Neutralization of Intracellular pH Homeostasis to Inhibit Osteoclasts Based on a Spatiotemporally Selective Delivery System.

Osteoporosis is a global disease caused by abnormal overactivation of osteoclasts. The acidic environment in sealing zone of osteoclasts with H+ pumped from cytoplasm is critical to the maturation of osteoclasts. Therefore, reducing the intracellular H+ concentration can reduce the H+ secretion of osteoclasts from the source. In our study, we developed a novel nanovesicle which encapsulates Na2HPO4 with a liposome hybridizes with preosteoclast membrane (Na2HPO4@Lipo-pOCm). These nanovesicles release Na2HPO4 into the preosteoclast by targeting preosteoclasts and membrane fusion, reducing the intracellular H+ concentration, and achieve biological cascade regulation of osteoclasts through simple pH regulation. In vitro and in vivo experiments confirmed that these nanovesicles reduce mitochondrial membrane potential by decreasing intracellular H+ concentration, thereby reducing the ROS in osteoclasts as well as the expression of the upstream transcription factor FOXM1 of Acp5. In short, this nanovesicle can significantly inhibit the osteoclasts and ameliorate osteoporosis caused by OVX.

An Organoplatinum(II) Metallacycle-Based Supramolecular Amphiphile and Its Application in Enzyme-Responsive Controlled Release.

Enzyme-responsive nanomaterials are emerging as important candidates for bioanalytical and biomedical applications due to their good biocompatibilities and sensitivities. However, the lack of promising operation platforms compatible with enzyme responsiveness greatly limits the scope and functionality of smart materials. Herein, we report the design and synthesis of a naphthalene-functionalized organoplatinum(II) metallacycle 1 by means of coordination-driven self-assembly, which is subsequently exploited as the organometallic platform to enable enzyme-responsive supramolecular materials. Specifically, a [2 + 2] self-assembled metallacycle 1 first self-assembles into nanosheets in aqueous solution, which can further transform into vesicles with the introduction of ß-cyclodextrin (ß-CD) because of the formation of a bola-type supramolecular amphiphile ß-CD-1. Interestingly, these vesicles show rare α-amylase responsiveness, as demonstrated by structurally transforming back into nanosheets after the addition of α-amylase to their solutions due to the enzyme-induced degradation of cyclodextrins. We also demonstrate the potential application of the self-assembled vesicles in amylase-responsive controlled release.

Selective Separation of Phenanthrene from Aromatic Isomer Mixtures by a Water-Soluble Azobenzene-Based Macrocycle.

Selective separation of phenanthrene (PHE) from aromatic isomer mixtures is a big challenge in industry. In this work, a light-responsive water-soluble azobenzene-based macrocycle 1 is synthesized and an aqueous solution of E,E-1 is employed to separate PHE from anthracene via a solid-liquid extraction method under ambient conditions. After five extraction cycles, the average purity for PHE is about 91.1% and macrocycle 1 can be reused at least five times without obvious reduction of separation performance for PHE. This work not only comprises a new and clean way to separate PHE by taking advantage of a macrocyclic host but also promotes the application of host-guest chemistry.

Chemoresponsive Supramolecular Polypseudorotaxanes with Infinite Switching Capability.

Chemoresponsive supramolecular systems with infinite switching capability are important for applications in recycled materials and intelligent devices. To attain this objective, here a chemoresponsive polypseudorotaxane is reported on the basis of a bis(p-phenylene)-34-crown-10 macrocycle (H) and a cyano-substituted viologen guest (G). H and G form a [2]pseudorotaxane (H⊃G) both in solution and in the solid state. Upon addition of AgSF6 , a polypseudorotaxane (denoted as [H⋅G⋅Ag]n ) forms as synergistically driven by host-guest complexation and metal-coordination interactions. [H⋅G⋅Ag]n depolymerizes into a [3]pseudorotaxane (denoted as H2 ⋅G⋅Ag2 ⋅acetone2 ) upon addition of H and AgSF6 , while it reforms with successive addition of G. The transformations between [H⋅G⋅Ag]n and H2 ⋅G⋅Ag2 ⋅acetone2 can be switched for infinite cycles, superior to the conventional chemoresponsive supramolecular polymeric systems with limited switching capability.

Formation of Planar Chiral Platinum Triangles via Pillar[5]arene for Circularly Polarized Luminescence.

Chiral metal-organic complexes hold great promise as new functional materials that exhibit unique stereochemical and optical properties. Here, we report the formation of optically pure pillar[5]arene-based platinum chiral metallacycles. By coordination with 60° and 90° Pt(II) acceptors, planar chiral platinum triangles were self-assembled efficiently and characterized by multiple spectroscopic techniques. Optical studies indicated that these metallacycles had chiral properties: pS enantiomers showed a negative Cotton effect, and pR enantiomers exhibited a positive Cotton effect. In addition, these metallacycles also exhibited circularly polarized luminescence.

Pillararene Host-Guest Complexation Induced Chirality Amplification: A New Way to Detect Cryptochiral Compounds.

The contradiction between the rising demands of optical chirality sensing and the failure in chiral detection of cryptochiral compounds encourages researchers to find new methods for chirality amplification. Inspired by planar chirality and the host-guest recognition of pillararenes, we establish a new concept for amplifying CD signals of cryptochiral molecules by pillararene host-guest complexation induced chirality amplification. The planar chirality of pillararenes is induced and stabilized in the presence of the chiral guest, which makes the cryptochiral molecule detectable by CD spectroscopy. Several chiral guests are selected in these experiments and the mechanism of chiral amplification is studied with a non-rotatable pillararene derivative and density functional theory calculations. We believe this work affords deeper understanding of chirality and provides a new perspective for chiral sensing.

Spontaneous Formation of a Cross-Linked Supramolecular Polymer Both in the Solid State and in Solution, Driven by Platinum(II) Metallacycle-Based Host-Guest Interactions.

The recent progress in platinum(II) coordination-driven supramolecular polymers has had a substantial effect on the design of functional soft materials. However, the prospect of realizing polymerization induced by platinum(II) metallacycle-based host-guest interactions has received little attention until recently. Here we report the realization of supramolecular polymerization driven by platinum(II) metallacycle-based host-guest interactions both in the solid state and in solution. On the basis of the disclosed polymerization mechanism, we present a new strategy for the preparation of platinum(II) metallacycle-based supramolecular polymers.

Construction of Metallacage-Cored Supramolecular Gel by Hierarchical Self-Assembly of Metal Coordination and Pillar[5]arene-Based Host-Guest Recognition.

In this work, a Pd2 L4 metallacage 2•([BF4 ]- )4 with four pillar[5]arene units is first prepared and characterized by 1D multinuclear NMR (1 H, 11 B, and 19 F NMR), 2D 1 H-1 H correlation spectra, 1 H-13 C heteronuclear single quantum coherence, and diffusion-ordered NMR spectroscopy, and electrospray ionization time-of-flight mass spectrometry. By the introduction of a ditopic guest molecule 3 into a chloroform solution of 2•([BF4 ]- )4 , a supramolecular polymer network gel is successfully constructed based on the metal coordination interactions and host-guest recognition between the pillar[5]arene units of 2•([BF4 ]- )4 and neutral ditopic guest molecule 3. The temperature and pH responsivenesses of the supramolecular gel are studied, which are further employed for the controlled release of different cargos. As a demonstration, emodin and methylene blue are trapped in the cavities of the metallacage and in the pores of the supramolecular gel, respectively. Methylene blue is first released along with the gel-sol transition while emodin is then released by the further addition of acid to destroy the metallacage. This study explores the use of metallacage-cored supramolecular network gels for sequential controlled release and contributes to the development of smart and adaptive materials.

Targeting initial tumour-osteoclast spatiotemporal interaction to prevent bone metastasis.

Bone is the most common site of metastasis, and although low proliferation and immunoediting at the early stage make existing treatment modalities less effective, the microenvironment-inducing behaviour could be a target for early intervention. Here we report on a spatiotemporal coupling interaction between tumour cells and osteoclasts, and named the tumour-associated osteoclast 'tumasteoclast'-a subtype of osteoclasts in bone metastases induced by tumour-migrasome-mediated cytoplasmic transfer. We subsequently propose an in situ decoupling-killing strategy in which tetracycline-modified nanoliposomes encapsulating sodium bicarbonate and sodium hydrogen phosphate are designed to specifically release high concentrations of hydrogen phosphate ions triggered by tumasteoclasts, which depletes calcium ions and forms calcium-phosphorus crystals. This can inhibit the formation of migrasomes for decoupling and disrupt cell membrane for killing, thereby achieving early prevention of bone metastasis. This study provides a research model for exploring tumour cell behaviour in detail and a proof-of-concept for behaviour-targeting strategy.

Extracellular Vesicle Mimetics: Preparation from Top-Down Approaches and Biological Functions.

Extracellular vesicles (EVs) have attracted attention as delivery vehicles due to their structure, composition, and unique properties in regeneration and immunomodulation. However, difficulties during production and isolation processes of EVs limit their large-scale clinical applications. EV mimetics (EVMs), prepared via top-down strategies that improve the yield of nanoparticles while retaining biological properties similar to those of EVs have been used to address these limitations. Herein, the preparation of EVMs is reviewed and their characteristics in terms of structure, composition, targeting ability, cellular uptake mechanism, and immunogenicity, as well as their strengths, limitations, and future clinical application prospects as EV alternatives are summarized.

Rationally Designed Self-Immolative Rotaxane Sensor Based on Pillar[5]arene for Fluoride Sensing.

We develop a self-immolative rotaxane sensor for fluoride sensing based on host-guest interactions between pillar[5]arene and fluoride-promoted cleavage of Si-O bond. Because of the selective and fast reaction between silane and fluoride, the rotaxane sensor shows anion selectivity and rapid response. The self-immolative nature of the rotaxane improve its sensitivity. Moreover, a fluoride sensing test paper based on the rotaxane sensor is made, which shows the practicable application of the rotaxane sensor.

Supramolecular peptide constructed by molecular Lego allowing programmable self-assembly for photodynamic therapy.

Peptide self-assemblies with multiple nanostructures have great potentials in functional biomaterials, and yet the tedious and costly covalent peptide modification and the lack of facile controllability on self-assembly morphology retard the peptide-related exploration. Here we report a simple approach to fabricate a supramolecular peptide that shows programmable self-assembly with multiple morphologies and application in photodynamic therapy. Pillar[5]arene-based host-guest recognition is used to construct a supramolecular peptide, which simplify the peptide modification and promote the controllability of the self-assembly behavior. Due to the ERGDS sequences on the exterior surfaces and hydrophobic cores of self-assemblies, the nanoparticles formed from the supramolecular peptide are suitable vehicles to encapsulate a photosensitizer for photodynamic therapy. In vitro and in vivo studies demonstrate that the inherent targeting capability and supramolecular strategy greatly boost its photodynamic therapeutic efficiency. This supramolecular peptide holds promising potentials in precise cancer therapy and perspectives for the peptide modification.

Supramolecular therapeutics to treat the side effects induced by a depolarizing neuromuscular blocking agent.

Succinylcholine (Sch) is the only depolarizing neuromuscular blocking agent widely used for rapid sequence induction in emergency rooms. Unfortunately, a variety of (sometimes lethal) adverse effects, such as hyperkalemia and cardiac arrest, are associated with its use, and currently there are no specific antidotes to reverse Sch or to treat these side-effects. Methods: The binding behaviors of Sch and several synthetic receptors, including cucurbit[7]uril, sulfo-calix[4]arene and water-soluble carboxylatopillar[6]arene (WP[6]), were first investigated. With a mouse model, a leathal dose of Sch was selected for evaluation of the antidotal effects of these synthetic receptors on Sch induced mortality. The antidotal effects of a selected synthetic receptor, WP[6], on Sch induced cardiac arrhythmias, hyperkalemia, rhabdomyolysis and paralysis were subsequently evaluated with rat and mouse models. The reversal mechanism was also investigated at a cellular level. Results: All of these macrocyclic molecules exhibited relatively high binding affinities with Sch in vitro. In a Sch-overdosed mouse model, immediate injection of these synthetic receptors right after Sch administration increased the overall survival rate, with WP[6] standing out with the most effective antidotal effects. In addition, administration of WP[6] also reversed the paralysis induced by Sch in a mouse model. Moreover, infusion of WP[6] to Sch-overdosed rats reduced the incidence of cardiac arrhythmia, inhibited the otherwise abnormally high serum potassium levels, and relieved the muscular damage. At the cellular level, WP[6] reversed the Sch induced depolarization and reduced the efflux of intracellular potassium. Conclusion: Synthetic receptors, particularly WP[6], exhibited high binding affinities towards Sch, and presented a significant potential as supramolecular therapeutics to treat the various side effects of Sch by specifically sequestering Sch in vivo.

A multi-responsive cross-linked supramolecular polymer network constructed by mussel yield coordination interaction and pillar[5]arene-based host-guest complexation.

Here a novel cross-linked supramolecular polymer network with thermal, pH, and H2S responsiveness was prepared inspired by mussel yield catechol-Fe3+ coordination and pillar[5]arene-based host-guest interactions.

Novel rare earth fluorescent supramolecular polymeric assemblies constructed by orthogonal pillar[5]arene-based molecular recognition, Eu(iii)-coordination and π-π donor-acceptor interactions.

Here, a facile strategy is provided to prepare pillar[5]arene-based fluorescent supramolecular polymer assemblies by orthogonal Eu(iii)-coordination and two non-interfering noncovalent interactions.

Enhancing the solubility and bioactivity of anticancer drug tamoxifen by water-soluble pillar[6]arene-based host-guest complexation.

A water-soluble pillar[6]arene functions as a solubilizing agent to enhance the solubility and bioactivity of poorly water-soluble anticancer drug tamoxifen by host-guest complexation between it and tamoxifen.

Control on the photo-responsive assembly of a stilbene-containing amphiphile by using pillar[5]arene-based host-guest interactions.

A supra-amphiphilic system with a tunable supra-amphiphilic type and self-assembled morphology was constructed and controlled via light and host-guest interactions based on a water-soluble pillar[5]arene and a stiff-stilbene.