Single Molecular Nanomedicines Based on Macrocyclic Carrier-Drug Conjugates for Concentration-Independent Encapsulation and Precise Activation of Drugs.

Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.

Expanding the Hydrophobic Cavity Surface of Azocalix[4]arene to Enable Biotin/Avidin Affinity with Controlled Release.

The development of artificial receptors that combine ultrahigh-affinity binding and controllable release for active guests holds significant importance in biomedical applications. On one hand, a complex with an exceedingly high binding affinity can resist unwanted dissociation induced by dilution effect and complex interferents within physiological environments. On the other hand, stimulus-responsive release of the guest is essential for precisely activating its function. In this context, we expanded hydrophobic cavity surface of a hypoxia-responsive azocalix[4]arene, affording Naph-SAC4A. This modification significantly enhanced its aqueous binding affinity to 1013 M-1, akin to the naturally occurring strongest recognition pair, biotin/(strept-)avidin. Consequently, Naph-SAC4A emerges as the first artificial receptor to simultaneously integrate ultrahigh recognition affinity and actively controllable release. The markedly enhanced affinity not only improved Naph-SAC4A's sensitivity in detecting rocuronium bromide in serum, but also refined the precision of hypoxia-responsive doxorubicin delivery at the cellular level, demonstrating its immense potential for diverse practical applications.

A Direct-Contact Photocurrent-Direction-Switching Biosensing Platform Based on In Situ Formation of CN QDs/TiO2 Nanodiscs and Double-Supported 3D DNA Walking Amplification.

Herein, a direct-contact photocurrent-direction-switching photoelectrochemical (PEC) biosensing platform for the ultrasensitive and selective detection of soluble CD146 (sCD146) is reported for the first time via in situ formation of carbon nitride quantum dots (CN QDs)/titanium dioxide (TiO2 ) nanodiscs with the double-supported 3D DNA walking amplification. In this platform, metal organic frameworks (MOFs)-derived porous TiO2 nanodiscs exhibit excellent anodic photocurrent, whereas a single-stranded auxiliary DNA (ssDNA) as biogate is absorbed onto the TiO2 nanodiscs to block active sites. Subsequently, with the help of intermediate DNAs from target sCD146-induced double-supported 3D DNA walking signal amplification, the ssDNA can leave away from the surface of TiO2 nanodiscs due to the specific hybridization with intermediate DNAs. Afterward, the successful direct contact of CN QDs on TiO2 nanodiscs by porosity and electrostatic adsorption, leads to the effective photocurrent-direction switching from anodic to cathodic photocurrent. Based on direct-contact photocurrent-direction-switching CN QDs/TiO2 nanodiscs system and double-supported 3D DNA walking signal amplification, sCD146 is detected sensitively with a wide linear range (10 fg mL-1 to 5 ng mL-1 ) and a low limit of detection (2.1 fg mL-1 ). Also, the environmentally friendly and direct-contact photocurrent-direction-switching PEC biosensor has an application prospect for cancer biomarker detection.

A Chiral Emissive Conjugated Corral for High-Affinity and Highly Enantioselective Recognition in Water.

Accurately distinguishing between enantiomeric molecules is a fundamental challenge in the field of chemistry. However, there is still significant room for improvement in both the enantiomeric selectivity (KR(S) /KS(R) ) and binding strength of most reported macrocyclic chiral receptors to meet the demands of practical application scenarios. Herein, we synthesized a water-soluble conjugated tubular host-namely, corral[4]BINOL-using a chiral 1,1'-bi-2-naphthol (BINOL) derivative as the repeating unit. The conjugated chiral backbone endows corral[4]BINOL with good fluorescent emission (QY=34 % ) and circularly polarized luminescence (|glum | up to 1.4×10-3 ) in water. Notably, corral[4]BINOL exhibits high recognition affinity up to 8.6×1010  M-1 towards achiral guests in water, and manifested excellent enantioselectivity up to 18.7 towards chiral substrates, both of which represent the highest values observed among chiral macrocycles in aqueous solution. The ultrastrong binding strength, outstanding enantioselectivity, and facile accessibility, together with the superior fluorescent and chiroptical properties, endow corral[4]BINOL with great potential for a wide range of applications.

Integrating Pt16 Te Nanotroughs and Nanopillars into a 3D "Self-Supported" Hierarchical Nanostructure for Boosting Methanol Electrooxidation.

To develop durable and low-price catalysts of methanol oxidation to commercialize direct methanol fuel cell, many attempts have been made at fabricating Pt-based hybrids by designing component-, morphology-, facet-, integration-pattern-varied nanostructures, and have achieved considerable successes. However, most of present catalysts still lack robust catalytic durability especially owing to the corrosion of mixed carbon and the poor mechanical stability of catalyst layer. Herein, Te nanowire array is transformed at an air/water interface into a 3D Pt16 Te hierarchical nanostructure via an interface-confined galvanic replacement reaction. As-formed Pt16 Te nanostructure has an asymmetrical architecture composed of nanotroughs and nanopillars, and nanopillars are perpendicular to nanotroughs with a loose arrangement. Pt16 Te hierarchical nanostructure has a "self-supported" feature and, when directly used as the catalyst of methanol electrooxidation, exhibits superior catalytic activity (>four times larger in mass activity than state-of-the-art Pt/C in either acidic or basic solution) and long-term durability (after 500 cycles of cyclic voltammetric measurement, more than 55% of the initial specific activity remains whereas Pt/C only remains 22.2% in acidic solution and almost loses all activity in basic solution). This study fully demonstrates that designing "self-supported" catalyst film may be the next promising step for improving the catalytic performance of Pt-based hybrids.

Coassembly of hypoxia-sensitive macrocyclic amphiphiles and extracellular vesicles for targeted kidney injury imaging and therapy.

BACKGROUND: Hypoxia is a major contributor to global kidney diseases. Targeting hypoxia is a promising therapeutic option against both acute kidney injury and chronic kidney disease; however, an effective strategy that can achieve simultaneous targeted kidney hypoxia imaging and therapy has yet to be established. Herein, we fabricated a unique nano-sized hypoxia-sensitive coassembly (Pc/C5A@EVs) via molecular recognition and self-assembly, which is composed of the macrocyclic amphiphile C5A, the commercial dye sulfonated aluminum phthalocyanine (Pc) and mesenchymal stem cell-excreted extracellular vesicles (MSC-EVs). RESULTS: In murine models of unilateral or bilateral ischemia/reperfusion injury, MSC-EVs protected the Pc/C5A complex from immune metabolism, prolonged the circulation time of the complex, and specifically led Pc/C5A to hypoxic kidneys via surface integrin receptor α4ß1 and αLß2, where Pc/C5A released the near-infrared fluorescence of Pc and achieved enhanced hypoxia-sensitive imaging. Meanwhile, the coassembly significantly recovered kidney function by attenuating cell apoptosis, inhibiting the progression of renal fibrosis and reducing tubulointerstitial inflammation. Mechanistically, the Pc/C5A coassembly induced M1-to-M2 macrophage transition by inhibiting the HIF-1α expression in hypoxic renal tubular epithelial cells (TECs) and downstream NF-κB signaling pathway to exert their regenerative effects. CONCLUSION: This synergetic nanoscale coassembly with great translational potential provides a novel strategy for precise kidney hypoxia diagnosis and efficient kidney injury treatment. Furthermore, our strategy of coassembling exogenous macrocyclic receptors with endogenous cell-derived membranous structures may offer a functional platform to address multiple clinical needs.

Supramolecular prodrugs based on host-guest interactions.

Classic prodrug strategies rely on covalent modification of active drugs to provide systems with superior pharmacokinetic properties than the parent drug and facilitate administration. Supramolecular chemistry is providing a new approach to developing prodrug-like systems, wherein the characteristics of a drug are modified in a beneficial manner by creating host-guest complexes that then permit the stimulus-induced release of the active species in a controlled manner. These complexes are termed "supramolecular prodrugs". In this review, we outline the concept of supramolecular drugs via host-guest chemistry and detail progress made in the area. This summary is designed to highlight the many advantages of supramolecular prodrugs, including ease-of-preparation, molecular-level protection, sensitive response to bio-stimuli, traceless release, and adaptability to different drugs. Limitations of the approach and opportunities for future growth are also detailed.

Supramolecular Bioimaging through Signal Amplification by Combining Indicator Displacement Assay with Förster Resonance Energy Transfer.

Fluorescent chemosensors are powerful imaging tools in the fields of life sciences and engineering. Based on the principle of supramolecular chemistry, indicator displacement assay (IDA) provides an alternative approach for constructing and optimizing chemosensors, which has the advantages of simplicity, tunability, and modularity. However, the application of IDA in bioimaging continues to face a series of challenges, including interfering signals, background noise, and inconsistent spatial location. Accordingly, we herein report a supramolecular bioimaging strategy of Förster resonance energy transfer (FRET)-assisted IDA by employing macrocyclic amphiphiles as the operating platform. By merging FRET with IDA, the limitations of IDA in bioimaging were addressed. As a proof of concept, the study achieved mitochondria-targeted imaging of adenosine triphosphate in live cells with signal amplification. This study opens a non-covalent avenue for bioimaging with advancements in tunability, generality, and simplicity, apart from the covalent approach.

Host-Guest Complexation of Amphiphilic Molecules at the Air-Water Interface Prevents Oxidation by Hydroxyl Radicals and Singlet Oxygen.

The oxidation of antioxidants by oxidizers imposes great challenges to both living organisms and the food industry. Here we show that the host-guest complexation of the carefully designed, positively charged, amphiphilic guanidinocalix[5]arene pentadodecyl ether (GC5A-12C) and negatively charged oleic acid (OA), a well-known cell membrane antioxidant, prevents the oxidation of the complex monolayers at the air-water interface from two potent oxidizers hydroxyl radicals (OH) and singlet delta oxygen (SDO). OH is generated from the gas phase and attacks from the top of the monolayer, while SDO is generated inside the monolayer and attacks amphiphiles from a lateral direction. Field-induced droplet ionization mass spectrometry results have demonstrated that the host-guest complexation achieves steric shielding and prevents both types of oxidation as a result of the tight and "sleeved in" physical arrangement, rather than the chemical reactivity, of the complexes.

A Noncovalent Fluorescence Turn-on Strategy for Hypoxia Imaging.

Hypoxia plays crucial roles in many diseases and is a central target for them. Present hypoxia imaging is restricted to the covalent approach, which needs tedious synthesis. In this work, a new supramolecular host-guest approach, based on the complexation of a hypoxia-responsive macrocycle with a commercial dye, is proposed. To exemplify the strategy, a carboxyl-modified azocalix[4]arene (CAC4A) was designed that binds to rhodamine 123 (Rho123) and quenches its fluorescence. The azo groups of CAC4A were selectively reduced under hypoxia, leading to the release of Rho123 and recovery of its fluorescence. The noncovalent strategy was validated through hypoxia imaging in living cells treated with the CAC4A-Rho123 reporter pair.

Complexation of a guanidinium-modified calixarene with diverse dyes and investigation of the corresponding photophysical response.

We herein describe the comprehensive investigation of the complexation behavior of a guanidinium-modified calix[5]arene pentaisohexyl ether (GC5A) with a variety of typical luminescent dyes. Fluorescein, eosin Y, rose bengal, tetraphenylporphine sulfonate and sulfonated aluminum phthalocyanine were employed as classical aggregation-induced quenching dyes. 2-(p-Toluidinyl)naphthalene-6-sulfonic acid and 1-anilinonaphthalene-8-sulfonic acid were selected as representatives of intramolecular charge-transfer dyes. Phosphated tetraphenylethylene was involved as the classical aggregation-induced emission dye. Sulfonated acedan representing one example of two-photon fluorescent probes, was also investigated. A ruthenium(II) complex with carboxylated bipyridyl ligands was included as a representative candidate of luminescent transition-metal complexes. We determined the association constants of the GC5A-dye complexes by fluorescence titration and discuss the complexation-induced photophysical changes. In addition, a comparison of the complexation behavior of GC5A with that of other macrocycles and potential applications according to the diverse photophysical responses are provided.

Biomarker Displacement Activation: A General Host-Guest Strategy for Targeted Phototheranostics in Vivo.

Activatable phototheranostics is highly appealing to meet the demand of precision medicine. However, although it displays efficacy in the construction of activatable photosensitizers (PSs), direct covalent decoration still shows some inevitable issues, such as complex molecular design, tedious synthesis, possible photoactivity changes, and potential toxicity. Herein, we propose a novel concept of biomarker displacement activation (BDA) using host-guest strategy. To exemplify BDA, we engineered a PS-loaded nanocarrier by utilizing a macrocyclic amphiphile, where the fluorescence and photoactivity of PS were completely annihilated by the complexation of macrocyclic receptor (OFF state). When nanocarriers were accumulated into tumor tissues via the enhanced permeability and retention effect, the overexpressed biomarker adenosine triphosphates displaced PSs, accompanied by their fluorescence and photoactivity recovered (ON state). These reinstallations are unattainable in normal tissues, allowing us to concurrently achieve selective tumor imaging and targeted therapy in vivo. Compared with widely used covalent approach, the present BDA strategy provides the following advantages: (1) employment of approved PSs without custom covalent decoration; (2) traceless release of PSs with high fidelity by biomarker displacement; (3) adaptability to different PSs for establishing a universal platform and promised facile combination of diverse PSs to enhance photon utility in light window. Such a host-guest BDA strategy is easily amenable to other ensembles and targets, so that versatile biomedical applications can be envisaged.

What dictates which ion, I- or Br-, mediates the growth of cubic Pd nanocrystals?

Cubic Pd nanocrystals (CPNCs) as one of typical nanostructures are generally fabricated using I- or Br- as capping ions. However, which ion, I- or Br-, exclusively mediates the growth of CPNCs in a given reaction system is not well understood. Herein, regardless of I- or Br- as the capping ion, we successfully achieved CPNCs in the same reaction system simply by adjusting the pH. Based on the Finke-Watzky kinetic model, an increase in pH accelerates the overall reduction rate of Pd2+, and the formation of CPNCs only occurs over the range of specific solution reduction rate constants (k1). This kinetically illuminates that the reduction rate of Pd2+ is the physicochemical parameter that determines which ion, I- or Br-, dictates the growth of CPNCs. Also, density functional theory (DFT) calculations further elucidate the dependence of the reduction rate of Pd2+ on pH and the configuration of the activated Pd2+ complex.

Supramolecular interaction in the action of drug delivery systems.

Complex diseases and diverse clinical needs necessitate drug delivery systems (DDSs), yet the current performance of DDSs is far from ideal. Supramolecular interactions play a pivotal role in various aspects of drug delivery, encompassing biocompatibility, drug loading, stability, crossing biological barriers, targeting, and controlled release. Nevertheless, despite having some understanding of the role of supramolecular interactions in drug delivery, their incorporation is frequently overlooked in the design and development of DDSs. This perspective provides a brief analysis of the involved supramolecular interactions in the action of drug delivery, with a primary emphasis on the DDSs employed in the clinic, mainly liposomes and polymers, and recognized phenomena in research, such as the protein corona. The supramolecular interactions implicated in various aspects of drug delivery systems, including biocompatibility, drug loading, stability, spatiotemporal distribution, and controlled release, were individually analyzed and discussed. This perspective aims to trigger a comprehensive and systematic consideration of supramolecular interactions in the further development of DDSs. Supramolecular interactions embody the true essence of the interplay between the majority of DDSs and biological systems.

[Structure motif guided mining of MHET hydrolase and development of a two-enzyme cascade for plastics depolymerization at mild temperature].

The utilization of polyethylene terephthalate (PET) has caused significant and prolonged ecological repercussions. Enzymatic degradation is an environmentally friendly approach to addressing PET contamination. Hydrolysis of mono(2-hydroxyethyl) terephthalate (MHET), a competitively inhibited intermediate in PET degradation, is catalyzed by MHET degrading enzymes. Herein, we employed bioinformatic methods that combined with sequence and structural information to discover an MHET hydrolase, BurkMHETase. Enzymatic characterization showed that the enzyme was relatively stable at pH 7.5-10.0 and 30-45 ℃. The kinetic parameters kcat and Km on MHET were (24.2±0.5)/s and (1.8±0.2) µmol/L, respectively, which were similar to that of the well-known IsMHETase with higher substrate affinity. BurkMHETase coupled with PET degradation enzymes improved the degradation of PET films. Structural analysis and mutation experiments indicated that BurkMHETase may have evolved specific structural features to hydrolyze MHET. For MHET degrading enzymes, aromatic amino acids at position 495 and the synergistic interactions between active sites or distal amino acids appear to be required for MHET hydrolytic activity. Therefore, BurkMHETase may have substantial potential in a dual-enzyme PET degradation system while the bioinformatic methods can be used to broaden the scope of applicable MHETase enzymes.

Computational redesign of a hydrolase for nearly complete PET depolymerization at industrially relevant high-solids loading.

Biotechnological plastic recycling has emerged as a suitable option for addressing the pollution crisis. A major breakthrough in the biodegradation of poly(ethylene terephthalate) (PET) is achieved by using a LCC variant, which permits 90% conversion at an industrial level. Despite the achievements, its applications have been hampered by the remaining 10% of nonbiodegradable PET. Herein, we address current challenges by employing a computational strategy to engineer a hydrolase from the bacterium HR29. The redesigned variant, TurboPETase, outperforms other well-known PET hydrolases. Nearly complete depolymerization is accomplished in 8 h at a solids loading of 200 g kg-1. Kinetic and structural analysis suggest that the improved performance may be attributed to a more flexible PET-binding groove that facilitates the targeting of more specific attack sites. Collectively, our results constitute a significant advance in understanding and engineering of industrially applicable polyester hydrolases, and provide guidance for further efforts on other polymer types.

Supramolecular 3 in 1: A Lubrication and Co-Delivery System for Synergistic Advanced Osteoarthritis Therapy.

The complexity, heterogeneity, and drug resistance of diseases necessitate a shift in therapeutic paradigms from monotherapy to combination therapy, which could augment treatment efficiency. Effective treatment of advanced osteoarthritis (OA) requires addressing three key factors contributing to its deterioration: chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation. Herein, we present a supramolecular nanomedicine of multifunctionality via molecular recognition and self-assembly. The employed macrocyclic carrier, zwitterion-modified cavitand (CV-2), not only accurately loads various drugs but also functions as a therapeutic agent with lubricating properties for the treatment of OA. Kartogenin (KGN), a drug for articular cartilage regeneration and protection, and flurbiprofen (FP), an anti-inflammatory agent, were coloaded onto CV-2 assembly, forming a supramolecular nanomedicine KGN&FP@CV-2. The three-in-one combination therapy of KGN&FP@CV-2 addresses the three pathological features for treating OA collectively, and thus provides long-term therapeutic benefits for OA through sustained drug release and intrinsic lubrication in vivo. The multifunctional integration of macrocyclic delivery and therapeutics provides a simple, flexible, and universal platform for the synergistic treatment of diseases involving multiple drugs.

Active targeting tumor therapy using host-guest drug delivery system based on biotin functionalized azocalix[4]arene.

Host-guest drug delivery systems (HGDDSs) provided a facile method for incorporating biomedical functions, including efficient drug-loading, passive targeting, and controlled drug release. However, developing HGDDSs with active targeting is hindered by the difficult functionalization of popular macrocycles. Herein, we report an active targeting HGDDS based on biotin-modified sulfonated azocalix[4]arene (Biotin-SAC4A) to efficiently deliver drug into cancer cells for improving anti-tumor effect. Biotin-SAC4A was synthesized by amide condensation and azo coupling. Biotin-SAC4A demonstrated hypoxia responsive targeting and active targeting through azo and biotin groups, respectively. DOX@Biotin-SAC4A, which was prepared by loading doxorubicin (DOX) in Biotin-SAC4A, was evaluated for tumor targeting and therapy in vitro and in vivo. DOX@Biotin-SAC4A formulation effectively killed cancer cells in vitro and more efficiently delivered DOX to the lesion than the similar formulation without active targeting. Therefore, DOX@Biotin-SAC4A significantly improved the in vivo anti-tumor effect of free DOX. The facilely prepared Biotin-SAC4A offers strong DOX complexation, active targeting, and hypoxia-triggered release, providing a favorable host for effective breast cancer chemotherapy in HGDDSs. Moreover, Biotin-SAC4A also has potential to deliver agents for other therapeutic modalities and diseases.

A dual-model immobilization-free photoelectrochemical/visual colorimetric bioanalysis based on microemulsion self-assemblies mediated multifunctional signal amplification strategy.

Herein, a novel silver ion-loaded gold microemulsion assemblies (Au/Ag+ MAs) mediated multifunctional signal amplification strategy was proposed to construct a sensitive immobilization-free photoelectrochemical (PEC)/colorimetric biosensor for carcinoembryonic antigen (CEA) detection. Through the sandwiched reaction among CEA, the CEA aptamer (DNA1) loaded on the Au nanoparticles (NPs) functionalized iron oxide (Fe3O4) nanospheres and another CEA aptamer (DNA2) immobilized on Au/Ag+ MAs, a complex is formed and acquired by magnetic separation. Then, Au/Ag+ MAs of the complex are disassembled into Au NPs and Ag+ ions driven by an acetone response, and the obtained demulsification solution is transferred to the cadmium sulfide/cadmium telluride (CdS/CdTe) photoactive composites modified electrode. Based on the multiple inhibition functions (blocking effect of oleylamine; energy transfer effect of Au NPs; and electron snatching effect of Ag+), the photocurrent of the electrode decreases obviously, resulting in the ultrasensitive detection of CEA (a detection limit of 16 fg mL-1). Interestingly, the ion-exchange reactions between CdS/CdTe composites and Ag+ ions generate silver sulfide/silver telluride (Ag2S/Ag2Te) composites, and a color change of composites can be distinguished directly, leading to a quick visual detection of CEA. Compared with the traditional single-modal assay for CEA, such dual-modal PEC/colorimetric assay is a more accurate and reliable due to different mechanisms and independent signal conversion. This work will offer a new perspective for the applications of various self-assemblies in PEC bioanalysis.

Engineering composition-varied Au/PtTe hetero-junction-abundant nanotrough arrays as robust electrocatalysts for ethanol electrooxidation.

Pt-based multi-metallic electrocatalysts containing hetero-junctions are found to have superior catalytic performance to composition-equivalent counterparts. However, in bulk solution, controllable preparation of Pt-based hetero-junction electrocatalyst is an extremely random work owing to the complexity of solution reactions. Herein, we develop an interface-confined transformation strategy, subtly achieving Au/PtTe hetero-junction-abundant nanostructures by employing interfacial Te nanowires as sacrificing templates. By controlling the reaction conditions, composition-varied Au/PtTe can be easily obtained, such as Au75/Pt20Te5, Au55/Pt34Te11, and Au5/Pt69Te26. Moreover, each Au/PtTe hetero-junction nanostructure appears to be an array consisting of side-by-side Au/PtTe nanotrough units and can be directly used as a catalyst layer without further post-treatment. All Au/PtTe hetero-junction nanostructures show better catalytic activity towards ethanol electrooxidation than commercial Pt/C because of the combining contributions of Au/Pt hetero-junctions and the collective effects of multi-metallic elements, where Au75/Pt20Te5 exhibits the best electrocatalytic performance among three Au/PtTe nanostructures owing to its optimal composition. This study may provide technically feasible guidance for further maximizing the catalytic activity of Pt-based hybrid catalysts.