A Fully Integrated Conformal Wearable Ultrasound Patch for Continuous Sonodynamic Therapy.

Cancer treatment is a continuous process, that the current therapy cannot meet the requirement well, including radiotherapy and chemotherapy. Wearable ultrasound device has the potential for continuous sonodynamic therapy due to its portability. However, the miniaturization of ultrasonic probe, system integration of device, and the strategy of continuous treatment are still urgent issues to be addressed. Herein, a portable wearable antitumor system is introduced, which utilizes a custom-developed multiplexed ultrasonic patch array (CWUS Patch) to accurately focus ultrasound on the lesion site and controllably stimulate sonosensitizer to produce a large amount of toxic reactive oxygen species (ROS). The system enables dynamic control of the ultrasound patches and allows real-time adjustments to optimize their performance in various applications, providing greater flexibility and precision in healthcare technology. Furthermore, the excellent penetration property of ultrasound into tumor tissues that induce synchronous apoptosis of tumor cells from the inside out is verified through a mouse model of breast cancer. This fully integrated conformal wearable ultrasound system provides a promising approach to noninvasively, continuously, and efficiently treat deep tumors.

Ultrasound-Induced Enrichment of Ultra-Trace miRNA Biosensing in Nanoliter Samples.

The rapid and accurate analysis of micro-samples is a crucial foundation for precision medicine, particularly for early screening and monitoring of cancer, where it holds significant importance. Ultrasound-based multifunctional biocompatible manipulation techniques have been extensively applied in a variety of biomedical fields, providing insights for the development of rapid, cost-effective, and accurate biomarker detection strategies. In this chapter, we combine ultrasound-based gradient pressure fields with functionalized microsphere enrichment to develop a biosensing method for ultra-trace miRNA enrichment in nanoliter samples without PCR. This system relies on inexpensive capillaries, enabling simultaneous visual imaging and trace sample detection.

Two-Dimensional Nickel Porphyrinic Metal-Organic Framework-Modified Electrode for Electrochemical Sensing.

Due to their highly exposed active sites and high aspect ratio caused by their substantial lateral dimension and thin thickness, two-dimensional (2D) metal-organic framework (MOF) nanosheets are currently considered a potential hybrid material for electrochemical sensing. Herein, we present a nickel-based porphyrinic MOF nanosheet as a versatile and robust platform with an enhanced electrochemical detection performance. It is important to note that the nickel porphyrin ligand reacted with Cu(NO3)2·3H2O in a solvothermal process, with polyvinylpyrrolidone (PVP) acting as the surfactant to control the anisotropic development of creating a 2D Cu-TCPP(Ni) MOF nanosheet structure. To realize the exceptional selectivity, sensitivity, and stability of the synthesized 2D Cu-TCPP(Ni) MOF nanosheet, a laser-induced graphene electrode was modified with the MOF nanosheet and employed as a sensor for the detection of p-nitrophenol (p-NP). With a detection range of 0.5-200 µM for differential pulse voltammetry (DPV) and 0.9-300 µM for cyclic voltammetry (CV), the proposed sensor demonstrated enhanced electrochemical performance, with the limit of detection (LOD) for DPV and CV as 0.1 and 0.3 µM, respectively. The outstanding outcome of the sensor is attributed to the 2D Cu-TCPP(Ni) MOF nanosheet's substantial active surface area, innate catalytic activity, and superior adsorption capacity. Furthermore, it is anticipated that the proposed electrode sensor will make it possible to create high-performance electrochemical sensors for environmental point-of-care testing since it successfully detected p-NP in real sample analysis.

Fully Integrated Ratiometric Fluorescence Enrichment Platform for High-Sensitivity POC Testing of Salivary Cancer Biomarkers.

The point-of-care (POC) testing of cancer biomarkers in saliva with both high sensitivity and accuracy remains a serious challenge in modern clinical medicine. Herein, we develop a new fully integrated ratiometric fluorescence enrichment platform that utilizes acoustic radiation forces to enrich dual-emission sandwich immune complexes for a POC visual assay. As a result, the color signals from red and green fluorescence (capture probe and report probe, respectively) are enhanced by nearly 10 times, and colorimetric sensitivity is effectively improved. When illuminated using a portable UV lamp, the fluorescence color changing from red to green can be clearly seen with the naked eye, which allows a semiqualitative assessment of the carcinoembryonic antigen (CEA) level. In combination with a homemade smartphone-based portable device, cancer biomarkers like CEA are quantified, achieving a limit of detection as low as 0.012 ng/mL. We also directly quantify CEA in human saliva samples to investigate the reliability of this fully integrated platform, thus validating the usefulness of the proposed strategy for clinical diagnosis and home monitoring of physical conditions.

Copper Single-Atom Jellyfish-like Nanomotors for Enhanced Tumor Penetration and Nanocatalytic Therapy.

Single-atom catalysts with extraordinary catalytic activity have been receiving great attention in tumor therapy. However, most single-atom catalysts lack self-propulsion properties, restricting them from actively approaching cancer cells or penetrating the interior of tumors. Herein, we design N-doped jellyfish-like mesoporous carbon nanomotors coordinated with single-atom copper (Cu-JMCNs). It is a combination of single-atom nanocatalytic medicine and nanomotor self-propulsion for cancer therapy. The Cu single atom can catalyze H2O2 into toxic hydroxyl radical (•OH) for chemodynamic therapy (CDT). Near-infrared light triggers Cu-JMCNs to achieve self-thermophoretic motion because of the jellyfish-like asymmetric structure and photothermal property of carbon, which significantly improves the cellular uptake and the penetration of three-dimensional tumors. In vivo experiments indicate that the combination of single-atom Cu for CDT and near-infrared light propulsion can achieve over 85% tumor inhibition rate. This work sheds light on the development of advanced nanomotors with single-atom catalysts for biomedical applications.

Programmable Microparticle Array for In Situ Modification and Multiple miRNA Detection.

Simultaneous detection of multiple miRNAs of one disease can greatly reduce misdiagnosis and improve the detection rate, which is helpful for early cancer diagnosis. Here, a programmable microparticle-array-based acoustic microchip for in situ simultaneous multiple miRNAs detection is developed. On this microchip, the multiple probes-labeled microparticle array can be procedurally arranged in a microfluidic reaction chamber when four orthogonally piezoelectric transducers are applied. The probes-labeled microparticle array offers a platform for full molecular contact under dynamic ultrasonic streaming, and the array supplies a multipoint data correction to reduce the false positive of the detection results for more precisely visible fluorescence multiple target miRNAs sensing. We employed miRNA-21, miRNA-210, and miRNA-155 as specific biomarkers of pancreatic cancer and successfully finished the multiple miRNAs simultaneous detection in the microchip with a detection limit of 139.1, 179.9, and 111.4 pM, respectively. Such a device is programmable by adjusting the imputing frequency and voltage, and target biomarkers can be easily collected when the ultrasound force is released for further analysis, which shows great potential in multiple miRNAs enrichment and simultaneous detection for cancer clinical diagnosis.

Cancer Cell Membrane Camouflaged Semi-Yolk@Spiky-Shell Nanomotor for Enhanced Cell Adhesion and Synergistic Therapy.

Cell adhesion of nanosystems is significant for efficient cellular uptake and drug delivery in cancer therapy. Herein, a near-infrared (NIR) light-driven biomimetic nanomotor is reported to achieve the improved cell adhesion and cellular uptake for synergistic photothermal and chemotherapy of breast cancer. The nanomotor is composed of carbon@silica (C@SiO2 ) with semi-yolk@spiky-shell structure, loaded with the anticancer drug doxorubicin (DOX) and camouflaged with MCF-7 breast cancer cell membrane (i.e., mC@SiO2 @DOX). Such biomimetic mC@SiO2 @DOX nanomotors display efficient self-thermophoretic propulsion due to a thermal gradient generated by asymmetrically spatial distribution. Moreover, the MCF-7 cancer cell membrane coating can remarkably reduce the bioadhesion of nanomotors in biological medium and exhibit highly specific self-recognition of the source cell line. The combination of effective propulsion and homologous targeting dramatically improves cell adhesion and the resultant cellular uptake efficiency in vitro from 26.2% to 67.5%. Therefore, the biomimetic mC@SiO2 @DOX displays excellent synergistic photothermal and chemotherapy with over 91% MCF-7 cell growth inhibition rate. Such smart design of the fuel-free, NIR light-powered biomimetic nanomotor may pave the way for the application of self-propelled nanomotors in biomedicine.

Droplet array for open-channel high-throughput SERS biosensing.

Open-channel and high throughput are two important aspects of clinical diagnosis, correlation biochemical analysis, cell culture techniques and food safety. Here, we propose the mini-pillar based array for open-channel and high-throughput SERS detection of miRNA. The polydimethylsiloxane (PDMS) mini-pillars are used as a high-throughput platform, which have good anchoring and aggregation effects on microdroplets, greatly reducing the amount of analytical solution and facilitate the homogeneous sample distribution after evaporation. The deposited gold nanorods (Au NRs) on the pillars with optimized diameter served as SERS-active substrate, can greatly improve the sensitivity of SERS signal compared to other planar substrates. On the open-channel biological chip, sensitive, simultaneous, and specific detection of breast cancer marker miRNA-1246 can be performed. In this mini-pillar array SERS system, the limit of detection (LOD) is 10-12 M. The mini-pillar array shows enormous potential for open channel, high-throughput biomolecular detection, providing an opportunity for biomedical point-of-care testing (POCT) and drug screening.

An open source and reduce expenditure ROS generation strategy for chemodynamic/photodynamic synergistic therapy.

The therapeutic effect of reactive oxygen species (ROS)-involved cancer therapies is significantly limited by shortage of oxy-substrates, such as hypoxia in photodynamic therapy (PDT) and insufficient hydrogen peroxide (H2O2) in chemodynamic therapy (CDT). Here, we report a H2O2/O2 self-supplying nanoagent, (MSNs@CaO2-ICG)@LA, which consists of manganese silicate (MSN)-supported calcium peroxide (CaO2) and indocyanine green (ICG) with further surface modification of phase-change material lauric acid (LA). Under laser irradiation, ICG simultaneously generates singlet oxygen and emits heat to melt the LA. The exposed CaO2 reacts with water to produce O2 and H2O2 for hypoxia-relieved ICG-mediated PDT and H2O2-supplying MSN-based CDT, acting as an open source strategy for ROS production. Additionally, the MSNs-induced glutathione depletion protects ROS from scavenging, termed reduce expenditure. This open source and reduce expenditure strategy is effective in inhibiting tumor growth both in vitro and in vivo, and significantly improves ROS generation efficiency from multi-level for ROS-involved cancer therapies.

Graphene-Based Biosensors for Detection of Biomarkers.

The development of biosensors with high sensitivity and low-detection limits provides a new direction for medical and personal care. Graphene and graphene derivatives have been used to prepare various types of biosensors due to their excellent sensing performance (e.g., high specific surface area, extraordinary electronic properties, electron transport capabilities and ultrahigh flexibility). This perspective review focuses on graphene-based biosensors for quantitative detection of cancer-related biomarkers such as DNA, miRNA, small molecules and proteins by integrating with different signal outputting approaches including fluorescent, electrochemistry, surface plasmon resonance, surface enhanced Raman scattering, etc. The article also discussed their challenges and potential solutions along with future prospects.

Biodegradable Biomimic Copper/Manganese Silicate Nanospheres for Chemodynamic/Photodynamic Synergistic Therapy with Simultaneous Glutathione Depletion and Hypoxia Relief.

The integration of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhanced anticancer effects. Herein, we report biodegradable cancer cell membrane-coated mesoporous copper/manganese silicate nanospheres (mCMSNs) with homotypic targeting ability to the cancer cell lines and enhanced ROS generation through singlet oxygen (1O2) production and glutathione (GSH)-activated Fenton reaction, showing excellent CDT/PDT synergistic therapeutic effects. We demonstrate that mCMSNs are able to relieve the tumor hypoxia microenvironment by catalytic decomposition of endogenous H2O2 to O2 and further react with O2 to produce toxic 1O2 with a 635 nm laser irradiation. GSH-triggered mCMSNs biodegradation can simultaneously generate Fenton-like Cu+ and Mn2+ ions and deplete GSH for efficient hydroxyl radical (•OH) production. The specific recognition and homotypic targeting ability to the cancer cells were also revealed. Notably, relieving hypoxia and GSH depletion disrupts the tumor microenvironment (TME) and cellular antioxidant defense system, achieving exceptional cancer-targeting therapeutic effects in vitro and in vivo. The cancer cells growth was significantly inhibited. Moreover, the released Mn2+ can also act as an advanced contrast agent for cancer magnetic resonance imaging (MRI). Thus, together with photosensitizers, Fenton agent provider and MRI contrast effects along with the modulating of the TME allow mCMSNs to realize MRI-monitored enhanced CDT/PDT synergistic therapy. It provides a paradigm to rationally design TME-responsive and ROS-involved therapeutic strategies based on a single polymetallic silicate nanomaterial with enhanced anticancer effects.

Target-Triggered Catalytic Hairpin Assembly-Induced Core-Satellite Nanostructures for High-Sensitive "Off-to-On" SERS Detection of Intracellular MicroRNA.

Surface-enhanced Raman scattering (SERS) technology is emerging as a powerful molecules detection method with distinct advantages of high stability, good specificity, and low background signal compared with current prevailing fluorescence technique. However, the relative low sensitivity of SERS limits its wide applications. Engineered metallic nanoparticle aggregates with strong electromagnetic hot spots are urgently needed for low abundant molecules SERS detection. Herein, a microRNA (miRNA)-triggered catalytic hairpin assembly (CHA)-induced core-satellite (CS) nanostructure with multiple hot spots and strong electromagnetic field in nanogaps is designed. The unique plasmonic CS nanostructure is constructed by plasmonic Au nanodumbbells (Au NDs) as core and Au nanoparticles (Au NPs) as satellites, and it possesses enhanced electromagnetic field compared to that of Au NPs-Au nanorods (Au NRs) CS and Au NPs only. The "off-to-on" SERS strategy leads to a wide linear miRNA detection range from 10-19 to 10-9 M with a limit of detection (LOD) down to 0.85 aM in vitro. Intracellular accurate and sensitive miRNAs SERS imaging detection in different cell lines with distinct different miRNA expression levels are also achieved. The proposed SERS platform contributes to engineering metallic nanoparticle aggregates with strong electromagnetic intensity and has potential application in quantitative and precise detection significant intracellular molecules.

Superwettable Electrochemical Biosensor toward Detection of Cancer Biomarkers.

Bioinspired superwettable micropatterns that combine two extreme states of superhydrophobicity and superhydrophilicity with the ability to enrich and absorb microdroplets are suitable for versatile and robust sensing applications. Here we introduce a superwettable microchip that integrates superhydrophobic-superhydrophilic micropatterns and a nanodendritic electrochemical biosensor toward the detection of prostate cancer biomarkers. On the superwettable microchip, the superhydrophobic area could confine the microdroplets in superhydrophilic microwells; such behavior is extremely helpful for reducing the amount of analytical solution. In contrast, superhydrophilic microwells exhibit a high adhesive force toward microdroplets, and the nanodendritic structures can improve probe-binding capacity and response signals, thus greatly enhancing the sensitivity. Sensitive and selective detection of prostate cancer biomarkers including miRNA-375, miRNA-141, and prostate-specific antigen on a single microchip is also achieved. Such a superwettable microchip with high sensitivity, low sample volume, and upside-down detection capability in a single microdroplet shows great potential to fabricate portable devices toward complex biosensing applications.

Free-Blockage Mesoporous Anticancer Nanoparticles Based on ROS-Responsive Wetting Behavior of Nanopores.

To achieve an excellent delivery effect of drug, stimuli-responsive nano "gate" with physical blockage units is usually constructed on the surface of the mesoporous silica nanocarriers (MSNs). In nature, the aquaporins in cell membrane can control the transport of water molecules by regulating the channel wettability, which is resulted from the conformational change of amino acids in the channel. Inspired by this phonomenon, herein a new concept of free-blockage controlled release system is proposed, which is achieved by controlling the wettability of the internal surface of nanopores on MSNs. Such a new system is different from the physical-blockage controlled release system, which bypasses the use of nano "gate" and overcomes the limitations of traditional physical blockage system. Moreover, further studies have shown that the system can selectively release the entrapped doxorubicin in human breast adenocarcinoma (MCF-7) cells triggered by intracellular reactive oxygen species (ROS) but not in normalhuman umbilical vein endothelial cells (HUVECs) containing ROS with low levels. The wettability-determined free-blockage controlled release system is simple and effective, and it can also be triggered by intracellular biological stimuli, which provides a new approach for the future practical application of drug delivery and cancer therapy.

Cell micropatterns based on silicone-oil-modified slippery surfaces.

We demonstrate a simple and environment-friendly strategy to fabricate cell micropatterns on a nanodendritic superhydrophilic silica substrate separated by silicone-oil-modified superhydrophobic barriers. The superhydrophilic spots exhibit excellent cell adhesion capability due to the enhanced local topographic interaction between cell filopodia and the nanodendritic substrate interface, and result in sensational cell micropatterns. In contrast, the anti-adhesion of silicone-oil-modified superhydrophobic barriers prevents cell migration and results in long-term cell-repellency. Such superhydrophilic spots and silicone-oil-modified superhydrophobic barriers are very helpful for the formation of cell micropatterns. Moreover, co-culture of different cells can be achieved on the silicone-oil-modified micropatterns. The unique properties of our silicone-oil-modified micropatterns hold considerable promise for a wide range of biological applications, such as cell-based bioassays, tissue engineering, high-throughput screening and fundamental studies of cell biology.

Turning erythrocytes into functional micromotors.

Attempts to apply artificial nano/micromotors for diverse biomedical applications have inspired a variety of strategies for designing motors with diverse propulsion mechanisms and functions. However, existing artificial motors are made exclusively of synthetic materials, which are subject to serious immune attack and clearance upon entering the bloodstream. Herein we report an elegant approach that turns natural red blood cells (RBCs) into functional micromotors with the aid of ultrasound propulsion and magnetic guidance. Iron oxide nanoparticles are loaded into the RBCs, where their asymmetric distribution within the cells results in a net magnetization, thus enabling magnetic alignment and guidance under acoustic propulsion. The RBC motors display efficient guided and prolonged propulsion in various biological fluids, including undiluted whole blood. The stability and functionality of the RBC motors, as well as the tolerability of regular RBCs to the ultrasound operation, are carefully examined. Since the RBC motors preserve the biological and structural features of regular RBCs, these motors possess a wide range of antigenic, transport, and mechanical properties that common synthetic motors cannot achieve and thus hold considerable promise for a number of practical biomedical uses.

Underwater-transparent nanodendritic coatings for directly monitoring cancer cells.

Underwater-transparent nanodendritic coatings are easily fabricated by a three-step template process. After modification with anti-EpCAM, the coatings exhibit the capability for efficiently capturing rare number of cancer cells from whole blood. On the other hand, the unique underwater transparency enables the coatings to directly monitor captured cancer cells by optical imaging.

Programmable fractal nanostructured interfaces for specific recognition and electrochemical release of cancer cells.

Topographic recognition of cancer cells is triggered by fractal gold nanostructures (FAuNSs), leading to dramatically enhanced recognition capability and efficient release of cancer cells with little damage. The unique characteristic of FAuNSs is the similar fractal dimension of their surface and that of a cancer cell. The design of fractal nanostructures will open up opportunities for functional design of bio-interfaces for highly efficient recognition and release of disease-related rare cells, which will improve detection in a clinical environment.