Photoresponsive heparin ionic complexes toward controllable therapeutic efficacy of anticoagulation.

Controllable heparin-release is of great importance and necessity for the precise anticoagulant regulation. Efforts have been made on designing heparin-releasing systems, while, it remains a great challenge for gaining the external-stimuli responsive heparin-release in either intravenous or catheter delivery. In this study, an azobenzene-containing ammonium surfactant is designed and synthesized for the fabrication of photoresponsive heparin ionic complexes through the electrostatic complexation with heparin. Under the assistance of photoinduced trans-cis isomerization of azobenzene, the obtained heparin materials perform reversible athermal phase transition between ordered crystalline and isotropic liquid state at room temperature. Compared to the ordered state, the formation of isotropic state can effectively improve the dissolving of heparin from ionic materials in aqueous condition, which realizes the photo-modulation on the concentration of free heparin molecules. With good biocompatibility, such a heparin-releasing system addresses photoresponsive anticoagulation in both in vitro and in vivo biological studies, confirming its great potential clinical values. This work provides a new designing strategy for gaining anticoagulant regulation by light, also opening new opportunities for the development of photoresponsive drugs and biomedical materials based on biomolecules.

Advances in microneedles for transdermal diagnostics and sensing applications.

Microneedles, the miniaturized needles, which can pierce the skin with minimal invasiveness open up new possibilities for constructing personalized Point-of-Care (POC) diagnostic platforms. Recent advances in microneedle-based POC diagnostic systems, especially their successful implementation with wearable technologies, enable biochemical detection and physiological recordings in a user-friendly manner. This review presents an overview of the current advances in microneedle-based sensor devices, with emphasis on the biological basis of transdermal sensing, fabrication, and application of different types of microneedles, and a summary of microneedle devices based on various sensing strategies. It concludes with the challenges and future prospects of this swiftly growing field. The aim is to present a critical and thorough analysis of the state-of-the-art development of transdermal diagnostics and sensing devices based on microneedles, and to bridge the gap between microneedle technology and pragmatic applications.

A Super-Antifouling Electrochemical Biosensor for Protein Detection in Complex Biofluids Based on PEGylated Multifunctional Peptide.

Overcoming the influence of interfering substances in the environment and achieving superior sensing performance are significant challenges in biomarker detection within complex matrices. Herein, an integrated electrochemical sensing platform for sensitive detection of biomarkers in complex biofluids was developed based on a newly designed PEGylated multifunctional peptide (PEG-MPEP). The designed PEG-MPEP contains a poly(serine) sequence (-ssssss-) as the antifouling part and recognition peptide sequence (-avwgrwh) specific for the target human immunoglobulin G (IgG). To improve the peptide stability to protease hydrolysis, d-amino acids were adopted to synthesize the whole peptide. Additionally, the PEGylation can further enhance the stability of the peptide, and the PEG itself was also antifouling, ensuring superstrong antifouling capability of the PEG-MPEP. The designed PEG-MPEP-based biosensor possessed a high sensitivity for the detection of IgG in the range of 1.0 pg mL-1 to 1.0 µg mL-1, with a low limit of detection (0.41 pg mL-1), and it was capable of assaying targets accurately in real serum samples. Compared with conventional peptide-modified biosensors, the PEG-MPEP-modified biosensor exhibited superior antifouling and antihydrolysis properties in complex biofluid, showcasing promising potential for practical assay applications.

A highly stable electrochemical sensor with antifouling and antibacterial capabilities for mercury ion detection in seawater.

The monitoring of heavy metal ions in ocean is crucial for environment protection and assessment of seawater quality. However, the detection of heavy metal ions in seawater with electrochemical sensors, especially for long-term monitoring, always faces challenges due to marine biofouling caused by the nonspecific adsorption of microbial and biomolecules. Herein, an electrochemical aptasensor, integrating both antifouling and antibacterial properties, was developed for the detection of Hg2+ in the ocean. In this electrochemical aptasensor, eco-friendly peptides with superior hydrophilicity served as anti-biofouling materials, preventing nonspecific adsorption on the sensing interface, while silver nanoparticles were employed to eliminate bacteria. Subsequently, a ferrocene-modified aptamer was employed for the specific recognition of Hg2+, leveraging the aptamer's ability to fold into a thymine-Hg2+-thymine (T-Hg2+-T) structure upon interaction, and bringing ferrocene nearer to the sensor surface, significantly amplifying the electrochemical response. The prepared electrochemical aptasensor significantly reduced the nonspecific adsorption in seawater while maintaining sensitive electrochemical response. Furthermore, the biosensor exhibited a linear response range of 0.01-100 nM with a detection limit of 2.30 pM, and realized the accurate monitoring of mercury ions in real marine environment. The research results offer new insights into the preparation of marine antifouling sensing devices, and it is expected that sensors with antifouling and antimicrobial capabilities will find broad applications in the monitoring of marine pollutants.

A low-fouling electrochemical biosensor based on BSA hydrogel doped with carbon black for the detection of cortisol in human serum.

Electrochemical biosensors with high sensitivity can detect low concentrations of biomarkers, but their practical detection applications in complex biological environments such as human serum and sweat are severely limited by the biofouling. Herein, a conductive hydrogel based on bovine serum albumin (BSA) and conductive carbon black (CCB) was prepared for the construction of an antifouling biosensor. The BSA hydrogel (BSAG) was doped with CCB, and the prepared composite hydrogel exhibited good conductivity originated from the CCB and antifouling capability owing to the BSA hydrogel. An antifouling biosensor for the sensitive detection of cortisol was fabricated by drop-coating the conductive hydrogel onto a poly(3,4-ethylenedioxythiophene) (PEDOT) modified electrode and further immobilizing the cortisol aptamer. The constructed biosensor showed a linear range of 100 pg mL-1 - 10 µg mL-1 and a limit of detection of 26.0 pg mL-1 for the detection of cortisol, and it was capable of assaying cortisol accurately in complex human serum. This strategy of preparing antifouling and conductive hydrogels provides an effective way to develop robust electrochemical biosensors for biomarker detection in complex biological media.

Intelligent Cell Profiling and Precision Release: Multimolecular Marker-Activated Transmembrane DNA Computing Nanosystem.

Accurate classification of tumor cells is of importance for cancer diagnosis and further therapy. In this study, we develop multimolecular marker-activated transmembrane DNA computing systems (MTD). Employing the cell membrane as a native gate, the MTD system enables direct signal output following simple spatial events of "transmembrane" and "in-cell target encounter", bypassing the need of multistep signal conversion. The MTD system comprises two intelligent nanorobots capable of independently sensing three molecular markers (MUC1, EpCAM, and miR-21), resulting in comprehensive analysis. Our AND-AND logic-gated system (MTDAND-AND) demonstrates exceptional specificity, allowing targeted release of drug-DNA specifically in MCF-7 cells. Furthermore, the transformed OR-AND logic-gated system (MTDOR-AND) exhibits broader adaptability, facilitating the release of drug-DNA in three positive cancer cell lines (MCF-7, HeLa, and HepG2). Importantly, MTDAND-AND and MTDOR-AND, while possessing distinct personalized therapeutic potential, share the ability of outputting three imaging signals without any intermediate conversion steps. This feature ensures precise classification cross diverse cells (MCF-7, HeLa, HepG2, and MCF-10A), even in mixed populations. This study provides a straightforward yet effective solution to augment the versatility and precision of DNA computing systems, advancing their potential applications in biomedical diagnostic and therapeutic research.

Exogenous and Endogenous Dual-Activated Nanoladder for Precise Imaging of Mitochondrial Ferroptosis-Related Inhibition miRNA with Tumor Cell Specificity.

Developing precise tumor cell-specific mitochondrial ferroptosis-related inhibition miRNA imaging methods holds enormous potential for anticancer drug screening and cancer treatment. Nevertheless, traditional amplification methods still tolerated the limited tumor specificity because of the "off-tumor" signal leakage resulting from their "always-active" sensing mode. To overcome this limitation, we herein developed a dual (exogenous 808 nm NIR light and endogenous APE1) activated nanoladder for precise imaging of mitochondrial ferroptosis-related miRNA with tumor cell specificity and improved imaging resolution. Exogenous NIR light-activation can regulate the ferroptosis-related inhibition miRNA imaging signals within mitochondria, and endogenous enzyme-activation can confine signals to tumor cells. Based on this dual activation design, off-tumor signals were greatly reduced and tumor-to-background contrast was enhanced with an improved tumor/normal discrimination ratio, realizing tumor cell-specific precise imaging of mitochondrial ferroptosis-related inhibition miRNA.

DNA liquid crystals with AIE effect toward humidity-indicating biomaterials.

In this study, by fabricating DNA doped with tetraphenylethene-containing ammonium surfactant, the resulting solvent-free DNA ionic complex could undergo a humidity-induced phase change that could be well tracked by the fluorescence signal of the surfactant. Taking advantage of the humidity-induced change in fluorescence, the reported ionic DNA complex could accurately indicate the humidity in real time.

Renin imprinted Poly(methyldopa) for biomarker detection and disease therapy.

Conventional molecularly imprinted polymers (MIPs) perform their functions principally depended on their three dimensional (3D) imprinted cavities (recognition sites) of templates. Here, retaining the function of recognition sites resulted from the imprinting of template molecules, the role of functional monomers is explored and expanded. Briefly, a class of dual-functional renin imprinted poly(methyldopa) (RMIP) is prepared, consisting of a drug-type function monomer (methyldopa, clinical high blood pressure drug) and a corresponding disease biomarker (renin, biomarker for high blood pressure disease). To boost target-to-receptor binding ratio and sensitivity, the microstructure of recognition sites is beforehand calculated and designed by Density Functional Theory calculations, and the whole interfacial structure, property and thickness of RMIP film is regulated by adjusting the polymerization techniques. The dual-functional applications of RMIP for biomarker detection and disease therapy in vivo is explored. Such RMIP-based biosensors achieves highly sensitive biomarker detection, where the LODs reaches down to 1.31 × 10-6 and 1.26 × 10-6 ng mL-1 for electrochemical and chemical polymers, respectively, and the application for disease therapy in vivo has been verified where displays the obviously decreased blood pressure values of mice. No acute and long-term toxicity is found from the pathological slices, declaring the promising clinical application potential of such engineered RMIP nanostructure.

Plasmonic Gold Nanostar-Based Probes with Distance-Dependent Plasmon-Enhanced Fluorescence for Ultrasensitive DNA Methyltransferase Assay.

The ultrasensitive DNA methyltransferase (Dam MTase) assay is of high significance for biomedical research and clinical diagnosis because of its profound effect on gene regulation. However, detection sensitivity is still limited by shortcomings, including photobleaching and weak signal intensities of conventional fluorophores at low concentrations. Plasmonic nanostructures with ultrastrong electromagnetic fields and fluorescence enhancement capability that can overcome these intrinsic defects hold great potential for ultrasensitive bioanalysis. Herein, a silica-coated gold nanostars (Au NSTs@SiO2)-based plasmon-enhanced fluorescence (PEF) probe with 20 "hot spots" was developed for ultrasensitive detection of Dam MTase. Here, the Dam Mtase assay was achieved by detecting the byproduct PPi of the rolling circle amplification reaction. It is worth noting that, benefiting from the excellent fluorescence enhancement capability of Au NSTs originating from their 20 "hot spots", the detection limit of Dam Mtase was reduced by nearly 105 times. Moreover, the proposed Au NST-based PEF probe enabled versatile evaluation of Dam MTase inhibitors as well as endogenous Dam MTase detection in GW5100 and JM110 Escherichia coli cell lysates, demonstrating its potential in biomedical analysis.

Enhanced split-type photoelectrochemical aptasensor incorporating a robust antifouling coating derived from four-armed polyethylene glycol.

Antifouling biosensors capable of preventing protein nonspecific adhesion in real human bodily fluids are highly sought-after for precise disease diagnosis and treatment. In this context, an enhanced split-type photoelectrochemical (PEC) aptasensor was developed incorporating a four-armed polyethylene glycol (4A-PEG) to construct a robust antifouling coating, enabling accurate and sensitive bioanalysis. The split-type PEC system involved the photoelectrode and the biocathode, effectively separating signal converter with biorecogniton events. Specifically, the TiO2 electrode underwent sequential modification with ZnIn2S4 (ZIS) and polydopamine (PDA) to form the PDA/ZIS/TiO2 photoelectrode. The cathode substrate was synthesized as a hybrid of N-doped graphene loaded with Pt nanoparticles (NG-Pt), and subsequently modified with 4A-PEG to establish a robust antifouling coating. Following the anchoring of probe DNA (pDNA) on the 4A-PEG-grafted antifouling coating, the biocathode for model target of cancer antigen 125 (CA125) was obtained. Leveraging pronounced photocurrent output of the photoelectrode and commendable antifouling characteristics of the biocathode, the split-type PEC aptasensor showcased exceptional detection performances with high sensitivity, good selectivity, antifouling ability, and potential feasibility.

Antifouling strategies for electrochemical sensing in complex biological media.

Surface fouling poses a significant challenge that restricts the analytical performance of electrochemical sensors in both in vitro and in vivo applications. Biofouling resistance is paramount to guarantee the reliable operation of electrochemical sensors in complex biofluids (e.g., blood, serum, and urine). Seeking efficient strategies for surface fouling and establishing highly sensitive sensing platforms for applications in complex media have received increasing attention in the past. In this review, we provide a comprehensive overview of recent research efforts focused on antifouling electrochemical sensors. Initially, we present a detailed illustration of the concept about biofouling along with an exploration of four key antifouling mechanisms. Subsequently, we delve into the commonly employed antifouling strategies in the fabrication of electrochemical sensors. These encompass physical surface topography (micro/nanostructure coatings and filtration membranes) and chemical surface modifications (PEG and its derivatives, zwitterionic polymers, peptides, proteins, and various other antifouling materials). The progress in antifouling electrochemical sensors is proposed concerning the antifouling mechanisms as well as sensing capability assessments (e.g., sensitivity, stability, and practical application ability). Finally, we summarize the evolving trends in the field and highlight some key remaining limitations.

Robust Electrochemical Biosensors Based on Antifouling Peptide Nanoparticles for Protein Quantification in Complex Biofluids.

Peptides with distinct physiochemical properties and biocompatibility hold significant promise across diverse domains including antifouling biosensors. However, the stability of natural antifouling peptides in physiological conditions poses significant challenges to their viability for sustained practical applications. Herein, a unique antifouling peptide FFFGGGEKEKEKEK was designed and self-assembled to form peptide nanoparticles (PNPs), which possessed enhanced stability against enzymatic hydrolysis in biological fluids. The PNP-coated interfaces exhibited superior stability and antifouling properties in preventing adsorption of nonspecific materials, such as proteins and cells in biological samples. Moreover, a highly sensitive and ultralow fouling electrochemical biosensor was developed through the immobilization of the PNPs and specific aptamers onto the polyaniline nanowire-modified electrode, achieving the biomarker carcinoembryonic antigen detection in complex biofluids with reliable accuracy. This research not only addresses the challenge of the poor proteolytic resistance observed in natural peptides but also introduces a universal strategy for constructing ultralow fouling sensing devices.

Click Conjugation of Zwitterionic Peptide with DNA Strand: An Efficient Antifouling Strategy for Versatile Photoelectrochemical Aptasensor.

Advanced antifouling biosensors have garnered considerable attention for their potential for precise and sensitive analysis in complex human bodily fluids. Herein, a pioneering approach was utilized to establish a robust and versatile photoelectrochemical aptasensor by conjugating a zwitterionic peptide with a DNA strand. Specifically, the branched zwitterionic peptide (BZP) was efficiently linked to complementary DNA (cDNA) through a click reaction, forming the BZP-cDNA conjugate. This intriguing conjugate exploited the BZP domain to create an antifouling biointerface, while the cDNA component facilitated subsequent hybridization with probe DNA (pDNA). To advance the development of the aptasensor, an upgraded PDA/HOF-101/ZnO ternary photoelectrode was designed as the signal converter for the modification of the BZP-cDNA conjugate, while a bipyridinium (MCEPy) molecule with strong electron-withdrawing properties was labeled at the front end of the pDNA to form the pDNA-MCEPy signal probe. Targeting the model of mucin-1, a remarkable enhancement in the photocurrent signal was achieved through exonuclease-I-aided target recycling. Such an engineered zwitterionic peptide-DNA conjugate surpasses the limitations imposed by conventional peptide-based sensing modes, exhibiting unique advantages such as versatility in design and capability for signal amplification.

A stretchable wearable sensor with dual working electrodes for reliable detection of uric acid in sweat.

Wearable sweat sensors with stretch capabilities and robust performances are desired for continuous monitoring of human health, and it remains a challenge for sweat sensors to detect targets reliably in both static and dynamic states. Herein, a flexible sweat sensor was created using a cost-effective approach involving the utilization of three-dimensional graphene foam and polydimethylsiloxane (PDMS). The flexible electrochemical sensor was fabricated based on PDMS and Pt/Pd nanoparticles modified 3D graphene foam for the detection of uric acid in sweat. Pt/Pd nanoparticles were electrodeposited on the graphene foam to markedly enhance the electrocatalytic activity for uric acid detection. The graphene foam with excellent electrical property and high porosity, and PDMS with an ideal mechanical property endow the sensing device with high stretchability (tolerable strain up to 110 %), high sensitivity (0.87 µA µM-1 cm-2), and stability (remaining unchanged for more than 5000 cycles) for daily wear. To eliminate possible interferences, the wearable sensor was designed with dual working electrodes, and their response difference ensured reliable and accurate detection of targets. This strategy of constructing sweat sensors with dual working electrodes based on the flexible composite material represents a promising way for the development of robust wearable sensing devices.

Light and endogenous enzyme triggered plasmonic antennas for accurate subcellular molecular imaging with enhanced spatial resolution.

Developing accurate tumor-specific molecular imaging approaches holds great potential for evaluating cancer progression. However, traditional molecular imaging approaches still suffer from restricted tumor specificity due to the "off-tumor" signal leakage. In this work, we proposed light and endogenous APE1-triggered plasmonic antennas for accurate tumor-specific subcellular molecular imaging with enhanced spatial resolution. Light activation ensures subcellular molecular imaging and endogenous enzyme activation ensures tumor-specific molecular imaging. In addition, combined with the introduction of plasmon enhanced fluorescence (PEF), off-tumor signal leakage at the subcellular level was effectively reduced, resulting in the significantly enhanced discrimination ratio of tumor/normal cells (∼11.57-fold) which is better than in previous reports, demonstrating great prospects of these plasmonic antennas triggered by light and endogenous enzymes for tumor-specific molecular imaging at the subcellular level.

Enhanced Hydroxyl Adsorption in Ultrathin NiO/Cr2 O3 In-Plane Heterostructures for Efficient Alkaline Methanol Oxidation Reaction.

The exploration of advanced nickel-based electrocatalysts for alkaline methanol oxidation reaction (MOR) holds immense promise for value-added organic products coupled with hydrogen production, but still remain challenging. Herein, we construct ultrathin NiO/Cr2 O3 in-plane heterostructures to promote the alkaline MOR process. Experimental and theoretical studies reveal that NiO/Cr2 O3 in-plane heterostructures enable a favorable upshift of the d-band center and enhanced adsorption of hydroxyl species, leading to accelerated generation of active NiO(OH)ads species. Furthermore, ultrathin in-plane heterostructures endow the catalyst with good charge transfer ability and adsorption behavior of methanol molecules onto catalytic sites, contributing to the improvement of alkaline MOR kinetics. As a result, ultrathin NiO/Cr2 O3 in-plane heterostructures exhibit a remarkable MOR activity with a high current density of 221 mA cm-2 at 0.6 V vs Ag/AgCl, which is 7.1-fold larger than that of pure NiO nanosheets and comparable with other highly active catalysts reported so far. This work provides an effectual strategy to optimize the activity of nickel-based catalysts and highlights the dominate efficacy of ultrathin in-plane heterostructures in alkaline MOR.

Phospholipid Bilayer Integrated with Multifunctional Peptide for Ultralow-Fouling Electrochemical Detection of HER2 in Human Serum.

Electrochemical biosensing devices face challenges of severe nonspecific adsorption in complex biological matrices for the detection of biomarkers, and thus, there is a significant need for sensitive and antifouling biosensors. Herein, a sensitive electrochemical biosensor with antifouling and antiprotease hydrolysis ability was constructed for the detection of human epidermal growth factor receptor 2 (HER2) by integrating multifunctional branched peptides with distearoylphosphatidylethanolamine-poly(ethylene glycol) (DSPE-PEG) self-assembled bilayer. The peptide was designed to possess antifouling, antiprotease hydrolysis, and HER2 recognizing capabilities. Molecular dynamics simulations demonstrated that the DSPE was able to effectively self-assemble into a bilayer, and the water contact angle and electrochemical experiments verified that the combination of peptide with the DSPE-PEG bilayer was conducive to enhancing the hydrophilicity and antifouling performance of the modified surface. The constructed HER2 biosensor exhibited excellent antifouling and antiprotease hydrolysis capabilities, and it possessed a linear range of 1.0 pg mL-1 to 1.0 µg mL-1, and a limit of detection of 0.24 pg mL-1. In addition, the biosensor was able to detect HER2 in real human serum samples without significant biofouling, and the assaying results were highly consistent with those measured by the enzyme-linked immunosorbent assay (ELISA), indicating the promising potential of the antifouling biosensor for clinical diagnosis.

Designed Polyhydroxyproline Helical Peptide with Ultrarobust Antifouling Capability for Electrochemical Sensing in Diverse Complex Biological Fluids.

Developing a generalized strategy for the nonfouling detection of biomarkers in diverse biological fluids presents a significant challenge. Herein, a polyhydroxyproline helical peptide (PHHP) was designed and adopted to fabricate electrochemical microsensors capable of detecting targets in various biological media. The PHHP possessed unique properties such as strong hydrophilicity, rigid structure, and lack of ionizable side-chain groups. Compared with common zwitterionic peptides (ZIPs), the PHHP exhibited similar antifouling capability but exceptional stability, allowing its antifouling performance to be unaffected by environmental alteration. The PHHP can prevent biofouling even in fluctuating pH conditions, high ionic strength environments, and the presence of high-valence ions and resist the protease hydrolysis. The PHHP-modified carbon fiber microelectrode was further immobilized with an aptamer to construct an antifouling microsensor for cortisol detection across diverse biofluids, and the microsensor exhibited acceptable accuracy and higher sensitivity than the ELISA method. In addition, different biological samples of mice were collected in situ using a microsensing device, and cortisol levels were analyzed in each specifically tailored region. This nonfouling sensing strategy based on PHHP allows a comprehensive assessment of biomarkers in both spatial and temporal dimensions in diverse biological environments, holding promising potential for early disease diagnosis and real-time health monitoring.

An anti-fouling wearable molecular imprinting sensor based on semi-interpenetrating network hydrogel for the detection of tryptophan in sweat.

The challenge of heavy biofouling in complex sweat environments limits the potential of electrochemical sweat sensors for noninvasive physiological assessment. In this study, a novel semi-interpenetrating hydrogel of PSBMA/PEDOT:PSS was engineered by interlacing PEDOT:PSS conductive polymer with zwitterionic PSBMA network. This versatile hydrogel served as the foundation for developing an anti-fouling wearable molecular imprinting sensor capable of sensitive and robust detection of tryptophan (Trp) in complex sweat. The incorporation of PEDOT:PSS conductive polymer into the semi-interpenetrating hydrogel introduced diverse physical crosslinks, including hydrogen bonding, electrostatic interactions, and chain entanglement. This incorporation considerably boosted the hydrogel's mechanical robustness and imparted commendable self-healing property. At the same time, the synergistic coupling between the well-balanced charge of the zwitterionic network and the high conductivity of the PEDOT:PSS polymer facilitated efficient charge transfer. The formation of the desired molecular imprinting membrane of semi-interpenetrating hydrogel was triggered by self-polymerization of dopamine (DA) in the presence of Trp. The designed biosensor demonstrated good sensitivity, selectivity and stability in detecting the target Trp. Notably, it also exhibited exceptional anti-fouling abilities, allowing for accurate Trp detection in complex real sweat samples, yielding results comparable to commercial enzyme-linked immunoassay (ELISA).