Defect-Rich Metastable MoS2 Promotes Macrophage Reprogramming in Breast Cancer: A Clinical Perspective.

Tumor-associated macrophages (TAMs) play a crucial function in solid tumor antigen clearance and immune suppression. Notably, 2D transitional metal dichalcogenides (i.e., molybdenum disulfide (MoS2) nanozymes) with enzyme-like activity are demonstrated in animal models for cancer immunotherapy. However, in situ engineering of TAMs polarization through sufficient accumulation of free radical reactive oxygen species for immunotherapy in clinical samples remains a significant challenge. In this study, defect-rich metastable MoS2 nanozymes, i.e., 1T2H-MoS2, are designed via reduction and phase transformation in molten sodium as a guided treatment for human breast cancer. The as-prepared 1T2H-MoS2 exhibited enhanced peroxidase-like activity (≈12-fold enhancement) than that of commercial MoS2, which is attributed to the charge redistribution and electronic state induced by the abundance of S vacancies. The 1T2H-MoS2 nanozyme can function as an extracellular hydroxyl radical generator, efficiently repolarizing TAMs into the M1-like phenotype and directly killing cancer cells. Moreover, the clinical feasibility of 1T2H-MoS2 is demonstrated via ex vivo therapeutic responses in human breast cancer samples. The apoptosis rate of cancer cells is 3.4 times greater than that of cells treated with chemotherapeutic drugs (i.e., doxorubicin).

Inactive Trojan Bacteria as Safe Drug Delivery Vehicles Crossing the Blood-Brain Barrier.

Escherichia coli K1 (EC-K1) can bypass the blood-brain barrier (BBB) and cause meningitis. Excitingly, we find the "dead EC-K1" can safely penetrate the BBB because they retain the intact structure and chemotaxis of the live EC-K1, while losing their pathogenicity. Based on this, we develop a safe "dead EC-K1"-based drug delivery system, in which EC-K1 engulf the maltodextrin (MD)-modified therapeutics through the bacteria-specific MD transporter pathway, followed by the inactivation via UV irradiation. We demonstrate that the dead bacteria could carry therapeutics (e.g., indocyanine green (ICG)) and together bypass the BBB after intravenous injection into the mice, delivering ∼3.0-fold higher doses into the brain than free ICG under the same conditions. What is more, all mice remain healthy even after 14 days of intravenous injection of ∼109 CFU of inactive bacteria. As a proof of concept, we demonstrate the developed strategy enables the therapy of bacterial meningitis and glioblastoma in mice.

NIR-II Photoacoustic-Active DNA Origami Nanoantenna for Early Diagnosis and Smart Therapy of Acute Kidney Injury.

Herein, we designed and synthesized a novel microRNA (miR)-responsive nanoantenna capable of early diagnosis and smart treatment of acute kidney injury (AKI). The nanoantenna was made of two miniature gold nanorods (AuNRs) (e.g., length: ∼48 nm; width: ∼9 nm) linked together by a rectangular DNA origami nanostructure (rDONs) scaffold (e.g., length: ∼90 nm; width: ∼60 nm) (rDONs@AuNR dimer). The surface plasmon resonance peak of the constructed nanoantenna is located within the NIR-II window (e.g., ∼1060 nm), thus guaranteeing photoacoustic (PA) imaging of the nanoantenna in deep tissues. Intriguingly, the nanoantenna displayed exclusive kidney retention in both healthy mice and ischemia reperfusion-induced AKI mice by leveraging the kidney-targeting ability of rDONs. Distinguished from the stable signals in the healthy mice, the PA signals of the nanoantenna would turn down in the AKI mice due to the AuNR detached from rDONs upon interaction with miR-21, which were up-expressed in AKI mice. The limit of detection toward miR-21 was down to 2.8 nM, enabling diagnosis of AKI as early as 10 min post-treatment with ischemia reperfusion, around 2 orders of magnitude earlier than most established probes. Moreover, the naked rDON scaffold generated by AKI could capture more reactive oxygen species (e.g., 1.5-fold more than rDONs@AuNR dimer), alleviating ischemic AKI. This strategy provided a new avenue for early diagnosis and smart treatment of AKI.

Multifunctional Flavonoid-Silica Nanohydrogel Enables Simultaneous Inhibition of Tumor Recurrence and Bacterial Infection in Post-Surgical Treatment.

A strategy to synthesize water-soluble and fluorescent flavonoid-silica nanocomposites (FSiNCs) simultaneously featuring anti-tumor and anti-bacterial abilities is developed. Furthermore, it is demonstrated that the therapeutic effects of FSiNCs are associated with the selective accumulation of reactive oxide species in both tumor and bacteria cells. Following that, the resultant FSiNCs are incorporated with thrombin and fibrinogen, being sprayed onto the tumor surgical wound site to in situ form fibrin gel (FSiNCs@Fibrin). Remarkably, such FSiNCs@Fibrin results in an ≈18-fold reduction in intratumoral bacteria numbers and ≈12-fold decrease in tumor regrowth compared to equivalent free flavonoid-loaded gel.

Trojan Nanobacteria System for Photothermal Programmable Destruction of Deep Tumor Tissues.

A novel bacteria-based drug delivery system, termed "Trojan nanobacteria system", has been developed in which nanoagents are internalized into engineered bacteria through bacteria-specific maltodextrin (MD) transporters. Compared to the method of attaching nanoagents to bacterial surfaces, this Trojan system features higher payloads and better stability. In cancer therapy, Trojan nanobacteria can specifically discriminate the tumor region and then penetrate deep tumor tissues. Once in the tumor, the Trojan nanobacteria systems are able to destroy deep tumor tissues due to the combined effects of antitumor protein expression (e.g., tumor necrosis factor-α, TNF-α) and photothermal properties.

Ex vivo and in vivo fluorescence detection and imaging of adenosine triphosphate.

BACKGROUND: Ex vivo and in vivo detection and imaging of adenosine triphosphate (ATP) is critically important for the diagnosis and treatment of diseases, which still remains challenges up to present. RESULTS: We herein demonstrate that ATP could be fluorescently detected and imaged ex vivo and in vivo. In particular, we fabricate a kind of fluorescent ATP probes, which are made of titanium carbide (TC) nanosheets modified with the ROX-tagged ATP-aptamer (TC/Apt). In the constructed TC/Apt, TC shows superior quenching efficiency against ROX (e.g., ~ 97%). While in the presence of ATP, ROX-tagged aptamer is released from TC surface, leading to the recovery of fluorescence of ROX under the 545-nm excitation. Consequently, a wide dynamic range from 1 µM to 1.5 mM ATP and a high sensitivity with a limit of detection (LOD) down to 0.2 µM ATP can be readily achieved by the prepared TC/Apt. We further demonstrate that the as-prepared TC/Apt probe is feasible for accurate discrimination of ATP in different samples including living cells, body fluids (e.g., mouse serum, mouse urine and human serum) and mouse tumor models. CONCLUSIONS: Fluorescence detection and imaging of ATP could be readily achieved in living cells, body fluids (e.g., urine and serum), as well as mouse tumor model through a new kind of fluorescent ATP nanoprobes, offering new powerful tools for the treatment of diseases related to abnormal fluctuation of ATP concentration.

Nitrogen-Doped Carbon-Coating Disproportionated SiO Materials as Long Cycling Stable Anode for Lithium Ion Batteries.

Silicon monoxide (SiO) is a kind of promising anode material for lithium-ion batteries because of its smaller volume change during the charge and discharge process than pure silicon and its higher theoretical capacity than commercialized graphite. However, its fast-fading capacity still restricts the development of practical application of SiO. A simple and cheap strategy to dope nitrogen and coat carbon on the surface of disproportionated SiO is proposed to improve the cycling stability significantly even at a high specific current. The capacity retention is nearly 85% after 250 cycles and more than 69% after 500 cycles at a specific current of 1000 mA g-1. Even at a specific current of 2000 mA g-1, its cycling performance behaves similarly to that of 1000 mA g-1. Nitrogen doping in materials could improve the conductivity of materials because pyridinic nitrogen and pyrrolic nitrogen could improve the electron conductivity and provide defects to contribute to the diffusion of lithium ions. The use of pitch and melamine, which are easily available industrial raw materials, makes it possible to contribute to the practical application.

Multifunctional Silicon-Carbon Nanohybrids Simultaneously Featuring Bright Fluorescence, High Antibacterial and Wound Healing Activity.

In this work, a class of multifunctional silicon-carbon nanohybrids (designated as SiCNs), which simultaneously possess aqueous dispersibility, bright fluorescence (photoluminescence quantum yield [PLQY]: ≈28%), as well as high antibacterial and wound healing activity, is presented. Taking advantage of these unique merits, cell distribution and pharmacological behavior of the SiCNs is first investigated through tracking their strong and stable fluorescence. The high bacteria inhibition ability (≈82.9% killing rate toward S. aureus) and hemostatic effects (shorten the bleeding time from ≈60 to ≈15 s) of the resultant SiCNs are then demonstrated. Moreover, the wound closure promotion activity (10% lead in wound contraction) is systematically demonstrated in vivo, which is especially suitable for wound healing applications. The results suggest the SiCNs as a new kind of high-performance multifunctional nanoagents suitable for various biological and biomedical utilizations.

Fluorescent Silicon Nanorods-Based Ratiometric Sensors for Long-Term and Real-Time Measurements of Intracellular pH in Live Cells.

Long-term and real-time investigation of the dynamic process of pHi changes is critically significant for understanding the related pathogenesis of diseases and the design of intracellular drug delivery systems. Herein, we present a one-step synthetic strategy to construct ratiometric pH sensors, which are made of europium (Eu)-doped one-dimensional silicon nanorods (Eu@SiNRs). The as-prepared Eu@SiNRs have distinct emission maxima peaks at 470 and 620 nm under 405 nm excitation. Of particular note, the fluorescence emission intensity at 470 nm decreases along with the increase of pH, while the one at 620 nm is nearly unaffected by pH changes, making Eu@SiNRs a feasible probe for pH sensing ratiometrically. Moreover, Eu@SiNRs are found to be responsive to a broad pH range (ca. 3-9), biocompatible (e.g., ∼100% of cell viability during 24 h treatment) and photostable (e.g., ∼10% loss of intensity after 40 min continuous UV irradiation). Taking advantages of these merits, we employ Eu@SiNRs for the visualization of the cytoplasmic alkalization process mediated by nigericin in living cells, for around 30 min without interruption, revealing important information for understanding the dynamic process of pHi fluctuations.

One-Dimensional Fluorescent Silicon Nanorods Featuring Ultrahigh Photostability, Favorable Biocompatibility, and Excitation Wavelength-Dependent Emission Spectra.

We herein report a kind of one-dimensional biocompatible fluorescent silicon nanorods (SiNRs) with tunable lengths ranging ∼100-250 nm, which can be facilely prepared through one-pot microwave synthesis. In addition to the strong fluorescence (quantum yield value: ∼15%) and negligible toxicity, the resultant SiNRs exhibit excitation wavelength-dependent photoluminescence whose maximum emission wavelength ranges from ∼450 to ∼600 nm under serial excitation wavelengths from 390 to 560 nm, providing feasibility for multicolor biological imaging. More significantly, the SiNRs are ultrahighly photostable, preserving strong and nearly unchanged fluorescence under 400 min high-power UV irradiation, which is in sharp contrast to severe fluorescence quenching of organic dyes (e.g., FITC) or II-VI quantum dots (QDs) (e.g., CdTe QDs and CdSe/ZnS QDs) within 15 or 160 min UV treatment under the same experiment conditions, respectively. Taking advantage of these attractive merits, we further exploit the SiNRs as a novel type of color converters for the construction of white light-emitting diodes (LED), which is the first proof-of-concept demonstration of LED device fabricated using the one-dimensional fluorescent silicon nanostructures.

Fluorescent and Photostable Silicon Nanoparticles Sensors for Real-Time and Long-Term Intracellular pH Measurement in Live Cells.

Fluorescent sensors suitable for dynamic measurement of intracellular pH (pHi) fluctuations should feature the following properties: feeble cytotoxicity, wide-pH range response, and strong fluorescence coupled with good photostability, which are still remaining scanty to date. Herein, by functionalizing fluorescent silicon nanoparticles (SiNPs) with pH-sensitive dopamine (DA) and pH-insensitive rhodamine B isothiocyanate (RBITC), we present the first demonstration of fluorescent SiNPs-based sensors, simultaneously exhibiting minimal toxicity (cell viability of treated cells remains above 95% during 24-h treatment), sensitive fluorescent response to a broad pH range (∼4-10), and bright fluorescence coupled with robust photostability (∼9% loss of fluorescence intensity after 40 min continuous excitation; in contrast, fluorescence of Lyso-tracker is rapidly quenched in 5 min under the same experiment conditions). Taking advantage of these merits, we further employ the resultant fluorescent SiNPs sensors for the detection of lysosomal pH change mediated by nigericin in live HeLa and MCF-7 cells in long-term (e.g., 30 min) manners. Interestingly, two consecutive stages, i.e., alkalization lag phase and logarithmic growth phase, are observed based on recording the whole process of pH change, offering important information for understanding the dynamic process of pHi fluctuations.

Biomimetic Preparation and Dual-Color Bioimaging of Fluorescent Silicon Nanoparticles.

Fluorescent silicon nanoparticles (SiNPs), as the most important zero-dimensional silicon nanostructures, hold high promise for long-awaited silicon-based optic applications. There currently remain major challenges for the green, inexpensive, and mass production of fluorescent SiNPs, resulting in difficulties in sufficiently exploiting the properties of these remarkable materials. Here, we show that fluorescent small-sized (∼3.8 nm) SiNPs can be produced through biomimetic synthesis in rapid (10 min), low-cost, and environmentally benign manners. The as-prepared SiNPs simultaneously feature bright fluorescence (quantum yield (QY), ∼15-20%), narrow emission spectral width (full width at half-maximum (fwhm), ∼30 nm), and nontoxicity, making them as high-quality fluorescent probes for biological imaging in vitro and in vivo.

Triboelectric-Responsive Drug Delivery Hydrogel for Accelerating Infected Wound Healing.

Electrotherapy is of great interest in the field of tissue repair as an effective, well-tolerated, and noninvasive treatment. Triboelectric nanogenerator (TENG) has shown advantages in promoting wound healing due to its peak output characteristic and low Joule heating effect. However, it is limited in infected wound healing due to poor antimicrobial capacity. Here, a wearable triboelectric stimulator (WTS) is developed that consists of a flexible TENG (F-TENG) and a triboelectric-responsive drug delivery hydrogel (TR-DDH) for healing of bacterium-infected wounds. F-TENG can generate pulsed current to wounds by converting mechanical energy from body movements. Polypyrrole is prone to reduction and volume contraction under electrical stimulation, resulting in desorption of curcumin nanoparticles (CUR NPs) from the polypyrrole in TR-DDH. Therefore, the highly efficient and controllable release of CUR NPs can be achieved by triboelectric stimulation. According to the in vitro and in vivo experiments, WTS has the greatest antimicrobial effect and the fastest promotion of infected wound healing compared to treatment with electrical stimulation or curcumin. Finally, the safety assessment demonstrates that the WTS has excellent tissue safety for chronic wound healing. Synergistic therapy with WTS provides an efficient strategy for chronic wound healing and smart-responsive drug delivery systems.

Photoactivated Gas-Generating Nanocontrast Agents for Long-Term Ultrasonic Imaging-Guided Combined Therapy of Tumors.

To date, long-term and continuous ultrasonic imaging for guiding the puncture biopsy remains a challenge. In order to address this issue, a multimodality imaging and therapeutic method was developed in the present study to facilitate long-term ultrasonic and fluorescence imaging-guided precision diagnosis and combined therapy of tumors. In this regard, certain types of photoactivated gas-generating nanocontrast agents (PGNAs), capable of exhibiting both ultrasonic and fluorescence imaging ability along with photothermal and sonodynamic function, were designed and fabricated. The advantages of these fabricated PGNAs were then utilized against tumors in vivo, and high therapeutic efficacy was achieved through long-term ultrasonic imaging-guided treatment. In particular, the as-prepared multifunctional PGNAs were applied successfully for the fluorescence-based determination of patient tumor samples collected through puncture biopsy in clinics, and superior performance was observed compared to the clinically used SonoVue contrast agents that are incapable of specifically distinguishing the tumor in ex vivo tissues.

Framework Nucleic Acids Combined with 3D Hybridization Chain Reaction Amplifiers for Monitoring Multiple Human Tear Cytokines.

Existing tear sensors are difficult to perform multiplexed assays due to the minute amounts of biomolecules in tears and the tiny volume of tears. Herein, the authors leverage DNA tetrahedral frameworks (DTFs) modified on the wireless portable electrodes to effectively capture 3D hybridization chain reaction (HCR) amplifiers for automatic and sensitive monitoring of multiple cytokines in human tears. The developed sensors allow the sensitive determination of various dry eye syndrome (DES)-associated cytokines in human tears with the limit of detection down to 0.1 pg mL-1, consuming as little as 3 mL of tear fluid. Double-blind testing of clinical DES samples using the developed sensor and commercial ELISA shows no significant difference between them. Compared with single-biomarker diagnosis, the diagnostic accuracy of this sensor based on multiple biomarkers has improved by ≈16%. The developed system offers the potential for tear sensors to enable personalized and accurate diagnosis of various ocular diseases.

ECG signal classification in wearable devices based on compressed domain.

Wearable devices are often used to diagnose arrhythmia, but the electrocardiogram (ECG) monitoring process generates a large amount of data, which will affect the detection speed and accuracy. In order to solve this problem, many studies have applied deep compressed sensing (DCS) technology to ECG monitoring, which can under-sampling and reconstruct ECG signals, greatly optimizing the diagnosis process, but the reconstruction process is complex and expensive. In this paper, we propose an improved classification scheme for deep compressed sensing models. The framework is comprised of four modules: pre-processing; compression; and classification. Firstly, the normalized ECG signals are compressed adaptively in the three convolutional layers, and then the compressed data is directly put into the classification network to obtain the results of four kinds of ECG signals. We conducted our experiments on the MIT-BIH Arrhythmia Database and Ali Cloud Tianchi ECG signal Database to validate the robustness of our model, adopting Accuracy, Precision, Sensitivity and F1-score as the evaluation metrics. When the compression ratio (CR) is 0.2, our model has 98.16% accuracy, 98.28% average accuracy, 98.09% Sensitivity and 98.06% F1-score, all of which are better than other models.

Fluorescence, ultrasonic and photoacoustic imaging for analysis and diagnosis of diseases.

Biomedical imaging technology, which allows us to peer deeply within living subjects and visually explore the delivery and distribution of agents in living things, is producing tremendous opportunities for the early diagnosis and precise therapy of diseases. In this feature article, based on reviewing the latest representative examples of progress together with our recent efforts in the bioimaging field, we intend to introduce three typical kinds of non-invasive imaging technologies, i.e., fluorescence, ultrasonic and photoacoustic imaging, in which optical and/or acoustic signals are employed for analyzing various diseases. In particular, fluorescence imaging possesses a series of outstanding advantages, such as high temporal resolution, as well as rapid and sensitive feedback. Hence, in the first section, we will introduce the latest studies on developing novel fluorescence imaging methods for imaging bacterial infections, cancer and lymph node metastasis in a long-term and real-time manner. However, the issues of imaging penetration depth induced by photon scattering and light attenuation of biological tissue limit their widespread in vivo imaging applications. Taking advantage of the excellect penetration depth of acoustic signals, ultrasonic imaging has been widely applied for determining the location, size and shape of organs, identifying normal and abnormal tissues, as well as confirming the edges of lesions in hospitals. Thus, in the second section, we will briefly summarize recent advances in ultrasonic imaging techniques for diagnosing diseases in deep tissues. Nevertheless, the absence of lesion targeting and dependency on a professional technician may lead to the possibility of false-positive diagnosis. By combining the merits of both optical and acoustic signals, newly-developed photoacoustic imaging, simultaneously featuring higher temporal and spatial resolution with good sensitivity, as well as deeper penetration depth, is discussed in the third secretion. In the final part, we further discuss the major challenges and prospects for developing imaging technology for accurate disease diagnosis. We believe that these non-invasive imaging technologies will introduce a new perspective for the precise diagnosis of various diseases in the future.

Camouflage Nanoparticles Enable in Situ Bioluminescence-Driven Optogenetic Therapy of Retinoblastoma.

Optogenetic therapy has emerged as a promising technique for the treatment of ocular diseases; however, most optogenetic tools rely on external blue light to activate the photoswitch, whose relatively strong phototoxicity may induce retinal damage. Herein, we present the demonstration of camouflage nanoparticle-based vectors for in situ bioluminescence-driven optogenetic therapy of retinoblastoma. In biomimetic vectors, the photoreceptor CRY2 and its interacting partner CIB1 plasmid are camouflaged with folic acid ligands and luciferase NanoLuc-modified macrophage membranes. To conduct proof-of-concept research, this study employs a mouse model of retinoblastoma. In comparison to external blue light irradiation, the developed system enables an in situ bioluminescence-activated apoptotic pathway to inhibit tumor growth with greater therapeutic efficacy, resulting in a significant reduction in ocular tumor size. Furthermore, unlike external blue light irradiation, which causes retinal damage and corneal neovascularization, the camouflage nanoparticle-based optogenetic system maintains retinal structural integrity while avoiding corneal neovascularization.

Antisense Oligonucleotides Selectively Enter Human-Derived Antibiotic-Resistant Bacteria through Bacterial-Specific ATP-Binding Cassette Sugar Transporter.

Current vehicles used to deliver antisense oligonucleotides (ASOs) cannot distinguish between bacterial and mammalian cells, greatly hindering the preclinical or clinical treatment of bacterial infections, especially those caused by antibiotic-resistant bacteria. Herein, bacteria-specific ATP-binding cassette (ABC) sugar transporters are leveraged to selectively internalize ASOs by hitchhiking them on α (1-4)-glucosidically linked glucose polymers. Compared with their cell-penetrating peptide counterparts, which are non-specifically engulfed by mammalian and bacterial cells, the presented therapeutics consisting of glucose polymer and antisense peptide nucleic-acid-modified nanoparticles are selectively internalized into the human-derived multidrug-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus, and they display a much higher uptake rate (i.e., 51.6%). The developed strategy allows specific and efficient killing of nearly 100% of the antibiotic-resistant bacteria. Its significant curative efficacy against bacterial keratitis and endophthalmitis is also shown. This strategy will expand the focus of antisense technology to include bacterial cells other than mammalian cells.

In vivo bioluminescence imaging of natural bacteria within deep tissues via ATP-binding cassette sugar transporter.

Most existing bioluminescence imaging methods can only visualize the location of engineered bacteria in vivo, generally precluding the imaging of natural bacteria. Herein, we leverage bacteria-specific ATP-binding cassette sugar transporters to internalize luciferase and luciferin by hitchhiking them on the unique carbon source of bacteria. Typically, the synthesized bioluminescent probes are made of glucose polymer (GP), luciferase, Cy5 and ICG-modified silicon nanoparticles and their substrates are made of GP and D-luciferin-modified silicon nanoparticles. Compared with bacteria with mutations in transporters, which hardly internalize the probes in vitro (i.e., ~2% of uptake rate), various bacteria could robustly engulf the probes with a high uptake rate of around 50%. Notably, the developed strategy enables ex vivo bioluminescence imaging of human vitreous containing ten species of pathogens collected from patients with bacterial endophthalmitis. By using this platform, we further differentiate bacterial and non-bacterial nephritis and colitis in mice, while their chemiluminescent counterparts are unable to distinguish them.