Supramolecular cage-mediated cargo transport.

A steady stream of material transport based on carriers and channels in living systems plays an extremely important role in normal life activities. Inspired by nature, researchers have extensively applied supramolecular cages in cargo transport because of their unique three-dimensional structures and excellent physicochemical properties. In this review, we will focus on the development of supramolecular cages as carriers and channels for cargo transport in abiotic and biological systems over the past fifteen years. In addition, we will discuss future challenges and potential applications of supramolecular cages in substance transport.

Fluorogenic Peptide Sensor Array Derived from Angiotensin-Converting Enzyme 2 Classifies Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern.

The devastating COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made society acutely aware of the urgency in developing effective techniques to timely monitor the outbreak of previously unknown viral species as well as their mutants, which could be even more lethal and/or contagious. Here, we report a fluorogenic sensor array consisting of peptides truncated from the binding domain of human angiotensin-converting enzyme 2 (hACE2) for SARS-CoV-2. A set of five fluorescently tagged peptides were used to construct the senor array in the presence of different low-dimensional quenching materials. When orthogonally incubated with the wild-type SARS-CoV-2 and its variants of concern (VOCs), the fluorescence of each peptide probe was specifically recovered, and the different recovery rates provide a "fingerprint" characteristic of each viral strain. This, in turn, allows them to be differentiated from each other using principal component analysis. Interestingly, the classification result from our sensor array agrees well with the evolutionary relationship similarity of the VOCs. This study offers insight into the development of effective sensing tools for highly contagious viruses and their mutants based on rationally truncating peptide ligands from human receptors.

Efficient Self-Sorting Behaviours of Metallacages with Subtle Structural Differences.

Investigating the self-sorting behaviour of assemblies with subtle structural differences is a captivating yet challenging endeavour. Herein, we elucidate the unusual self-sorting behaviour of metallacages with subtle structural differences in batch reactors and microdroplets. Narcissistic self-sorting of metallacages has been observed for two ligands with identical sizes, shapes, and symmetries, with only minor differences in the substituted groups. In particular, the self-sorting process in microdroplets occurs within 1 min at room temperature, in stark contrast to batch reactors, which require equilibration for 30 min. To reveal the mechanism of self-sorting and the role of microdroplets, we conducted a series of experiments and theoretical calculations, including competitive self-assembly, cage-to-cage transformation, control experiments involving model metallacages with larger cavities, noncovalent interaction analysis, and root mean square deviation (RMSD) analysis. This research demonstrates an unusual case of self-sorting of very similar assemblies and provides a new strategy for facilitating the self-sorting efficiency of supramolecular systems.

Orthogonally Engineered Albumin with Attenuated Macrophage Phagocytosis for the Targeted Visualization and Phototherapy of Liver Cancer.

The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host-guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.

Highly Efficient Self-Assembly of Metallacages and Their Supramolecular Catalysis Behaviors in Microdroplets.

Developing a new strategy to improve the self-assembly efficiency of functional assemblies in a confined space and construct hybrid functional materials is a significant and fascinating endeavor. Herein, we present a highly efficient strategy for achieving the supramolecular self-assembly of well-defined metallacages in microdroplets through continuous-flow microfluidic devices. The high efficiency and versatility of this approach are demonstrated by the generation of five representative metallacages in different solvents containing water, DMF, acetonitrile, and methanol in a few minutes with nearly quantitative yields, in contrast to the yields obtained with the hour-scale reaction time in a batch reactor. A ring-opening catalytic reaction of the metallacages was selected as a model reaction for exploring supramolecular catalysis in microdroplets, whereby the catalytic yield was enhanced by 2.22-fold compared to that of the same reaction in the batch reactor. This work illustrates a new promising approach for the self-assembly of supramolecular systems.

Ferrocene-Labelled Electroactive Aptamer-Based Sensors (Aptasensors) for Glycated Haemoglobin.

Glycated haemoglobin (HbA1c) is a diagnostic biomarker for type 2 diabetes. Traditional analytical methods for haemoglobin (Hb) detection rely on chromatography, which requires significant instrumentation and is labour-intensive; consequently, miniaturized devices that can rapidly sense HbA1c are urgently required. With this research, we report on an aptamer-based sensor (aptasensor) for the rapid and selective electrochemical detection of HbA1c. Aptamers that specifically bind HbA1c and Hb were modified with a sulfhydryl and ferrocene group at the 3' and 5'-end, respectively. The modified aptamers were coated through sulfhydryl-gold self-assembly onto screen printed electrodes, producing aptasensors with built in electroactivity. When haemoglobin was added to the electrodes, the current intensity of the ferrocene in the sensor system was reduced in a concentration-dependent manner as determined by differential pulse voltammetry. In addition, electrochemical impedance spectroscopy confirmed selective binding of the analytes to the aptamer-coated electrode. This research offers new insight into the development of portable electrochemical sensors for the detection of HbA1c.

Fluorescence Imaging of Alzheimer's Disease with a Flat Ensemble Formed between a Quinoline-Malononitrile AIEgen and Thin-Layer Molybdenum Disulfide.

The sensitive imaging of amyloid-ß (Aß) peptides is important for the timely detection of neurodegenerative diseases, such as Alzheimer's disease (AD). Although clinically the diagnosis of AD relies on the use of radiolabeled imaging reagents, herein we report the simple construction of a "flat ensemble" formed between a quinoline-malononitrile AIEgen (EDS) and thin-layer molybdenum disulfide (2D MoS2 ) for the sensitive detection of Aß by means of fluorescence-based techniques. Self-assembly between EDS and 2D MoS2 in aqueous buffer solution produces the flat ensemble, and the subsequent interaction of the material ensemble with oligomeric and aggregated Aß peptides leads to up to 19-fold enhanced fluorescence of EDS. The ensemble is also applicable for staining Aß aggregates in vivo.

An ESIPT Probe for the Ratiometric Imaging of Peroxynitrite Facilitated by Binding to Aß-Aggregates.

A series of 3-hydroxyflavone (3-HF) ESIPT (excited-state intramolecular proton transfer) boronate-based fluorescent probes have been developed for the detection of peroxynitrite (ONOO-). The dyes are environmentally sensitive, and each probe exhibited a ratiometric response toward ONOO- in a micellar environment. The probes were used to image different aggregation states of amyloid-ß (Aß) in the presence of ONOO-. The 3-HF-OMe probe was found to produce a ratiometric response toward ONOO- when bound to Aß aggregates, resulting in a novel host-guest ensemble, which adds insight into the development of other ESIPT-based probes for the simultaneous sensing of fibrous proteins/peptides and environmental ROS/RNS.

Supramolecular Nanostructures of Structurally Defined Graphene Nanoribbons in the Aqueous Phase.

Structurally well-defined graphene nanoribbons (GNRs) have attracted great interest because of their unique optical, electronic, and magnetic properties. However, strong π-π interactions within GNRs result in poor liquid-phase dispersibility, which impedes further investigation of these materials in numerous research areas, including supramolecular self-assembly. Structurally defined GNRs were synthesized by a bottom-up strategy, involving grafting of hydrophilic poly(ethylene oxide) (PEO) chains of different lengths (GNR-PEO). PEO grafting of 42-51 % percent produces GNR-PEO materials with excellent dispersibility in water with high GNR concentrations of up to 0.5 mg mL-1 . The "rod-coil" brush-like architecture of GNR-PEO resulted in 1D hierarchical self-assembly behavior in the aqueous phase, leading to the formation of ultralong nanobelts, or spring-like helices, with tunable mean diameters and pitches. In aqueous dispersions the superstructures absorbed in the near-infrared range, which enabled highly efficient conversion of photon energy into thermal energy.

Vibration-Induced-Emission (VIE) for imaging amyloid ß fibrils.

This paper discusses the use of N,N'-disubstituted-dihydrodibenzo[a,c]phenazines with typical Vibration-Induced-Emission (VIE) properties for imaging amyloid ß (Aß) fibrils, which are a signature of neurological disorders such as Alzheimer's disease. A water-soluble VIEgen with a red fluorescence emission shows a pronounced, blue-shifted emission with Aß peptide monomers and fibrils. The enhancement in blue fluorescence can be ascribed to the restriction of the molecular vibration by selectively binding to Aß. We determine an increasing blue-to-red emission ratio of the VIEgen with both the concentration and fibrogenesis time of Aß, thereby enabling a ratiometric detection of Aß in its different morphological forms. Importantly, the VIEgen was proven to be suitable for the fluorescence imaging of small Aß plaques in the hippocampus of a transgenic mouse brain (five months old), with the blue and red emissions well overlapped on the Aß. This research offers a new rationale to design molecular VIE probes for biological applications.

Metal-organic cages for gas adsorption and separation.

The unique high surface area and tunable cavity size endow metal-organic cages (MOCs) with superior performance and broad application in gas adsorption and separation. Over the past three decades, for instance, numerous MOCs have been widely explored in adsorbing diverse types of gas including energy gases, greenhouse gases, toxic gases, noble gases, etc. To gain a better understanding of the structure-performance relationships, great endeavors have been devoted to ligand design, metal node regulation, active metal site construction, cavity size adjustment, and function-oriented ligand modification, thus opening up routes toward rationally designed MOCs with enhanced capabilities. Focusing on the unveiled structure-performance relationships of MOCs towards target gas molecules, this review consists of two parts, gas adsorption and gas separation, which are discussed separately. Each part discusses the cage assembly process, gas adsorption strategies, host-guest chemistry, and adsorption properties. Finally, we briefly overviewed the challenges and future directions in the rational development of MOC-based sorbents for application in challenging gas adsorption and separation, including the development of high adsorption capacity MOCs oriented by adsorbability and the development of highly selective adsorption MOCs oriented by separation performance.

Cage-based sensors for circular dichroism analysis.

Quantitative chiral sensing relying on circular dichroism (CD) is very important for determining the enantiomeric excess or concentration of small molecules without strong chromophores, because they form chiral complexes with sensors, yielding strong CD signals. Three-dimensional cages are promising platforms for chiral CD due to their stereochemical flexibility and their variety of cavity and external binding sites that can be used as chiral CD sensors. In this minireview, we discuss recent advances, future challenges, and opportunities in the quantitative sensing of small molecules in host-guest and peripheral complexes with cage sensors by chiral CD. We aim to provide inspiration for the rational design of cage sensors for quantitative chiral sensing of small molecules based on CD.

Fluorescence Analysis of Circulating Exosomes for Breast Cancer Diagnosis Using a Sensor Array and Deep Learning.

Emerging liquid biopsy methods for investigating biomarkers in bodily fluids such as blood, saliva, or urine can be used to perform noninvasive cancer detection. However, the complexity and heterogeneity of exosomes require improved methods to achieve the desired sensitivity and accuracy. Herein, we report our study on developing a breast cancer liquid biopsy system, including a fluorescence sensor array and deep learning (DL) tool AggMapNet. In particular, we used a 12-unit sensor array composed of conjugated polyelectrolytes, fluorophore-labeled peptides, and monosaccharides or glycans to collect fluorescence signals from cells and exosomes. Linear discriminant analysis (LDA) processed the fluorescence spectral data of cells and cell-derived exosomes, demonstrating successful discrimination between normal and different cancerous cells and 100% accurate classification of different BC cells. For heterogeneous plasma-derived exosome analysis, CNN-based DL tool AggMapNet was applied to transform the unordered fluorescence spectra into feature maps (Fmaps), which gave a straightforward visual demonstration of the difference between healthy donors and BC patients with 100% prediction accuracy. Our work indicates that our fluorescent sensor array and DL model can be used as a promising noninvasive method for BC diagnosis.

Fluorescent probes for the detection of disease-associated biomarkers.

Fluorescent probes have emerged as indispensable chemical tools to the field of chemical biology and medicine. The ability to detect intracellular species and monitor physiological processes has not only advanced our knowledge in biology but has provided new approaches towards disease diagnosis. In this review, we detail the design criteria and strategies for some recently reported fluorescent probes that can detect a wide range of biologically important species in cells and in vivo. In doing so, we highlight the importance of each biological species and their role in biological systems and for disease progression. We then discuss the current problems and challenges of existing technologies and provide our perspective on the future directions of the research area. Overall, we hope this review will provide inspiration for researchers and prove as useful guide for the development of the next generation of fluorescent probes.

Fluorescence evidence of annexin A6 translocation across membrane in model matrix vesicles during apatite formation.

Matrix vesicles (MVs) are 100-300 nm spherical structures released by mineralization competent cells to initiate formation of apatite, the mineral component in bones. Among proteins present in MVs, annexin A6 (AnxA6) is thought to be ubiquitously distributed in the MVs' lumen, on the surface of the internal and external leaflets of the membrane and also inserted in the lipid bilayer. To determine the molecular mechanism(s) that lead to the different locations of AnxA6, we hypothesized the occurrence of a pH drop during the mineralization. Such a change would induce the AnxA6 protonation, which in turn, and because of its isoelectric point of 5.41, would change the protein hydrophobicity facilitating its insertion into the MVs' bilayer. The various distributions of AnxA6 are likely to disturb membrane phospholipid organization. To examine this possibility, we used fluorescein as pH reporter, and established that pH decreased inside MVs during apatite formation. Then, 4-(14-phenyldibenzo[a,c]phenazin-9(14H)-yl)-phenol, a vibration-induced emission fluorescent probe, was used as a reporter of changes in membrane organization occurring with the varying mode of AnxA6 binding. Proteoliposomes containing AnxA6 and 1,2-Dimyristoyl-sn-glycero-3phosphocholine (DMPC) or 1,2-Dimyristoyl-sn-glycero-3phosphocholine: 1,2-Dipalmitoyl-sn-glycero-3-phosphoserine (DMPC:DPPS 9:1), to mimic the external and internal MV membrane leaflet, respectively, served as biomimetic models to investigate the nature of AnxA6 binding. Addition of Anx6 to DMPC at pH 7.4 and 5.4, or DMPC:DPPS (9:1) at pH 7.4 induced a decrease in membrane fluidity, consistent with AnxA6 interactions with the bilayer surface. In contrast, AnxA6 addition to DMPC:DPPS (9:1) at pH 5.4 increased the fluidity of the membrane. This latest result was interpreted as reflecting the insertion of AnxA6 into the bilayer. Taken together, these findings point to a possible mechanism of AnxA6 translocation in MVs from the surface of the internal leaflet into the phospholipid bilayer stimulated upon acidification of the MVs' lumen during formation of apatite.

Graphene nanoribbon-based supramolecular ensembles with dual-receptor targeting function for targeted photothermal tumor therapy.

Triple negative breast cancer (TNBC) is one of the most malignant subtypes of breast cancer. Here, we report the construction of graphene nanoribbon (GNR)-based supramolecular ensembles with dual-receptor (mannose and αvß3 integrin receptors) targeting function, denoted as GNR-Man/PRGD, for targeted photothermal treatment (PTT) of TNBC. The GNR-Man/PRGD ensembles were constructed through the solution-based self-assembly of mannose-grafted GNRs (GNR-Man) with a pyrene-tagged αvß3 integrin ligand (PRGD). Enhanced PTT efficacies were achieved both in vitro and in vivo compared to that of the non-targeting equivalents. Tumor-bearing live mice were administered (tail vein) with GNR-Man/PRGD and then each mice group was subjected to PTT. Remarkably, GNR-Man/PRGD induced complete ablation of the solid tumors, and no tumor regrowth was observed over a period of 15 days. This study demonstrates a new and promising platform for the development of photothermal nanomaterials for targeted tumor therapy.

Supramolecular fluorogenic peptide sensor array based on graphene oxide for the differential sensing of ebola virus.

We report on a supramolecular sensor array using fluorogenic peptide probes and graphene oxide that can target glycoproteins on a viral caspid, facilitating the differentiation of ebola virus from marburg virus and receptor-extensive vesicular stomatitis virus using principal component analysis.

Correction: Fluorescence imaging of a potential diagnostic biomarker for breast cancer cells using a peptide-functionalized fluorogenic 2D material.

Correction for 'Fluorescence imaging of a potential diagnostic biomarker for breast cancer cells using a peptide-functionalized fluorogenic 2D material' by Wei-Tao Dou et al., Chem. Commun., 2019, 55, 13235-13238.

Self-assembled sialyllactosyl probes with aggregation-enhanced properties for ratiometric detection and blocking of influenza viruses.

Infection and dissemination of influenza viruses (IVs) causes serious health concerns worldwide. However, effective tools for the accurate detection and blocking of IVs remain elusive. Here, we develop a new sialyllactosyl probe with self-assembled core-shell structure for the ratiometric detection and blocking of IVs. N,N'-diaryl-dihydrodibenzo[a,c]phenazines were used to form the core structure by hydrophobic assembly in an aqueous solution with an aggregation-enhanced blue fluorescence mission. Subsequently, dicyanomethylene-4H-pyran-based sialyllactosides were used for self-assembly with the core structure, producing the sialyllactosyl probe that emits a red fluorescence due to Förster resonance energy transfer. The probe developed has been proven to be available for (1) the fluorescence ratiometric detection of IVs through selective interaction with the sialyllactosyl-binding proteins on the virus surface, and (2) effectively blocking the invasion of human-infecting IVs towards host cells as accentuated by the sialyllactosides on the surface of the probes.

Fluorescence imaging of a potential diagnostic biomarker for breast cancer cells using a peptide-functionalized fluorogenic 2D material.

Protein C receptor (PROCR) is a recently discovered transmembrane biomarker for several tissue stem cells and is highly expressed in triple-negative breast cancer (TNBC) patient-derived xenografts. Herein, to enrich the toolbox for the biochemical evaluation of PROCR, we have developed a peptide-functionalized fluorogenic 2D material based on the self-assembly between a fluorescent peptide probe and thin-layer molybdenum disulfide. The material developed was suitable for the sensitive detection of PROCR recombinant protein in buffer solution and the fluorescence imaging of TNBC cells that express high levels of PROCR.