Closed Bipolar Nanoelectrode Array for Ultra-Sensitive Detection of Alkaline Phosphatase and Two-Dimensional Imaging of Epidermal Growth Factor Receptors.

The combination of closed bipolar electrodes (cBPE) with electrochemiluminescence (ECL) imaging has demonstrated remarkable capabilities in the field of bioanalysis. Here, we established a cBPE-ECL platform for ultrasensitive detection of alkaline phosphatase (ALP) and two-dimensional imaging of epidermal growth factor receptor (EGFR). This cBPE-ECL system consists of a high-density gold nanowire array in anodic aluminum oxide (AAO) membrane as the cBPE coupled with ECL of highly luminescent cadmium selenide quantum dots (CdSe QDs) luminophores to achieve cathodic electro-optical conversion. When an enzyme-catalyzed amplification effect of ALP with 4-aminophenyl phosphate monosodium salt hydrate (p-APP) as the substrate and 4-aminophenol (p-AP) as the electroactive probe is introduced, a significant improvement of sensing sensitivity with a detection limit as low as 0.5 fM for ALP on the cBPE-ECL platform can be obtained. In addition, the cBPE-ECL sensing system can also be used to detect cancer cells with an impressive detection limit of 50 cells/mL by labeling ALP onto the EGFR protein on A431 human epidermal cancer cell membranes. Thus, two-dimensional (2D) imaging of the EGFR proteins on the cell surface can be achieved, demonstrating that the established cBPE-ECL sensing system is of high resolution for spatiotemporal cell imaging.

High-Throughput Single-Molecule Surface-Enhanced Raman Spectroscopic Profiling of Single-Amino Acid Substitutions in Peptides by a Gold Plasmonic Nanopore.

Simultaneous detection and structural characterization of protein variants on a single platform are highly desirable but technically challenging. Herein, we present a single-molecule spectral system based on a gold plasmonic nanopore for analyzing two peptides and their single-point mutated variants. The gold plasmonic nanopore enabled the high-throughput acquisition of surface-enhanced Raman scattering (SERS) spectra at the single-molecule level by electrically driving analytes into hot spots. Furthermore, a statistical method based on Boolean operations was developed to extract prominent features from fluctuated single-molecule SERS spectra. The effects of the single-amino acid substitutions on both the intramolecular interactions and the peptide conformations were directly characterized by the nanopore system, and the results agreed with the predictions by AlphaFold2. This study highlights the mutual benefits of spectroscopy and nanopore technology, whereby the gold plasmonic nanopore offers a powerful tool for the structural analysis of single-molecule proteins.

Molecular architectures of iron complexes for oxygen reduction catalysis-Activity enhancement by hydroxide ions coupling.

Developing cost-effective and high-performance electrocatalysts for oxygen reduction reaction (ORR) is critical for clean energy generation. Here, we propose an approach to the synthesis of iron phthalocyanine nanotubes (FePc NTs) as a highly active and selective electrocatalyst for ORR. The performance is significantly superior to FePc in randomly aggregated and molecularly dispersed states, as well as the commercial Pt/C catalyst. When FePc NTs are anchored on graphene, the resulting architecture shifts the ORR potentials above the redox potentials of Fe2+/3+ sites. This does not obey the redox-mediated mechanism operative on conventional FePc with a Fe2+-N moiety serving as the active sites. Pourbaix analysis shows that the redox of Fe2+/3+ sites couples with HO- ions transfer, forming a HO-Fe3+-N moiety serving as the ORR active sites under the turnover condition. The chemisorption of ORR intermediates is appropriately weakened on the HO-Fe3+-N moiety compared to the Fe2+-N state and thus is intrinsically more ORR active.

Core-Shell Reactor Partitioning Enzyme and Prodrug by ZIF-8 for NADPH-Sensitive In Situ Prodrug Activation.

Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core-shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC50 value (26.3±2.6 µg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core-shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.

Integrated separation and detection of exosomes via a label-free magnetic SERS platform.

A label-free magnetic surface enhanced Raman scattering (SERS) platform was constructed, which was composed of superparamagnetic Fe3O4 nanoparticles as cores for separation and Au layers as shells for label-free SERS detection. Our method could effectively distinguish exosomes from different cell sources for cancer diagnosis and showed high sensitivity and specificity within a 95% confidence interval. As a low-cost and efficient exosome analysis method, the designed integrated platform for separation and detection has promising applicability in clinical diagnostics.

Design of Near-Infrared-Triggered Metallo-Photosensitizers via a Self-Assembly-Induced Vibronic Decoupling Strategy.

Development of highly efficient near-infrared (NIR)-excited photosensitizers is hampered by the fast nonradiative vibrational relaxation process regulated by the energy gap law. Here, from the fundamental perspective we propose that the intermolecular coupling of well-designed photosensitizers has the potential to facilitate exciton delocalization and hence reduce the exciton-vibration coupling, thereby boosting their phototherapeutic efficacy via inhibition of the vibrational relaxation pathway. Such conceived NIR-excited metallo-photosensitizers (IrHA1 and IrHA2) were prepared and studied for experimental validation. The resulting iridium complexes exhibited a little singlet oxygen (1O2) production in the monomeric state, but produced substantially enhanced 1O2 generation efficiency via benefiting from the exciton-vibration decoupling in the self-assembly state. Particularly, IrHA2 exhibits an unprecedented high 1O2 quantum yield of 54.9% (FDA-approved NIR dye indocyanine green: ΦΔ = 0.2%) under 808 nm laser irradiation with negligible heat generation, probably attributed to the suppression of vibronic couplings from the stretching mode of the acceptor ligand. In phototherapy, IrHA2-NPs with high biocompatibility and low dark toxicity can induce substantial tumor regression with 92.9% tumor volume reduction in vivo. This self-assembly-induced vibronic decoupling strategy would offer an effective approach to the design of high-performance NIR-excited photosensitizers.

Surface-Roughened SERS-Active Single Silver Nanowire for Simultaneous Detection of Intracellular and Extracellular pHs.

The simultaneous and accurate detection of intracellular pH (pHi) and extracellular pH (pHe) is essential for studying the complex physiological activities of cancer cells and exploring pH-related therapeutic mechanisms. Here, we developed a super-long silver nanowire-based surface-enhanced Raman scattering (SERS) detection strategy for simultaneous sensing of pHi and pHe. A surface-roughened silver nanowire (AgNW) with a high aspect ratio is prepared at a nanoelectrode tip using a Cu-mediated oxidation process, which is then modified by pH-sensitive 4-mercaptobenzoic acid (4-MBA) to form 4-MBA@AgNW as a pH sensing probe. With the assistance of a 4D microcontroller, 4-MBA@AgNW is efficient in simultaneously detecting pHi and pHe in both 2D and 3D culture cancer cells by SERS, with minimal invasiveness, high sensitivity, and spatial resolution. Further investigation proves that the surface-roughened single AgNW can also be used in monitoring the dynamic variation of pHi and pHe of cancer cells upon stimulation with anticancer drugs or under a hypoxic environment.

Ultrasensitive Multiplex Imaging of Cell Surface Proteins via Core-Shell Surface-Enhanced Raman Scattering Nanoprobes.

Cell surface proteins, as important components of biological membranes, cover a wide range of important markers of diseases and even cancers. In this regard, precise detection of their expression levels is of crucial importance for both cancer diagnosis and the development of responsive therapeutic strategies. Herein, a size-controlled core-shell Au@ Copper(II) benzene-1,3,5-tricarboxylate (Au@Cu-BTC) nanomaterial was synthesized for specific and simultaneous imaging of multiple protein expression levels on cell membranes. The porous shell of Cu-BTC constructed on Au nanoparticles enabled effective loading of Raman reporter molecules, followed by further modification of the targeting moieties, which equipped the nanoprobe with good specificity and stability. Additionally, given the flexibility of the types of Raman reporter molecules available for loading, the nanoprobes were also demonstrated with good multichannel imaging capabilities. Ultimately, the present strategy of electromagnetic and chemical dual Raman scattering enhancement was successfully applied for the simultaneous detection of varied proteins on cell surfaces with high sensitivity and accuracy. The proposed nanomaterial holds promising applications in biosensing and therapeutic fields, which could not only provide a general strategy for the synthesis of metal-organic framework-based core-shell surface-enhanced Raman scattering nanoprobes but also enable further utilization in multitarget and multichannel cell imaging.

Single-cell thermometry with a nanothermocouple probe.

Herein, a nanopipette-based thermocouple probe that possesses high temperature resolution, rapid response, good reversibility and stability was constructed and successfully applied for single-cell temperature sensing. Different intracellular temperatures were observed in diverse types of cells, which reveals differences in their metabolism levels. Temperature responses of cancer and normal cells against various exogenous drugs were also demonstrated. The spatially resolved temperature sensing of three-dimensional cell culture models unveils the existence of their inner temperature gradients. This work would facilitate drug screening and disease diagnosis.

A supramolecular photosensitizer derived from an Arene-Ru(II) complex self-assembly for NIR activated photodynamic and photothermal therapy.

Effective photosensitizers are of particular importance for the widespread clinical utilization of phototherapy. However, conventional photosensitizers are usually plagued by short-wavelength absorption, inadequate photostability, low reactive oxygen species (ROS) quantum yields, and aggregation-caused ROS quenching. Here, we report a near-infrared (NIR)-supramolecular photosensitizer (RuDA) via self-assembly of an organometallic Ru(II)-arene complex in aqueous solution. RuDA can generate singlet oxygen (1O2) only in aggregate state, showing distinct aggregation-induced 1O2 generation behavior due to the greatly increased singlet-triplet intersystem crossing process. Upon 808 nm laser irradiation, RuDA with excellent photostability displays efficient 1O2 and heat generation in a 1O2 quantum yield of 16.4% (FDA-approved indocyanine green: ΦΔ = 0.2%) together with high photothermal conversion efficiency of 24.2% (commercial gold nanorods: 21.0%, gold nanoshells: 13.0%). In addition, RuDA-NPs with good biocompatibility can be preferably accumulated at tumor sites, inducing significant tumor regression with a 95.2% tumor volume reduction in vivo during photodynamic therapy. This aggregation enhanced photodynamic therapy provides a strategy for the design of photosensitizers with promising photophysical and photochemical characteristics.

Morphologically Flex Sm-MOF Based Electrochemical Immunosensor for Ultrasensitive Detection of a Colon Cancer Biomarker.

Despite having the potential to synthesize stable metal-organic frameworks (MOFs), rare earth metal-based MOFs have not been exploited extensively. Owing to the high coordination numbers, the MOFs can generate a suitable coordination environment for various applications. Herein, samarium (Sm)-based MOFs were synthesized with three different organic linkers, namely, trimesic acid (TMA), meso-tetra(4-carboxyphenyl)porphine (TCPP), and 1,3,6,8-tetra(4-carboxylphenyl) pyrene(TBPy) by the solvothermal approach. The morphologies of Sm-TMA MOF, Sm-TCPP MOF, Sm-TBPy MOF were rod-shaped, cubic consisting of stacked 2D layers, and spherical made of small cubic structures, respectively. After the electrochemical properties of the synthesized MOFs were investigated, the MOFs were used to fabricate immunosensors for detection of carcinoembryonic antigen using a label-free signaling strategy. The immunosensors exhibited a wide linear detection range and a lower detection limit. The exhibited reproducibility and selectivity of the immunosensors were within the tolerable limits. The established label-free immunosensor has been successfully applied for detection of carcinoembryonic antigen in human serum samples, demonstrating that the rare earth metal-based MOFs are promising for construction of biosensors for medical diagnosis.

Plasmon-Accelerated Generation of Singlet Oxygen on an Au/MoS2 Nanohybrid for Enhanced Photodynamic Killing of Bacterial Pathogens/Cancerous Cells.

Benefiting from its strong cytotoxic features, singlet oxygen (1O2) has garnered considerable research attention in photodynamic therapy (PDT) and thus, plenty of inorganic PDT agents have been recently developed. However, inorganic PDT agents consisting of metal/semiconductor hybrids are surprisingly rare, bearing very low 1O2 quantum yield, and their in vivo PDT applications remain elusive. Herein, we provide an unprecedented report that the Au/MoS2 hybrid under plasmon resonant excitation can sensitize 1O2 generation with a quantum yield of about 0.22, which is much higher than that of the reported hybrid-based photosensitizers (PSs). This significant enhancement in 1O2 quantum yield is attributed to the hot-electron injection from plasmonic AuNPs to MoS2 NSs due to the matched energy levels. Electron paramagnetic resonance (EPR) spectroscopy with spin trapping and spin labeling verifies the plasmonic generation of hot charge carriers and reactive oxygen species such as superoxide and 1O2. This plasmonic PDT agent shows a remarkable photodynamic bacterial inactivation in vitro and anti-cancer therapeutic ability both in vitro and in vivo, which is solely attributed to high 1O2 generation rather than the plasmonic photothermal effect. Hence, plasmonic Au/MoS2 with enhanced 1O2 quantum yield and appreciable in vivo cancer plasmonic PDT performance holds great promise as an inorganic PS to treat near-surface tumors. As a first demonstration of how metal localized surface plasmon resonance could enhance 1O2 generation, the present study opens up promising opportunities for enhancing 1O2 quantum yield of hybrid-based PSs, leading to achieving a high therapeutic index in plasmon PDT.

Inorganic Nanomaterials with Intrinsic Singlet Oxygen Generation for Photodynamic Therapy.

Inorganic nanomaterials with intrinsic singlet oxygen (1 O2 ) generation capacity, are emerged yet dynamically developing materials as nano-photosensitizers (NPSs) for photodynamic therapy (PDT). Compared to previously reported nanomaterials that have been used as either carriers to load organic PSs or energy donors to excite the attached organic PSs through a Foster resonance energy transfer process, these NPSs possess intrinsic 1 O2 generation capacity with extremely high 1 O2 quantum yield (e.g., 1.56, 1.3, 1.26, and 1.09) than any classical organic PS reported to date, and thus are facilitating to make a revolution in PDT. In this review, the recent advances in the development of various inorganic nanomaterials as NPSs, including metal-based (gold, silver, and tungsten), metal oxide-based (titanium dioxide, tungsten oxide, and bismuth oxyhalide), metal sulfide-based (copper and molybdenum sulfide), carbon-based (graphene, fullerene, and graphitic carbon nitride), phosphorus-based, and others (hybrids and MXenes-based NPSs) are summarized, with an emphasis on the design principle and 1 O2 generation mechanism, and the photodynamic therapeutic performance against different types of cancers. Finally, the current challenges and an outlook of future research are also discussed. This review may provide a comprehensive account capable of explaining recent progress as well as future research of this emerging paradigm.

RETRACTED: Liposomal valinomycin mediated cellular K+ leak promoting apoptosis of liver cancer cells.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the corresponding author. It has been found that Fig 2B contains manipulated components, and Fig 5A partially overlaps with Fig 6 of a published paper authored by Mirza Muhammad Faran Ashraf Baig, et, al., The effective transfection of a low dose of negatively charged drug-loaded DNA-nanocarriers into cancer cells via scavenger receptors, J. Pharm. Anal. 11 (2021) 174-182, https://doi.org/10.1016/j.jpha.2020.10.003. The corresponding author indicated that they cannot guarantee the integrity of the images in the manuscript, as well as the conclusions of the paper. As a result, the Editor-in-Chief has decided to retract the paper. The corresponding author deeply regrets the circumstances and apologizes to the scientific community for not having detected this prior to publication.

One-Pot Preparation of Peptide-Doped Metal-Amino Acid Framework for General Encapsulation and Targeted Delivery.

Metal-organic frameworks (MOFs), especially those made by biological molecules (bio-MOFs), have been proved to be prospective candidates for biomedical applications. However, a simple and universal bio-MOF to load different substances for precise targeting is still lacking. In this work, we propose a facile one-pot method to prepare a peptide-doped bio-MOF for general encapsulation and targeted delivery. This bio-MOF is constructed by 9-fluorenylmethyloxycarbonyl-modified histidine (Fmoc-His) as a bridging linker that coordinates with Zn2+ ions, denoted as ZFH. The Fmoc-His-Asp-Gly-Arg peptide (Fmoc-HDGR) can be easily doped into the ZFH structure with different ratios to modulate the targeting ability of ZFH-DGR. Containing both hydrophobic Fmoc and hydrophilic His moieties, this framework is compatible with encapsulating various types of payloads, including hydrophobic chemotherapeutic, hydrophilic protein, and positively/negatively charged inorganic nanoparticles. It has also been proved to be highly biocompatible and stable in circulation, exhibit the capabilities to target ανß3 integrin overexpressed on tumor cells, and trigger drug release in a low pH microenvironment at the tumor site. As a proof of concept, Doxorubicin (Dox)-loaded ZFH-DGR (ZFH-DGR/Dox) demonstrated high cell selectivity between liver hepatocellular carcinoma (HepG2) cells and normal liver (L02) cells, which express high and low ανß3 integrin, respectively. This selectivity endows ZFH-DGR/Dox precise treatment and low toxicity in Heps-bearing liver cancer mice. This work develops a de novo approach to construct a peptide-doped bio-MOF system for universal load, precise delivery, and peptide drug combination therapy in the future.

Ultrasensitive plasmon enhanced Raman scattering detection of nucleolin using nanochannels of 3D hybrid plasmonic metamaterial.

Detection of cancer biomarker is of great significance in cancer diagnostics. In this work, we propose an ultrasensitive and in situ method for plasmon enhanced Raman scattering (PERS) detection of nucleolin (NCL) using a 3D hybrid plasmonic metamaterial (PM). In this aptasensor, thiolated complementary DNA (cDNA) immobilized on PM can hybridize with Rox-labeled NCL-binding aptamer (AS1411-Rox) to form a rigid double-stranded DNA (dsDNA). When NCL passes through the PM nanochannels under a transmembrane voltage bias, it interacts with AS1411-Rox to form G-quadruplexes (G4-AS1411-Rox), resulting in the release of AS1411-Rox from the nanochannels surface and the decrease in PERS signal of the reporter Rox. This change in PERS signals can be recorded in situ without the interference of external environment. With the help of the enrichment function of nanochannel, the present method is able to achieve fast NCL detection within 10 min with a detection limit as low as 71 pM. Furthermore, our method shows excellent specificity, reversibility, uniformity (relative standard deviation of ~6.86%) and reproducibility (~6.65%), providing a new platform for reliable cancer auxiliary diagnosis and drug screening.

Solid-state thiolate-stabilized copper nanoclusters with ultrahigh photoluminescence quantum yield for white light-emitting devices.

As a new emerging candidate for solid-state phosphors, copper nanoclusters (CuNCs) have gained tremendous interest in the field of white light-emitting devices (WLEDs). However, their further applications are impeded by the low photoluminescence quantum yield (PLQY) and poor emission color tunability of CuNCs. This work demonstrates the synthesis of cyan and orange emitting CuNCs, and their combination as color conversion phosphors in WLEDs. The cyan and orange emitting CuNCs were prepared employing 2-mercapto-1-methylimidazole (MMI) and N-acetyl-l-cysteine (NAC), respectively, as stabilizing-cum-reducing agents. The dispersions of MMI-CuNCs and NAC-CuNCs are weakly emissive. However, after processing into powders, they both possess ultrahigh PLQYs (45.2% for MMI-CuNCs, and 64.6% for NAC-CuNCs) owing to the effect of aggregation-induced emission (AIE). All-CuNC based WLEDs are then designed and developed using powdered MMI-CuNC and NAC-CuNC samples on commercially available 365 nm GaN LED chips. They display acceptable white light characteristics with a Commission Internationale de l'Eclairage coordinate value and color rendering index of (0.26, 0.30) and 83, respectively. We believe that these cost-effective and eco-friendly CuNCs with interesting AIE properties will vigorously promote the development of high-quality WLEDs for commercial applications.

Mass Transfer Modulation and Gas Mapping Based on Covalent Organic Frameworks-Covered Theta Micropipette.

Covalent organic frameworks (COFs) consist nanochannels that are fundamentally important for their application. Up to now, the effect of gas phase on COF nanochannels are hard to explore. Here, TAPB-PDA-COFs (triphenylbenzene-terephthaldehyde-COFs) was synthesized in situ at the tip of a theta micropipette. The COF-covered theta micropipette (CTP) create a stable gas-liquid interface inside the COF nanochannels, through which the humidity-modulated ion mass transfer in the COF nanochannels can be recorded by recording the current across the two channels of the theta micropipette. Results show that the humid air changes the mobility of the ions inside the COF nanochannels, which leads to the change of ionic current. Humid air showed different effects on the ion transfer depending on the solvent polarity index and vapor pressure. Current decreases linearly with the increase of relative humidity (RH) from 11% to 98%. The CTP was also mounted on the scanning electrochemical microscopy as a probe electrode for mapping micrometer-scale humidity distribution.