A Single-Molecule Pleuripotent Scaffold for Combinational Therapy of Alzheimer's Disease via Intranasal Administration.

The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood-brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium-modified calix[5]arene (GC5AY) is developed as a single-molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier.

Corral[n]Bicarbazoles: Redox-Active Chiral Macrocycles for Air-Stable Radical Cations Formation and Guest Capture/Release.

Macrocyclic compounds are pivotal in both supramolecular chemistry and materials science, as their preorganized cavities enable selective molecular recognition, while their cyclic frameworks facilitate electronic and spatial coupling of monomeric units to yield advanced optoelectronic and magnetic properties. However, macrocycles that combine exceptional host-guest recognition with these properties remain rare and challenging to design. Herein, we report the synthesis of three pairs of enantiopure, redox-active, conjugated macrocycles, termed corral[n]bicarbazole, employing axially chiral 4,4'-bicarbazole units.

Chiral covalent organic cages: Construction and chiral functions.

Covalent organic cages (COCs) are three-dimensional organic molecules with permanent cavities, known for their ordered pore structures, excellent processability, and modular design. They have shown significant potential in applications such as gas adsorption, molecular separation, and catalysis. Introducing chiral elements into COCs results in chiral COCs with confined chiral cavities, which endows them with unique chiral functions and expands their application prospects.

Multiple Host-Guest Interactions in Metal-Organic Frameworks Constructed by Inverted Calix[4]arenes.

Calixarenes are versatile macrocyclic compounds featuring unique basket-like cavities that are capable of encapsulating guest molecules selectively. Yet, their application potentials as the building blocks for supramolecular assemblies have not been thoroughly explored. In this work, a carboxyl-modified azocalix[4]arene (CAC4A) is selected as the organic ligand to construct metal-organic frameworks (MOFs), an emerging class of porous materials based on coordination units.

Architecting X-Aggregates as Charge Transport Pathways to Enhance Photocatalytic Activity of Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have demonstrated significant potential in photocatalysis. However, the impeded transport of charge carriers from the bulk to the surface creates a bottleneck that restricts the overall efficiency of photocatalytic reactions. To address this issue, in this study, charge carrier transport pathways are integrated into MOF photocatalysts by modulating the stacking arrangement of ligand chromophores.

Single-Molecule Macrocyclic Carrier Overcomes the Direct Transmembrane of Medium-Sized Cargoes.

Direct transmembrane transport plays an important role in the biomedical field. Although well-established methods exist for the direct membrane transport of small-sized cargoes (e.g.

Hypoxia-sensitive macrocycle inclusion complexes for targeted protein degradation.

PROteolysis TArgeting Chimeras (PROTACs) have gained significant attention for targeted protein degradation in cancer therapy. However, their clinical application is limited by low bioavailability, poor tumor distribution, and potential off-target effects. This study presents NaC4A-PROTACs, a hypoxia-responsive host-guest drug delivery system where azo-modified calixarene derivative (Naph-SAC4A) acts as the host molecule, encapsulating PROTAC molecules as the guest.

Ophthalmic formulation of methotrexate: a strategy of using the self-assembled LacAC4A nanoparticles for non-invasive drug delivery to the ocular posterior segment.

Drug delivery to ocular posterior segment remains difficult due to the challenges imposed by dynamic and static ocular barriers, lesion point targeting, and off-target effect. In this study, a novel approach is demonstrated for non-invasive drug delivery to the ocular posterior segments using lactose-modified azocalix[4] arene (LacAC4A) as a supramolecular ocular drug delivery platform. LacAC4A contains azo groups and is covalently modified by lactose groups, which confers active targeting to the retina, and induces a hypoxic response.

α-Synuclein targeted therapy with multiple pathological improvement for Parkinson's disease by macrocyclic amphiphile nanomedicine.

The toxic species formed by the pathological aggregation of α-synuclein (α-Syn) is one of the core pathogenic mechanisms in Parkinson's disease, leading to mitochondrial dysfunction, oxidative stress and ultimately degeneration and loss of dopaminergic neurons. Developing effective inhibitors targeting α-Syn fibrillization critically requires the simultaneous achievement of (1) strong and selective binding of α-Syn for efficient disintegration of fibrils, as well as (2) robust transmembrane capability for efficient cellular uptake. Herein, the co-assembly of guanidinium-modified calixarene (GCA) and cyclodextrin (CD), termed GCA-CD, is screened fully accommodating these conditions.

Ultrahigh-Affinity Molecular Recognition in Water and Biomedical Applications.

Aqueous-phase molecular recognition pairs with ultrahigh binding affinity hold immense value in biotechnology and chemical applications. However, the rational design of synthetic pairs with such exceptional binding strength has long remained a significant challenge, with notable progress achieved only in recent years. In this minireview, we begin by defining the term "ultrahigh-affinity" through a comprehensive analysis of available data on aqueous-phase molecular recognition by water-soluble macrocyclic hosts.

Integrating Proteolysis-Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation.

Targeted protein degradation (TPD) using the proteolysis-targeting chimeras (PROTACs) is emerging as a revolutionary technology, offering a potential strategy for cancer treatment by inducing the degradation of overexpressed oncogenic proteins in tumors. PROTACs function by recruiting E3 ligases and utilizing the ubiquitin-proteasome pathway (UPS) to catalyze the degradation of target oncogenic proteins. Compared to traditional small molecules inhibitors, PROTACs exhibit enhanced selectivity, the ability to overcome drug resistance, and target proteins traditionally deemed "undruggable".

High-affinity 1 : 2 recognition based on naphthyl-azocalix[4]arene and its application as a cleavable noncovalent connector in constructing responsive supramolecular polymeric materials.

Macrocyclic hosts which can bind two guests simultaneously with high affinity, such as cucurbit[8]uril, are highly useful for a wide range of applications by acting as noncovalent connectors. However, the integration of stimuli-controlled release properties into such robust noncovalent connectors would be even more desirable. Here, we introduce Naph-SAC4A, a naphthyl-extended deep-cavity azocalix[4]arene with hypoxia-responsiveness, which exhibits exceptional 1 : 2 hosting abilities for organic dyes in aqueous solution with affinities ranging from 10 to 10 M.

Highly Sensitive, Specific, and Fast Fluorescent Sensing of Amphetamine via Structural Regulation.

How to modulate the molecular structure to finely manipulate the sensing performance is of great significance for propelling the oriented design of the optical sensing probe. Here, by taking the optical detection toward amphetamine (AMP) as a model, a structural regulation strategy for the D-π-A probe was proposed to manipulate the reaction activity and optical response. The optimal probe was screened out from a series of D-π-A molecules with an electrophilic site owing to its faster response and more remarkable emission shift, as well as the desirable specificity.

Rapid Detection of Zeranol Contamination in Cereals Using a Quaternary Ammonium-Functionalized Terphen[3]arene-Based Optical Sensor.

To ensure food safety and quality, sensitive and accurate methods for rapidly detecting mycotoxins have become imperative. Zeranols (ZERs) are a class of mycotoxins commonly found in cereals, posing serious health risks, including hormonal disruption and carcinogenic potential. In response to this pressing concern, we have developed a simple yet highly sensitive and high-throughput supramolecular sensing approach based on novel macrocycles known as extended biphen[]arenes for monitoring ZERs in cereal matrices.

Modeling and optimization of docosahexaenoic acid production by Schizochytrium sp. based on kinetic modeling and genetic algorithm optimized artificial neural network.

Docosahexaenoic acid (DHA), an essential ω-3 polyunsaturated fatty acid, is efficiently biosynthesized by Schizochytrium sp., yet its bioprocess optimization remains constrained by dynamic interdependencies between cultivation parameters and metabolic shifts. This study establishes a framework integrating kinetic modeling and machine learning to improve DHA production.

Supramolecular discrimination and diagnosis-guided treatment of intracellular bacteria.

Pathogenic intracellular bacteria pose a significant threat to global public health due to the barriers presented by host cells hindering the timely detection of hidden bacteria and the effective delivery of therapeutic agents. To address these challenges, we propose a tandem diagnosis-guided treatment paradigm. A supramolecular sensor array is developed for simple, rapid, accurate, and high-throughput identification of intracellular bacteria.

Assembly-enhanced recognition: A biomimetic pathway to achieve ultrahigh affinities.

On the one hand, nature utilizes hierarchical assemblies to create complex biological binding pockets, enabling ultrastrong recognition toward substrates in aqueous solutions. On the other hand, chemists have been fervently pursuing high-affinity recognition by constructing covalently well-preorganized stereoelectronic cavities. The potential of noncovalent assembly, however, for enhancing molecular recognition has long been underestimated.

Synthetic biology meets Aspergillus: engineering strategies for next-generation organic acid production.

Organic acids constitute a vital category of chemical raw materials. They have extensive applications in industries such as polymers, food, and pharmaceuticals. Currently, industrial production predominantly relies on microbial fermentation.

Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.

Hypoxic tumors present a significant challenge in cancer therapy due to their ability to adaptation in low-oxygen environments, which supports tumor survival and resistance to treatment. Enhanced mitophagy, the selective degradation of mitochondria by autophagy, is a crucial mechanism that helps sustain cellular homeostasis in hypoxic tumors. In this study, we develop an azocalix[4]arene-modified supramolecular albumin nanoparticle, that co-delivers hydroxychloroquine and a mitochondria-targeting photosensitizer, designed to induce cascaded oxidative stress by regulating mitophagy for the treatment of hypoxic tumors.

Vesicle-Encapsulated Chemosensing Ensembles Allow Monitoring of Transmembrane Uptake Coupled with Enzymatic Reactions.

Compartmentalized models with coupled catalytic networks are considered as "protocells" in the context of research related to the origin of life. To model the kinetics of a simple cellular uptake-metabolism process, we use a compartmentalized protocell system that combines liposome-encapsulated intravesicular reporter pairs with co-encapsulated enzymes to monitor the membrane transport of a substrate (analyte uptake) and its subsequent enzymatic reaction inside the vesicles (metabolism to the product). The intravesicular chemosensing ensembles consist of the macrocycles cucurbit[7]uril or p-sulfonatocalix[4]arene and matching fluorescent dyes to set up suitable reporter pairs.

A FRET Autophagy Imaging Platform by Macrocyclic Amphiphile.

Autophagy is a ubiquitous process of organelle interaction in eukaryotic cells, in which various organelles or proteins are recycled and operated through the autophagy pathway to ensure nutrient and energy homeostasis. Although numerous fluorescent probes have been developed to image autophagy, these environment-responsive probes suffer from inherent deficiencies such as inaccuracy and limited versatility. Here, we present a modular macrocyclic amphiphile Förster Resonance Energy Transfer (FRET) platform (SC6A12C/NCM, SN), constructed through the amphiphilic assembly of sulfonatocalix[6]arene (SC6A12C) with N-cetylmorpholine (NCM) for lysosome targeting.

Multi Targeted Therapy for Alzheimer's Disease by Guanidinium-Modified Calixarene and Cyclodextrin Co-Assembly Loaded with Insulin.

Amyloid-β (Aβ) is considered a primary therapeutic target for Alzheimer's disease (AD). However, just eliminating Aβ in patients with AD has exhibited restricted clinical efficacy, possibly failing to address the metabolic abnormalities caused by AD, such as insulin resistance. To address this concern, our research has employed two types of macrocyclic amphiphiles, guanidinium-modified calixarene and cyclodextrin coassembly (GCD), as delivery systems for insulin.