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).

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.

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.

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.

Efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors: a real-world, multicenter, observational study.

Introduction: Mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor-α (PDGFRA) render the available tyrosine kinase inhibitors (TKI) ineffective in treating advanced gastrointestinal stromal tumors (GIST). Ripretinib, a broad-spectrum switch-control kinase inhibitor, has shown increased efficacy and manageable safety, but real-world evidence remains scarce. This study evaluates the efficacy and safety of ripretinib among Chinese patients in a real-world setting. Methods: Advanced GIST patients (N=23) receiving ripretinib following progression on previous lines of TKI treatment were enrolled to determine the efficacy [progression-free survival (PFS) and overall survival (OS)]. Safety was assessed by the incidence and severity of adverse events (AEs). All statistical analyses were performed using SPSS version 20.0 and a p-value of <0.05 was considered significant. Results: The median PFS (mPFS) of efficacy analysis set (EAS) (N=21) was 7.1 months. mPFS of patients receiving ripretinib following ≤2 lines of previous TKI treatment and ≥3 prior lines of therapy were 7.1 and 9.2 months, respectively. The median OS (mOS) was 12.0 months and shorter interval between the end of the latest TKI and ripretinib therapy was correlated with longer median PFS and OS (p=0.054 and p=0.046), respectively. Alopecia and asthenia were the most common AEs observed. Conclusion: Compared to previous lines of TKI in advanced GIST patients, ripretinib showed superior efficacy with clinically manageable AEs. Real-world results are comparable to that of phase III INVICTUS study and its Chinese bridging study. Hence, ripretinib can be used for the clinical management of advanced GIST patients.

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.

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.

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.

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.

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.

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.

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.

Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy.

Bacteria can bypass the blood-brain barrier (BBB), suggesting the possibility of employment of bacteria for combating central nervous system diseases. Herein, we develop a bacteria-based drug delivery system for glioblastoma (GBM) photothermal immunotherapy. The system, which we name as 'Trojan bacteria', consists of bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected bacteria bypass the BBB, targeting and penetrating GBM tissues. Upon 808 nm-laser irradiation, the photothermal effects produced by ICG allow the destruction of bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual bacteria are effectively eliminated from the body, supporting the potential therapeutic use of this system.

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.

Effects of Co/Mn Content Variation on Structural and Electrochemical Properties of Single-Crystal Ni-Rich Layered Oxide Materials for Lithium Ion Batteries.

The development of single-crystal nickel-rich layered LiNixCoyMn1-x-yO2 materials (S-NCMs) represents the most significant progress for the electrification applications of nickel-rich ternary materials. There has been prior research on the important role of transition metal elements in agglomerated materials, supplemented by surface and internal lattice optimization to drive the performance improvements. However, studies on S-NCMs, especially on the role of transition metals (TM, i.e., Co and Mn), have not been reported. In this study, we synthesized four kinds of S-NCMs with different Co/Mn contents and studied their structural, electrochemical, kinetic, and thermodynamic properties with different Co/Mn contents. The results were as follows: (1) Electrochemically, Co was more effective than Mn at 25 °C at enhancing the intercalation/deintercalation kinetics, which resulted in an increased discharge capacity, an improved rate capability, and a reduced energy loss. (2) Thermodynamically, Mn was more effective at maintaining a higher thermal stability than Co, especially at a low cutoff voltage, but at a high cutoff voltage, the difference between the action of Co and Mn decreased. The main finding of this work was the enhanced structural stability provided by Co, which could be attributed to the following: (i) the absence of the H2/H3 phase transformation when Co exceeded 15%, which inhibited the irreversible phase transformation and reduced the volume strain, and (ii) the lower degrees of decrease in the cell parameters a and c with higher contents of Co, which contributed to a low cracking degree along the (003) crystal plane. The current work provides an important reference for the single-crystallization strategy of nickel-rich materials.

Bacteria eat nanoprobes for aggregation-enhanced imaging and killing diverse microorganisms.

Currently optical-based techniques for in vivo microbial population imaging are limited by low imaging depth and highly light-scattering tissue; and moreover, are generally effective against only one specific group of bacteria. Here, we introduce an imaging and therapy strategy, in which different bacteria actively eat the glucose polymer (GP)-modified gold nanoparticles through ATP-binding cassette (ABC) transporter pathway, followed by laser irradiation-mediated aggregation in the bacterial cells. As a result, the aggregates display ~15.2-fold enhancement in photoacoustic signals and ~3.0-fold enhancement in antibacterial rate compared with non-aggregated counterparts. Significantly, the developed strategy allows ultrasensitive imaging of bacteria in vivo as low ~105 colony-forming unit (CFU), which is around two orders of magnitude lower than most optical contrast agents. We further demonstrate the developed strategy enables the detection of ~107 CFU bacteria residing within tumour or gut. This technique enables visualization and treatment of diverse bacteria, setting the crucial step forward the study of microbial ecosystem.

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.

Nanoparticles as a Hedgehog signaling inhibitor for the suppression of cancer growth and metastasis.

Nanoparticles (NPs) have been intensively explored for the treatment of tumors during the past decade, yet little information has been provided on the NPs' inherent therapeutic activity against cancers. With this goal in mind, we reveal that biocompatible silicon (Si) NPs (SiNPs) feature excellent anti-growth and anti-metastasis activities against prostate cancer cells that show aberrant activation of the Hedgehog (HH) signaling pathway. Without activation by the Sonic hedgehog (Shh)-agonist, mouse embryonic fibroblast (NIH3T3) cells show no response to SiNP exposure. The distinct inhibitory effect of SiNPs on the HH signaling pathway leads to significant suppression of the proliferation, migration, and invasion of human prostate cancer cells. Crucially, in two mouse tumor models, the growth and metastasis of prostate cancer cells are also efficiently inhibited by SiNPs.

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.