Dumbbells,Trikes and Quads: Organic–Inorganic Hybrid Nanoarchitectures Based on “Clicked” Gold Nanoparticles

The controlled assembly of gold nanoparticles in terms of the spatial arrangement and number of particles is essential for many future applications like electronic devices, sensors and labeling. Here an approach is presented to build up oligomers of mono functionalized gold nanoparticles by the use of 1,3‐bipolar azide alkyne cycloaddition click chemistry. The gold nanoparticles of 1.3 nm diameter are stabilized by one dendritic thioether ligand comprising an alkyne function. Together with di‐, tri‐ and tetra‐azide linker molecules the gold nanoparticle can be covalently coupled by a wet chemical protocol. The reaction is tracked with IR and UV–vis spectroscopy and the yielded organic‐inorganic hybrid structures are analyzed by transmission electron microscopy. To evaluate the success of this click chemistry reaction statistical analysis of the formed oligomers is performed. The geometric and spatial arrangements of the found oligomers match perfectly the calculated values for the used linker molecules. Dimers, trimers and tetramers could be identified after the reaction with the corresponding linker molecule. The results of this model reaction suggest that the used click chemistry protocol is working well with mono functionalized gold nanoparticles.     

Thiol–Ene Click Reaction as a Facile and General Approach for Surface Functionalization of Colloidal Nanocrystals

Oleic acid (OA) and/or oleylamine (OAm) are generally used as the surface ligands for stabilization of inorganic nanocrystals (NCs). The hydrophobic and inert surface of the NCs limits their applications such as in biomedical areas. Hence, surface modifications are essential in many physical and chemical processes. Here, a facile and versatile strategy is reported for the modification of NCs by ultraviolet‐induced thiol–ene chemistry, in which thiol‐terminated poly(ethylene glycol) (HS? PEG) and its derivatives can react directly with double bonds in OA/OAm ligands to form covalent linking within one step. Through this strategy, various hydrophobic NCs with different compositions and morphologies are able to be transferred into water combining with functionalization of active groups. As a proof‐of‐concept, this strategy is successfully used to construct a sensor for detecting avidin based on upconverting luminescence analysis. Therefore, this strategy provides a new tool for designing and tuning the surface properties of NCs for different applications.     

Metal–Organic‐Framework‐Assisted In Vivo Bacterial Metabolic Labeling and Precise Antibacterial Therapy

Bacterial infection is one of the most serious physiological conditions threatening human health. There is an increasing demand for more effective bacterial diagnosis and treatment through noninvasive theranostic approaches. Herein, a new strategy is reported to achieve in vivo metabolic labeling of bacteria through the use of MIL‐100 (Fe) nanoparticles (NPs) as the nanocarrier for precise delivery of 3‐azido‐d ‐alanine (d ‐AzAla). After intravenous injection, MIL‐100 (Fe) NPs can accumulate preferentially and degrade rapidly within the high H₂O₂ inflammatory environment, releasing d ‐AzAla in the process. d ‐AzAla is selectively integrated into the cell walls of bacteria, which is confirmed by fluorescence signals from clickable DBCO‐Cy5. Ultrasmall photosensitizer NPs with aggregation‐induced emission characteristics are subsequently designed to react with the modified bacteria through in vivo click chemistry. Through photodynamic therapy, the amount of bacteria on the infected tissue can be significantly reduced. Overall, this study demonstrates the advantages of metal–organic‐framework‐assisted bacteria metabolic labeling strategy for precise bacterial detection and therapy guided by fluorescence imaging.     

Metal‐Free Click Chemistry Reactions on Surfaces

In the last decade, interest in the functionalization of surfaces and materials has increased dramatically. In this regard, click chemistry deserves a central focus because of its mild reaction conditions, high efficiency, and easy post‐treatment. Among such novel click reactions, those that do not require any metal catalyst are of special interest, as metals may have undesirable effects in many fields. In this Review, the backgrounds and application of such metal‐free click reactions for the modification of surfaces are highlighted.     

Imparting Designer Biorecognition Functionality to Metal–Organic Frameworks by a DNA‐Mediated Surface Engineering Strategy

Surface functionality is an essential component for processing and application of metal–organic frameworks (MOFs). A simple and cost‐effective strategy for DNA‐mediated surface engineering of zirconium‐based nanoscale MOFs (NMOFs) is presented, capable of endowing them with specific molecular recognition properties and thus expanding their potential for applications in nanotechnology and biotechnology. It is shown that efficient immobilization of functional DNA on NMOFs can be achieved via surface coordination chemistry. With this strategy, it is demonstrated that such porphyrin‐based NMOFs can be modified with a DNA aptamer for targeting specific cancer cells. Furthermore, the DNA–NMOFs can facilitate the delivery of therapeutic DNA (e.g., CpG) into cells for efficient recognition of endosomal Toll‐like receptor 9 and subsequent enhanced immunostimulatory activity in vitro and in vivo. No apparent toxicity is observed with systemic delivery of the DNA–NMOFs in vivo. Overall, these results suggest that the strategy allows for surface functionalization of MOFs with different functional DNAs, extending the use of these materials to diverse applications in biosensor, bioimaging, and nanomedicine.     

Click‐Chemistry Based Allergen Arrays Generated by Polymer Pen Lithography for Mast Cell Activation Studies

The profiling of allergic responses is a powerful tool in biomedical research and in judging therapeutic outcome in patients suffering from allergy. Novel insights into the signaling cascades and easier readouts can be achieved by shifting activation studies of bulk immune cells to the single cell level on patterned surfaces. The functionality of dinitrophenol (DNP) as a hapten in the induction of allergic reactions has allowed the activation process of single mast cells seeded on patterned surfaces to be studied following treatment with allergen specific Immunoglobulin E antibodies. Here, a click‐chemistry approach is applied in combination with polymer pen lithography (PPL) to pattern DNP‐azide on alkyne‐terminated surfaces to generate arrays of allergen. The large area functionalization offered by PPL allows an easy incorporation of such arrays into microfluidic chips. In such a setup, easy handling of cell suspension, incubation process, and read‐out by fluorescence microscopy will allow immune cell activation screening to be easily adapted for diagnostics and biomedical research.     

Two Dimensional Nanoarrays of Individual Protein Molecules

Protein molecules on solid surfaces are essential to a number of applications, such as biosensors, biomaterials, and drug delivery. In most approaches for protein immobilization, inter‐molecular distances on the solid surface are not controlled and this may lead to aggregation and crowding. Here, a simple approach to immobilize individual protein molecules in a well‐ordered 2D array is shown, using nanopatterns obtained from a polystyrene‐block‐poly(2‐hydroxyethyl methacrylate) (PS‐b‐PHEMA) diblock copolymer thin film. This water‐stable and protein‐resistant polymer film contains hexagonally ordered PS cylindrical domains in a PHEMA matrix. The PS domains are activated by incorporating alkyne‐functionalized PS and immobilizing azide‐tagged proteins specifically onto each PS domain using “Click” chemistry. The nanometer size of the PS domain dictates that each domain can accommodate no more than one protein molecule, as verified by atomic force microscopy imaging. Immunoassay shows that the amount of specifically bound antibody scales with the number density of individual protein molecules on the 2D nanoarrays.     

Wetting‐Controlled Localized Placement of Surface Functionalities within Nanopores

In the context of sensing and transport control, nanopores play an essential role. Designing multifunctional nanopores and placing multiple surface functionalities with nanoscale precision remains challenging. Interface effects together with a combination of different materials are used to obtain local multifunctionalization of nanoscale pores within a model pore system prepared by colloidal templating. Silica inverse colloidal monolayers are first functionalized with a gold layer to create a hybrid porous architecture with two distinct gold nanostructures on the top surface as well as at the pore bottom. Using orthogonal silane‐ and thiol‐based chemistry together with a control of the wetting state allows individual addressing of the different locations within each pore resulting in nanoscale localized functional placement of three different functional units. Ring‐opening metathesis polymerization is used for inner silica‐pore wall functionalization. The hydrophobized pores create a Cassie–Baxter wetting state with aqueous solutions of thiols, which enables an exclusive functionalization of the outer gold structures. In a third step, an ethanolic solution able to wet the pores is used to self‐assemble a thiol‐containing initiator at the pore bottom. Subsequent controlled radical polymerization provides functionalization of the pore bottom. It is demonstrated that the combination of orthogonal surface chemistry and controlled wetting states can be used for the localized functionalization of porous materials.     

Ultrathin, responsive polymer click capsules

We report a general click chemistry approach for the layer-by-layer assembly of ultrathin, polymer films on particles and the subsequent formation of polymer click capsules (CCs). Poly(acrylic acid) copolymers, synthesized with a minor component of either alkyne (PAA-Alk) or azide (PAA-Az) functionality, were alternately assembled on silica particles. The (PAA-Az/PAA-Alk)-coated particles were subsequently functionalized by exploiting the free alkyne click moieties present in the film upon exposure to an azide-modified rhodamine dye. Further, PAA CCs, obtained following removal of the silica particle template, were shown to exhibit pH-responsive behavior. This was demonstrated by reversible size changes of the CCs upon cycling between basic and acidic solutions. Polymer CCs are anticipated to find applications in various fields, including drug delivery and sensing.     

In Situ Bioorthogonal Metabolic Labeling for Fluorescence Imaging of Virus Infection In Vivo

Optical fluorescence imaging is an important strategy to explore the mechanism of virus–host interaction. However, current fluorescent tag labeling strategies often dampen viral infectivity. The present study explores an in situ fluorescent labeling strategy in order to preserve viral infectivity and precisely monitor viral infection in vivo. In contrast to pre‐labeling strategy, mice are first intranasally infected with azide‐modified H5N1 pseudotype virus (N₃‐H5N1p), followed by injection of dibenzocyclooctyl (DBCO)‐functionalized fluorescence 6 h later. The results show that DBCO dye directly conjugated to N₃‐H5N1p in lung tissues through in vivo bioorthogonal chemistry with high specificity and efficacy. More remarkably, in situ labeling rather than conventional prelabeling strategy effectively preserves viral infectivity and immunogenicity both in vitro and in vivo. Hence, in situ bioorthogonal viral labeling is a promising and reliable strategy for imaging and tracking viral infection in vivo.     

Synthesis of Hydrogen‐Substituted Graphyne Film for Lithium–Sulfur Battery Applications

Graphyne (GY) is a new type of carbon allotrope, which is viewed as a rapidly rising star in the carbon family referred to as 2D carbon allotropes due to its extraordinary properties. Considering the dynamic nature of the alkyne metathesis reaction, a hydrogen‐substituted graphyne (HsGY) film is successfully synthesized on a gas/liquid interface using 1,3,5‐tripynylbenzene (TPB) as the precursor. The synthesized HsGY film is used as a sulfur host matrix to be applied in lithium–sulfur batteries (LSBs). The HsGY@S electrode is prepared using S₈ as sulfur source and presents excellent electrochemical performance.     

Bifunctional Au@Bi2Se3 Core–Shell Nanoparticle for Synergetic Therapy by SERS‐Traceable AntagomiR Delivery and Photothermal Treatment

For the first time, topological insulator bismuth selenide nanoparticles (Bi₂Se₃ NP) are core–shelled with gold (Au@Bi₂Se₃) i) to represent considerably small‐sized (11 nm) plasmonic nanoparticles, enabling accurate bioimaging in the near‐infrared region; ii) to substantially improve Bi₂Se₃ biocompatibility, iii) water dispersibility, and iv) surface functionalization capability through straightforward gold–thiol interaction. The Au@Bi₂Se₃ is subsequently functionalized for v) effective targeting of SH‐SY5Y cancer cells, vi) disrupting the endosome/lysosome membrane, vii) traceable delivery of antagomiR‐152 and further synergetic oncomiR knockdown and photothermal therapy (PTT). Unprecedentedly, it is observed that the Au shell thickness has a significant impact on evoking the exotic plasmonic features of Bi₂Se₃. The Au@Bi₂Se₃ possesses a high photothermal conversion efficiency (35.5%) and a remarkable surface plasmonic effect (both properties are approximately twofold higher than those of 50 nm Au nanoparticles). In contrast to the siRNA/miRNA delivery methods, the antagomiR delivery is based on strand displacement, in which the antagomiR‐152 is displaced by oncomiR‐152 followed by a surface‐enhanced Raman spectroscopy signal drop. This enables both cancer cell diagnosis and in vitro real‐time monitoring of the antagomiR release. This selective PTT nanoparticle can also efficiently target solid tumors and undergo in vivo PTT, indicating its potential clinical applications.     

Oberflächenmodifizierung von Titan zur Verbesserung der Grenzflächenverträglichkeit

Surface Modification of Titanium for Improvement of the Interfacial Biocompatibility We report the CVD‐polymerisation of amino‐functionalized [2,2]‐paracyclophane for polymer coating and functionalization of titanium surfaces. Additionally, the functionalization was carried out by silanization with 3‐aminopropyl‐triethoxysilane. The generated amino‐groups were used for covalent immobilization of bioactive substances to stimulate the adhesion and growth of osteoblasts. As bioactive substances the pentapeptide GRGDS and the growth factor BMP‐2 were chosen. The covalent bonding was achieved by activation with hexamethylene diisocyanate. Each modification step was characterized by X‐ray‐photoelectron‐spectroscopy (XPS), atomic force microscopy (AFM) and contact angle measurements. The covalent bonding of the bioactive substances was proven by radiolabelling and surface‐MALDI‐ToF‐MS. In vitro‐biocompatibility tests with primary, human osteoblasts demonstrated the improved cell adhesion and spreading on the bioactive modified titanium surfaces.     

Design Multifunctional Catalytic Interface: Toward Regulation of Polysulfide and Li2S Redox Conversion in Li–S Batteries

The polysulfide shuttle effect and sluggish reaction kinetics hamper the practical applications of lithium–sulfur (Li–S) batteries. Incorporating a functional interlayer to trapping and binding polysulfides has been found effective to block polysulfide migration. Furthermore, surface chemistry at soluble polysulfides/electrolyte interface is a crucial step for Li–S battery in which stable cycling depends on adsorption and reutilization of blocked polysulfides in the electrolyte. A multifunctional catalytic interface composed of niobium nitride/N‐doped graphene (NbN/NG) along the soluble polysulfides/electrolyte is designed and constructed to regulate corresponding interface chemical reaction, which can afford long‐range electron transfer surfaces, numerous strong chemisorption, and catalytic sites in a working lithium–sulfur battery. Both experimental and theoretical calculation results suggest that a new catalytic interface enabled by metal‐like NbN with superb electrocatalysis anchored on NG is highly effective in regulating the blocked polysulfide redox reaction and tailoring the Li₂S nucleation–growth–decomposition process. Therefore, the Li–S batteries with multifunctional NbN/NG barrier exhibit excellent rate performance (621.2 mAh g^?1 at 3 C) and high stable cycling life (81.5% capacity retention after 400 cycles). This work provides new insights to promote Li–S batteries via multifunctional catalytic interface engineering.     

Facile Method for the Site‐Specific,Covalent Attachment of Full‐Length IgG onto Nanoparticles

Antibodies, most commonly IgGs, have been widely used as targeting ligands in research and therapeutic applications due to their wide array of targets, high specificity and proven efficacy. Many of these applications require antibodies to be conjugated onto surfaces (e.g. nanoparticles and microplates); however, most conventional bioconjugation techniques exhibit low crosslinking efficiencies, reduced functionality due to non‐site‐specific labeling and random surface orientation, and/or require protein engineering (e.g. cysteine handles), which can be technically challenging. To overcome these limitations, we have recombinantly expressed Protein Z, which binds the Fc region of IgG, with an UV active non‐natural amino acid benzoylphenyalanine (BPA) within its binding domain. Upon exposure to long wavelength UV light, the BPA is activated and forms a covalent link between the Protein Z and the bound Fc region of IgG. This technology was combined with expressed protein ligation (EPL), which allowed for the introduction of a fluorophore and click chemistry‐compatible azide group onto the C‐terminus of Protein Z during the recombinant protein purification step. This enabled the crosslinked‐Protein Z‐IgG complexes to be efficiently and site‐specifically attached to aza‐dibenzocyclooctyne‐modified nanoparticles, via copper‐free click chemistry.     

Hybrid Nanomedicine Fabricated from Photosensitizer‐Terminated Metal–Organic Framework Nanoparticles for Photodynamic Therapy and Hypoxia‐Activated Cascade Chemotherapy

During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O₂‐consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia‐activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido‐/photosensitizer‐terminated UiO‐66 nanoscale metal–organic frameworks (UiO‐66‐H/N₃ NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered. Owing to the effective shielding of the nanoparticles, the stability of AQ4N is well preserved, highlighting the vital function of the nanocarriers. By virtue of strain‐promoted azide–alkyne cycloaddition, the nanocarriers are further decorated with a dense PEG layer to enhance their dispersion in the physiological environment and improve their therapeutic performance. Both in vitro and in vivo studies reveal that the O₂‐depleting PDT process indeed aggravates intracellular/tumor hypoxia that activates the cytotoxicity of AQ4N through a cascade process, consequently achieving PDT‐induced and hypoxia‐activated synergistic therapy. Benefiting from the localized therapeutic effect of PDT and hypoxia‐activated cytotoxicity of AQ4N, this hybrid nanomedicine exhibits enhanced therapeutic efficacy with negligible systemic toxicity, making it a promising candidate for cancer therapy.     

Engineering the Cell–Semiconductor Interface: A Materials Modification Approach using II‐VI and III‐V Semiconductor Materials

Developing functional biomedical devices based on semiconductor materials requires an understanding of interactions taking place at the material‐biosystem interface. Cell behavior is dependent on the local physicochemical environment. While standard routes of material preparation involve chemical functionalization of the active surface, this review emphasizes both biocompatibility of unmodified surfaces as well as use of topographic features in manipulating cell‐material interactions. Initially, the review discusses experiments involving unmodified II–VI and III–V semiconductors – a starting point for assessing cytotoxicity and biocompatibility – followed by specific surface modification, including the generation of submicron roughness or the potential effect of quantum dot structures. Finally, the discussion turns to more recent work in coupling topography and specific chemistry, enhancing the tunability of the cell‐semiconductor interface. With this broadened materials approach, researchers' ability to tune the interactions between semiconductors and biological environments continues to improve, reaching new heights in device function.     

A Versatile Multicomponent Assembly via β‐cyclodextrin Host–Guest Chemistry on Graphene for Biomedical Applications

A multi‐component nanosystem based on graphene and comprising individual cyclodextrins at its surface is assembled, creating hybrid structures enabling new and important functionalities: optical imaging, drug storage, and cell targeting for medical diagnosis and treatment. These nanohybrids are part of a universal system of interchangeable units, capable of mutilple functionalities. The surface components, made of individual β‐cyclodextrin molecules, are the “hosts” for functional units, which may be used as imaging agents, for anti‐cancer drug delivery, and as tumor‐specific ligands. Specifically, individual β‐cyclodextrin (β‐CD), with a known capability to host various molecules, is considered a module unit that is assembled onto graphene nanosheet (GNS). The cyclodextrin‐functionalized graphene nanosheet (GNS/β‐CD) enables “host–guest” chemistry between the nanohybrid and functional “payloads”. The structure, composition, and morphology of the graphene nanosheet hybrid have been investigated. The nanohybrid, GNS/β‐CD, is highly dispersive in various physiological solutions, reflecting the high biostability of cyclodextrin. Regarding the host capability, the nanohybrid is fully capable of selectively accommodating various biological and functional agents in a controlled fashion, including the antivirus drug amantadine, fluorescent dye [5(6)‐carboxyfluorescein], and Arg‐Gly‐Asp (RGD) peptide‐targeting ligands assisted by an adamantine linker. The loading ratio of 5(6)‐carboxyfluorescein is as high as 110% with a drug concentration of 0.45 mg mL^?1. The cyclic RGD‐functionalized nanohybrid exhibits remarkable targeting for HeLa cells.     

"Click chemistry" in the preparation of porous polymer-based particulate stationary phases for mu-HPLC separation of peptides and proteins

With the use of the copper(I)-catalyzed (3 + 2) azide-alkyne cycloaddition, an element of "click chemistry," stationary phases carrying long alkyl chains or soybean trypsin inhibitor have been prepared for use in HPLC separations in the reversed-phase and affinity modes, respectively. The ligands were attached via a triazole ring to size monodisperse porous beads containing either alkyne or azide pendant functionalities. Alkyne-containing beads prepared by direct copolymerization of propargyl acrylate with ethylene dimethacrylate were allowed to react with azidooctadecane to give a reversed-phase sorbent. Azide-functionalized beads were prepared by chemical modification of glycidyl methacrylate particles. Subsequent reaction with a terminal aliphatic alkyne produced a reversed-phase sorbent similar to that obtained from the alkyne beads. Soybean trypsin inhibitor was functionalized with N-(4-pentynoyloxy)succinimide to carry alkyne groups and then allowed to react with the azide-containing beads to produce an affinity sorbent for trypsin. The performance of these stationary phases was demonstrated with the HPLC separations of a variety of peptides and proteins.     

Synthesis and characterization of polyurethane-grafted single-walled carbon nanotubes via click chemistry

Polyurethane (PU)-grafted carbon nanotubes were synthesized by the coupling of alkyne moiety decorated single walled carbon nanotube (SWCNT) with azide moiety containing PU using Cu(I) catalyzed Huisgen [3 + 2] cycloaddition click chemistry. The azide moiety containing poly(s-caprolactone)diol was synthesized by ring-opening polymerization and further used for PU synthesis. Alkyne-functionalizion of SWCNT was completed by the reaction of p-aminophenyl propargyl ether with SWCNT using a solvent free diazotization procedure. Nuclear magnetic resonance, Fourier transform infrared, and Raman spectroscopic measurements confirmed the functionalization of SWCNT. Scanning electron microscopy and transmission electron microscopy images showed an excellent dispersion of SWCNTs, and specially debundling of SWCNTs could be observed due to polymer assisted dispersion. A quantitative grafting was successfully achieved even at high content of functional groups.