Visualization of Vaccine Dynamics with Quantum Dots for Immunotherapy.

The direct visualization of vaccine fate is important to investigate its immunoactivation process to elucidate the detailed molecular reaction process at single-molecular level. Yet, visualization of the spatiotemporal trafficking of vaccines remains poorly explored. Here, we show that quantum dot (QD) nanomaterials allow for monitoring vaccine dynamics and for amplified immune response. Synthetic QDs enable efficient conjugation of antigen and adjuvants to target tissues and cells, and non-invasive imaging the trafficking dynamics to lymph nodes and cellular compartments. The nanoparticle vaccine elicits potent immune responses and anti-tumor efficacy alone or in combination with programmed cell death protein 1 blockade. The synthetic QDs showed high fluorescence quantum yield and superior photostability, and the reliable and long-term spatiotemporal tracking of vaccine dynamics was realized for the first time by using the synthetic QDs, providing a powerful strategy for studying immune response and evaluating vaccine efficacy.

Biosynthesized Quantum Dot for Facile and Ultrasensitive Electrochemical and Electrochemiluminescence Immunoassay.

Nanomaterials are commonly utilized for amplified immunoassay of biomarkers. However, traditional nanomaterial-based immunoassay usually requires a time-consuming and labor-intensive nanoparticle modification and conjugation process, which impedes their practical applications. Here, a new immunoassay method based on biosynthesized nanomaterials is developed with versatile functions for facile and ultrasensitive detection of cancer biomarker. In this method, the utilized biosynthesized quantum dots (BQDs) allow convenient antibody conjugation and electrode modification, and demonstrate excellent electrochemical and electrochemiluminescent responses. The differential pulse voltammetric, faradaic impedance spectroscopy, and electrochemiluminescent measurements with the BQD-modified electrode show detection limits at picomolar levels as well as good specificity toward human prostate-specific antigen detection. The inherent recognization capability as well as the inherent electrochemical and electrochemiluminescence features thus enable BQDs as good candidates for facile immunosensors with high sensitivity. Such a biosynthesized nanomaterial-based approach opens up the possibility of using innovative designs for nanoparticle-based assays, and developing reliable and practical methods for early disease diagnosis.

Programming DNA Nanoassembly for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) has extraordinary promise for the treatment of many cancers. However, its clinical progress is impaired by the intrinsic hypoxic tumor microenvironment that limits PDT efficacy and the safety concern associated with biological specificity of photosensitizers or vehicles. Now it is demonstrated that rationally designed DNA nanosponges can load and delivery photosensitizer effectively, target tumor precisely, and relieve hypoxia-associated resistance remarkably to enhance the efficacy of PDT. Specifically, the approach exhibits a facile assembly process, provides programmable and versatile nanocarriers, and enables robust in vitro and in vivo anti-cancer efficacy with excellent biosafety. These findings represent a practical and safe approach by designer DNA nanoassemblies to combat cancer effectively and suggest a powerful strategy for broad biomedical application of PDT.

Lighting Up Fluorescent Silver Clusters via Target-Catalyzed Hairpin Assembly for Amplified Biosensing.

Isothermal enzyme-free nucleic acid circuits have been developed for carrying out diverse functions ranging from dictate biocomputing to amplified biosensing. Catalytic hairpin assembly (CHA), the catalyzed cross-opening of two hairpin substrates by an initiator, has attracted increasing attention because of its facile design and high amplification capacity. The complex labeling and frequent photobleaching of a conventional fluorescent CHA biosensor still remains a challenge that needs to be solved. Herein, we constructed a new label-free and enzyme-free isothermal CHA lighting up AgNCs strategy for amplified nucleic acid assay by integrating the interfacially and spatially sensitive feature of DNA-templated fluorescent silver nanoclusters (DNA-AgNCs) and the high signal amplification capability of the CHA circuit. In this strategy, one polyguanine-grafted hairpin and the other AgNCs-capturing hairpin were engineered as assembly constitutes, which were kinetically impeded from cross-hybridizations without target. However, in the presence of target, the CHA-catalyzed assembly of two functional hairpins was successively progressed and concomitantly accompanied by an efficient accommodation of AgNCs to the polyguanine-elongated dsDNA product, leading to highly efficient AgNCs-lighting up and to the generation of an amplified fluorescence signal. As a simple mix-and-detect strategy, the isothermal enzyme-free CHA-mediated lighting up AgNCs (CHA-AgNCs) system provided a facile visualization way for amplified detection of DNA with a detection limit of 20 pM, which was comparable to or even better than some enzyme-involved amplification methods. The homogeneous CHA-AgNCs system can be used as a general sensing platform and be easily adapted for analyzing other biologically important analytes, for example, microRNA (miRNA), by introducing the sensing module consisting of an auxiliary hairpin through an easy-to-integrate procedure. By taking advantage of the signal amplification features of CHA and the robust AgNCs-lighting up procedure, we anticipate that the CHA-lighting up AgNCs system can provide an important tool for biomedicine and bioimaging applications and thus should hold great promise in clinical diagnoses and treatment fields.

Deep learning-based methods for natural hazard named entity recognition.

Natural hazard named entity recognition is a technique used to recognize natural hazard entities from a large number of texts. The method of natural hazard named entity recognition can facilitate acquisition of natural hazards information and provide reference for natural hazard mitigation. The method of named entity recognition has many challenges, such as fast change, multiple types and various forms of named entities. This can introduce difficulties in research of natural hazard named entity recognition. To address the above problem, this paper constructed a natural disaster annotated corpus for training and evaluation model, and selected and compared several deep learning methods based on word vector features. A deep learning method for natural hazard named entity recognition can automatically mine text features and reduce the dependence on manual rules. This paper compares and analyzes the deep learning models from three aspects: pretraining, feature extraction and decoding. A natural hazard named entity recognition method based on deep learning is proposed, namely XLNet-BiLSTM-CRF model. Finally, the research hotspots of natural hazards papers in the past 10 years were obtained through this model. After training, the precision of the XLNet-BilSTM-CRF model is 92.80%, the recall rate is 91.74%, and the F1-score is 92.27%. The results show that this method, which is superior to other methods, can effectively recognize natural hazard named entities.

Multifunctional DNAzyme-Anchored Metal-Organic Framework for Efficient Suppression of Tumor Metastasis.

High mortality and rapid development of metastasis requires the development of more effective antimetastasis strategies. However, conventional therapeutic methods, including surgery, radiation therapy, and chemotherapy, show less effectiveness in curbing the metastatic spread of cancer cells and the formation of metastases. A therapeutic platform, targeting the early stage of metastasis cascade, could effectively prevent metastasis dissemination. Herein, Fe/Mn-based metal-organic frameworks (FMM) were constructed for the delivery of a specific DNAzyme with high catalytic cleavage activity on the metastasis-involved Twist mRNA, thus efficiently inhibiting the invasion of cancer cells through DNAzyme-catalyzed gene silencing. Highly potent combined gene/chemodynamic therapy is achieved from the self-supplied DNAzyme cofactors and efficient glutathione depletion. Importantly, by virtue of the intrinsic photo-to-thermal conversion of the FMM nanocarriers, our combined therapeutic strategy could be further promoted under photothermal stimuli to speed up the Fenton reaction and to accelerate the release of the Twist DNAzyme with efficient gene therapy. Consequently, the effective elimination of tumors and the blockage of metastasis are simultaneously achieved under photothermal/magnetic resonance imaging guidance. This work aims at developing versatile theranostic agents to combat metastatic tumors.

Boosting Cancer Immunotherapy via the Convenient A2AR Inhibition Using a Tunable Nanocatalyst with Light-Enhanced Activity.

Blockade of A2A adenosine receptors (A2AR)-adenosinergic signaling shows high potency to mobilize antitumor immunity for its in-depth involvement in immune regulation of nearly all immune cells. Available A2AR inhibition strategies are mainly based on small molecules or proteins inhibitors, yet are limited by the non-specific operation as well as the off-target toxicity. Herein, the first effort to design a convenient tumor-specific A2AR inhibition strategy to improve antitumor immune responses via the spatiotemporally controlled oxygen supply by virtue of a versatile photo-modulated nanoreactor is reported on. This nanoreactor, consisting of a catalase-mimicking shell (Pt nanocatalyst) and a photothermal core (polydopamine), is rationally designed for achieving the near-infrared radiation (NIR)-guided/accelerated oxygen supplementation on tumor site, and for relieving the A2AR-mediated immunosuppression without toxicity concern. Meanwhile, the NIR light could also mediate the direct photothermal ablation of tumor, and elicit immunogenic cell deaths to boost antitumor immunity. In a poorly immunogenic breast cancer model, the intravenous injection of the nanoreactor leads to the improved immune response with an increased animal survival rate, and achieves the long-term immunological memory effect against tumor recurrence as well as rechallenge. This convenient nanoreactor-stimulated A2AR inhibition approach provides a versatile promising paradigm for improving these existing immunotherapies.

Enhanced Immunostimulatory Activity of a Cytosine-Phosphate-Guanosine Immunomodulator by the Assembly of Polymer DNA Wires and Spheres.

Unmethylated cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides are immunostimulatory nucleic acids wildly utilized as adjuvants or for vaccines to treat diseases. However, there is a lack of simple and efficient vectors for CpG oligodeoxynucleotide delivery with long-lasting immune stimulation. Herein, self-assembled polymer wires consisting of CpG motifs by hybridization chain reaction were constructed with excellent biocompatibility and immunostimulatory activity. The designed polymer DNA wires acted as programmable multivalent immunoadjuvants and triggered immune response, stimulated pro-inflammatory cytokine secretion, and induced the apoptosis of cancer cells. More strikingly, polymer nanospheres assembled from the polymer DNA wires and cationic poly-l-lysine further improved cellular uptake and continuously stimulate the lysosomal Toll-like receptor 9 of immune cells, thereby remarkably enhancing the activation of immune cells. These results demonstrated that self-assembled polymer DNA nanoassemblies with multivalent CpG could trigger strong immune response and further induce cancer cell death.

Treating Immunologically Cold Tumors by Precise Cancer Photoimmunotherapy with an Extendable Nanoplatform.

Although immunotherapy has merged as an ideal cancer therapeutic strategy for preventing tumor growth and recurrence, effective approaches to treat immunologically cold tumors are still lacking. Herein, we reported a practical and extendable nanoplatform (HA/ZIF-8@ICG@IMQ) that facilely integrated various therapeutics and functions for boosting host antitumor immunity to treat immunologically cold tumors. The tumor-targeted and microenvironment-responsive HA/ZIF-8@ICG@IMQ facilitated the tumor-specific accumulation and release of photothermal agents and immune adjuvants. With near-infrared irradiation, the designed nanoparticles effectively enhanced the infiltration of cytotoxic T lymphocytes and helper T cells and effectively blocked the growth of primary and distant tumors. Moreover, the smart therapeutic could effectively prevent tumor rechallenge and recurrence with a long-term host immunological memory response. This method shows an effective immunologically cold tumor treatment using extendable nanotherapeutics and may have reference significance for clinical cancer therapy.

Regulation of redox balance using a biocompatible nanoplatform enhances phototherapy efficacy and suppresses tumor metastasis.

Many cancer treatments including photodynamic therapy (PDT) utilize reactive oxygen species (ROS) to kill tumor cells. However, elevated antioxidant defense systems in cancer cells result in resistance to the therapy involving ROS. Here we describe a highly effective phototherapy through regulation of redox homeostasis with a biocompatible and versatile nanotherapeutic to inhibit tumor growth and metastasis. We systematically explore and exploit methylene blue adsorbed polydopamine nanoparticles as a targeted and precise nanocarrier, oxidative stress amplifier, photodynamic/photothermal agent, and multimodal probe for fluorescence, photothermal and photoacoustic imaging to enhance anti-tumor efficacy. Remarkably, following the glutathione-stimulated photosensitizer release to generate exogenous ROS, polydopamine eliminates the endogenous ROS scavenging system through depleting the primary antioxidant, thus amplifying the phototherapy and effectively suppressing tumor growth in vitro and in vivo. Furthermore, this approach enables a robust inhibition against breast cancer metastasis, as oxidative stress is a vital impediment to distant metastasis in tumor cells. Innovative, safe and effective nanotherapeutics via regulation of redox balance may provide a clinically relevant approach for cancer treatment.

Quantum dot-pulsed dendritic cell vaccines plus macrophage polarization for amplified cancer immunotherapy.

Dendritic cell (DC) vaccines hold great potential in cancer immunotherapy, but the suboptimal design of DC vaccines and the immunosuppressive tumor microenvironment largely impair their anti-tumor efficacy. Here, quantum dot (QD) pulsed-DC vaccines integrating with tumor-associated macrophage polarization are developed for amplified anti-tumor immunity. Semiconductor QDs are engineered with diverse functions to act as fluorescence nanoprobes, immunomodulatory adjuvants, and nanocarriers to load tumor antigens and Toll-like receptor 9 agonists. The QD-pulsed DC vaccines enable spatiotemporal tracking of lymphatic drainage and efficacy evaluation of DC immunotherapy, and trigger potent immunoactivation. Specifically, designer DC vaccine plus macrophage polarization elicits potent immune response to stimulate innate and adaptive antitumor immunity and ameliorate the immunosuppressive tumor microenvironment. As a new combination therapy, this strategy greatly boosts antigen-specific T-cell immunity and thus strongly inhibits local tumor growth and tumor metastasis in vivo. This study may provide an applicable treatment for cancer immunotherapy.

Interfacial engineering of carbon dots with benzenediboronic acid for fluorescent biosensing.

Glucose assay is highly important in clinical diagnostics of diabetes. Herein, we engineered the surface of carbon dots by complexation with functional ligand and constructed fluorescent biosensors for the detection of hydrogen peroxide and glucose. In this study, benzenediboronic acid is conjugated to the surface of citric acid-derived carbon dots through formation of boronate complexes with the nanoparticles. The oxidation of benzenediboronic acid with hydrogen peroxide effectively quenches fluorescence of carbon dots through electron transfer process. The sensing performance of the system according to different engineered surfaces of carbon dots was studied by using carbon dots derived from various precursors and different benzenediboronic acid analogues. As a simple mix-and-detect strategy, this system is facilely applied for glucose sensing as hydrogen peroxide is the product catalyzed by glucose oxidase. The benzenediboronic acid-conjugated carbon dots derived from citric acid act as excellent optical probes for sensitive analysis of glucose with detection limit of 0.4 µM. This sensing system shows great selectivity toward interferent species such as analogues of glucose, and can be used to determine glucose in human serum. Engineering the surface of carbon dots by complexation with ligand of interest provides a feasible way to facilitate the development of biological applications.

Highly sensitive glutathione assay and intracellular imaging with functionalized semiconductor quantum dots.

Glutathione (GSH) plays a vital role in biological systems and is associated with human pathology. The engineering of semiconductor quantum dots (QDs) as fluorescent probes for GSH sensing and bioimaging is a potential yet rarely reported approach. Herein, we report the in situ growth of manganese dioxide nanosheets (MnO2) on silica-coated semiconductor quantum dots (QD@SiO2), to prepare a stable and biocompatible fluorescent nanoprobe (QD@SiO2-MnO2) for the selective and sensitive detection of GSH. The modification of QD@SiO2 with MnO2 significantly quenched the fluorescence of CdSe/ZnS QDs, yet the addition of GSH efficiently recovered the fluorescence of the nanoprobe due to the decomposition of MnO2 by GSH. This nanosensor showed a rapid response to GSH with a low detection limit, and high selectivity towards GSH over potential interferences. Furthermore, the MnO2-engineered QDs had good biocompatibility and cellular uptake ability, and were successfully applied for the real-time imaging of intracellular GSH. We envision that semiconductor QD-based probes will stimulate the study of GSH dynamics and facilitate the understanding of GSH-related pathophysiological events.