionite induced azo bond cleavage of NI-Azo, which was confirmed by matrix-assisted laser desorption ionization time-of-flight spectrometric data of the corresponding aromatic amine fragments. The anticancer drug, curcumin, was encapsulated inside NI-Azo vesicles that successfully killed B16F10 cells (cancer cells) in CoCl2-induced hypoxic environment owing to the azoreductase-responsive release of drug. The cancer cell killing efficiency by curcumin-loaded NI-Azo vesicles in the hypoxic condition was 2.15-fold higher than that of the normoxic environment and 2.4-fold higher compared to that of native curcumin in the hypoxic condition. Notably, cancer cell killing efficiency of curcumin-loaded NI-Azo vesicles was 4.5- and 1.9-fold higher than that of noncancerous NIH3T3 cells in normoxic and hypoxic environments, respectively. Cell killing was found to be primarily through the early apoptotic pathway.