Ultrathin and Biodegradable Bismuth Oxycarbonate Nanosheets with Massive Oxygen Vacancies for Highly Efficient Tumor Therapy.

Nanomaterials doped with high atom number elements can improve the efficacy of cancer radiotherapy, but their clinical application faces obstacles, such as being difficult to degrade in vivo, or still requiring relatively high radiation dose. In this work, a bismuth oxycarbonate-based ultrathin nanosheet with the thickness of 2.8 nm for safe and efficient tumor radiotherapy under low dose of X-ray irradiation is proposed. The high oxygen content (62.5% at%) and selective exposure of the facets of ultrathin 2D nanostrusctures facilitate the escape of large amounts of oxygen atoms on bismuth nanosheets from surface, forming massive oxygen vacancies and generating reactive oxygen species that explode under the action of X-rays. Moreover, the exposure of almost all atoms to environmental factors and the nature of oxycarbonates makes the nanosheets easily degrade into biocompatible species. In vivo studies demonstrate that nanosheets could induce apoptosis in cancer cells after low dose of X-ray irradiation without causing any damage to the liver or kidney. The tumor growth inhibition effect of radiotherapy increases from 49.88% to 90.76% with the help of bismuth oxycarbonate nanosheets. This work offers a promising future for nanosheet-based clinical radiotherapies of malignant cancers.

Hydrophobicity Regulation of Energy Acceptors Confined in Mesoporous Silica Enabled Reversible Activation of Optogenetics for Closed-Loop Glycemic Control.

Optogenetics-based synthetic biology holds great promise as a cell-based therapy strategy for many clinical incurable diseases; however, precise control over genetic expression strength and timing through disease state-related closed-loop regulation remains a challenge due to the lack of reversible probes to indicate real-time metabolite fluctuations. Here, based on a novel mechanism of analyte-induced hydrophobicity regulation of energy acceptors confined in mesoporous silica, we developed a smart hydrogel platform comprising glucose reversible responsive upconversion nanoprobes and optogenetic engineered cells, in which the upconverted blue light strength was adaptively tuned through blood glucose levels to control optogenetic expressions for insulin secretion. The intelligent hydrogel system enabled convenient maintenance of glycemic homeostasis through simple near-infrared illuminations without any additional glucose concentration monitoring, which efficiently avoided genetic overexpression-induced hypoglycemia. This proof-of-concept strategy efficiently combines diagnostics with optogenetics-based synthetic biology for mellitus therapy, opening up a new avenue for nano-optogenetics.

Correction: Surface lanthanide activator doping for constructing highly efficient energy transfer-based nanoprobes for the on-site monitoring of atmospheric sulfur dioxide.

Correction for 'Surface lanthanide activator doping for constructing highly efficient energy transfer-based nanoprobes for the on-site monitoring of atmospheric sulfur dioxide' by Cuilan Zhang et al., Analyst, 2020, 145, 537-543, https://doi.org/10.1039/C9AN01725A.

Engineering a polymer-encapsulated manganese dioxide/upconversion nanoprobe for FRET-based hydrogen peroxide detection.

Hydrogen peroxide (H2O2) is considered a significant biomarker in various diseases and could induce deleterious health problems at irregular physiological concentrations. Therefore, developing a simple, efficient biocompatible nanoprobe for trace amount H2O2 detection with high sensitivity and specificity is of great help for early diagnosis and therapeutics. Herein, we designed amphiphilic poly(styrene-co-maleic anhydride) (PMSA)-encapsulated nanoclusters composed of upconversion nanoparticles (UCNPs) and manganese dioxide nanoparticles (MnO2 NPs) at a specific ratio to produce a near-infrared (NIR) excited luminescent nanoprobe for H2O2 detection. Our results revealed that the MnO2 NPs tended to experience catalytic decomposition when exposed to H2O2, while the UCNPs were retained inside the PSMA encapsulation, causing recovery of the UCNP emission band at 470 nm in accordance with H2O2 concentration. This luminescence recovery was linearly dependent on H2O2 concentrations, yielding a limit of detection (LOD) of 20 nM. The easy-to-interpret H2O2 nanoprobe also proved high selectivity in the presence of other interfering substances, and biocompatibility and water-dispersibility, making it an ideal candidate for real-time detection of disease-related H2O2 in living organisms.

Multi-target responsive nanoprobe with cellular-level accuracy for spatiotemporally selective photodynamic therapy.

Photodynamic therapy is known for its non-invasiveness to significantly reduce undesired side effects on patients. However, the infiltration and invasiveness of tumor growth are still beyond the specificity of traditional light-controlled photodynamic therapy (PDT), which lacks cellular-level accuracy to tumor cells, possibly leading to "off-target" damage to healthy tissues such as the skin or immune cells infiltrated. Here, upconversion nanoparticles (UCNPs) were co-encapsulated with manganese dioxide (MnO2) by amphiphilic polymers poly(styrene-co-methyl acrylate) (PSMA) and further coated with photosensitizer (riboflavin)-loaded mesoporous silica (C@S/V). The C@S/V nanoprobes exhibited shielded upconversion luminescence in normal conditions (pH 7.4, no hydroperoxide (H2O2)) under 980-nm irradiation and thus minimal reactive oxygen production from riboflavin. However, the excess H2O2 (1 mM) and acidic environment (pH 5.5) could decompose the MnO2 within the C@S/V, resulting in remarkable enhancement of upconversion luminescence and a favorable hypoxia-relieving condition for PDT, providing a spatiotemporal signal for therapy initiation. The C@S/V nanoprobes were applied to the co-culture of normal cells (HEK293) and pancreatic cancer cells (Panc02) and performed a selective killing on Panc02 under the 980-nm irradiation. By using the "double-safety" strategy, a responsive C@S/V nanoprobe was designed by the selective activation of acidic and H2O2-rich conditions and 980-nm irradiation for spatiotemporally selective photodynamic therapy with cellular-level accuracy.

ZIF-8 encapsulated upconversion nanoprobes to evaluate pH variations in food spoilage.

A novel nanoassembly was constructed through encapsulating upconversion nanoparticles (UCNPs) into a metal-organic framework structure (ZIF-8), in which doxorubicin (DOX) was absorbed into pores of ZIF-8. The blue emission of UCNPs was quenched by DOX through the fluorescence resonance energy transfer (FRET) strategy. When the nanoprobe was exposed to food samples with different pH values, ZIF-8 collapsed to release DOX molecules, resulting in upconversion recovery. The porous structure of ZIF-8 provides abundant space for DOX absorption, which significantly improves the detection capacities and accuracy. It is shown that the probe has a good linear relationship when pH values vary from 2.5 to 7.4, and can distinguish pH variations as low as 0.5 in real samples. This strategy has been successfully used to determine food spoilage by determination of pH variations.

Ratio-Adjustable Upconversion Luminescence Nanoprobe for Ultrasensitive In Vitro Diagnostics.

The development of precise medicine requires diagnostic probes to simultaneously satisfy an excellent detection limit and a wide linear analysis range because of enormous individual-discrepancy of disease biomarker concentrations, yet it remains challenging. Herein, an upconverison nanoprobe with a luminescence ratio flexibly tailored was designed for ultrasensitive monitoring exhaled nitric oxide to indicate the clinical course of asthma. Two independent emissions from the same nanoprobe can be discretionarily modulated to vary their intensity ratios for adapting different analysis requirements. Delightfully, this novel nanoprobe demonstrated a 100-fold lower detection limit compared with the traditional ratiometric fluorescence manner and a more broad linear detection range from the subpart per billion (ppb) level to hundreds of ppb. This ratio-adjustable fluorescence detection strategy holds great potential for miscellaneous disease diagnosis applications.

Luminescence Nanoprobe in the Near-Infrared-II Window for Ultrasensitive Detection of Hypochlorite.

Sensitive and selective detection of hypochlorite is in great demand for food safety, especially in fresh cold chain products. However, the detection limit of traditional visible emission-based strategies cannot satisfy the requirement of ultrasensitive analysis in practical applications. In this work, we explored a novel luminescent nanoprobe in the near-infrared-II (NIR-II) window to greatly improve the hypochlorite detection limit for analysis of real milk samples, which was based on the fluorescence resonance energy-transfer process between the hypochlorite-responsive dye (FD1080) and the lanthanide-doped downconverted nanoparticles. Specifically, the NIR-II luminescence from Yb ions was first suppressed by FD1080 due to the energy-transfer mechanism. In the presence of hypochlorite, FD1080 was bleached to recover the luminescence. As a proof-of-concept, the optimal nanoprobe exhibited a linear luminescence recovery in the range of 0.1-1 nM with the detection limit of 0.0295 nM for hypochlorite. Real milk sample detection experiments showed that the probe had good accuracy and precision.

Single-Line Flow Assay Platform Based on Orthogonal Emissive Upconversion Nanoparticles.

Lateral flow assay (LFA) has played pivotal roles in many emergency public safety incidents, such as coronavirus disease diagnostics; however, the present double-line (test and control line) design strategy for LFA strips greatly restricts their applications in high-throughput quantitative analysis because the limited sample diffusion distance on the strips constrains the number of test/control lines. Herein, a novel single-line-based LFA (sLFA) strip, which combines test and control line, is developed by exploiting an orthogonal emissive upconversion nanoparticle (UCNP) as a signal reporter on the test line, where one emission can be used as a reporting signal and the other as a calibrating signal. This UCNP-based test line with an interior reference also can play a validating role as a control line, and hence capturing antibodies are not needed for control lines, greatly saving fabrication costs. As a proof-of-concept, this novel sLFA strip is successfully explored to accurately and rapidly detect aflatoxin B1. Moreover, due to the removal of control lines, such a novel strategy greatly reduces the strip size, facilitating the design of a testing array for multiple detections of different samples. The test line herein is designed in a ring shape, and several test rings are assembled to be a chip for the testing of multiple samples. To our knowledge, this is the first demonstration of single-line-based LFA strips, which will significantly improve the detection capacities and accuracies and reduce the testing costs of LFA strips in real sample applications ranging from food analysis to in vitro diagnostics.

Surface lanthanide activator doping for constructing highly efficient energy transfer-based nanoprobes for the on-site monitoring of atmospheric sulfur dioxide.

The sensitive and on-site detection of sulfur dioxide (SO2) is in great demand in the fields of food safety and environmental protection. Here, we developed a novel upconversion nanoprobe based on the luminescence energy transfer mechanism for monitoring the atmospheric SO2 concentrations. The lanthanide emitters, Tm3+ ions, were optimized to be doped on the surface layer of the upconversion nanoparticles to improve their energy transfer efficiency by minimizing the distance between the emitters and the surface quencher, a cyanine dye. As a proof-of-concept, the optimal nanoprobe was utilized to detect SO2 water derivatives, bisulfite ions, exhibiting a linear luminescence increase in the range of 1 nM to 10 nM. Furthermore, we assembled the cyanine-modified upconversion nanoparticles onto a test paper, and used a smartphone-based detection platform to achieve portable and visual detection of SO2. The test paper showed a strong luminescence stability, homogeneity and good anti-interference. The limit of detection for SO2 gas was found to be 1 ng L-1. This novel upconversion test paper was also demonstrated to directly monitor the concentration of SO2 gas in atmosphere.

Fluorescent microbeads for point-of-care testing: a review.

Microbead-based point-of-care testing (POCT) has demonstrated great promise in translating detection modalities from bench-side to bed-side. This is due to the ease of visualization, high surface area-to-volume ratio of beads for efficient target binding, and efficient encoding capability for simultaneous detection of multiple analytes. This review (with 112 references) summarizes the progress made in the field of fluorescent microbead-based POCT. Following an introduction into the field, a first large section sums up techniques and materials for preparing microbeads, typically of dye-labelled particles, various kinds of quantum dots and upconversion materials. Further subsections cover the encapsulation of nanoparticles into microbeads, decoration of nanoparticles on microbeads, and in situ embedding of nanoparticles during microbead synthesis. A next large section summarizes microbead-based fluorometric POCT, with subsections on detection of nucleic acids, proteins, circulating tumor cells and bacteria. A further section covers emerging POCT based on the use of smartphones or flexible microchips. The last section gives conclusions and an outlook on current challenges and possible solutions. Aside from giving an overview on the state of the art, we expect this article to boost the further development of POCT technology. Graphical Abstract Schematic presentation of the fabrication of microbeads, the detection targets of interest including bacteria, circulating tumor cells (CTCs), protein and nucleic acid, and the emerging point-of-care testing (POCT) platform. The colored wheels of the bus represent the fluorescent materials embedded in (red color) or decorated on the surface of microbeads (green color).

White-light emissive upconversion nanoparticles for visual and colorimetric determination of the pesticide thiram.

The authors describe the use of white-light emitting upconversion nanoparticles (WL-UCNPs) for visual detection of the pesticide thiram. The method is demonstrated to undergo a better discernable color change upon target binding. The WL-UCNPs are modified with the lead(II)-dithizone complex which acts as the energy acceptor and recognition unit. This leads to quenching of the blue (475 nm) and green (545 nm) emissions of the WL-UCNPs, while the red emission (650 nm) remains unaffected. Upon addition of thiram, the quenched emissions are recovered, with a linear signal increase in the range from 2 nM to 20 nM of thiram and a limit of detection of 0.26 nM. The nanoprobe was further integrated into a test paper for visual detection. The concentration-dependent color change that varies from red to cyan and bluish violet and then to white can be visually distinguished. Graphical abstract Schematic presentation of a white-light emissive upconversion nanoparticle based test paper for color-discernable detection of the pesticide thiram. The test stripe exhibits a concentration-dependent color variation spanning from red, cyan, to bluish violet, and at last to white.

Real-Time Visualization of Cysteine Metabolism in Living Cells with Ratiometric Fluorescence Probes.

Sulfite from cysteine metabolism in living cells plays a crucial role in improving the water solubility of metabolic xenobiotics for their easier excretion in urine or bile. However, an imbalance of sulfite in vivo would lead to oxidative stress or age-related diseases, and an effective strategy for real-time imaging of cysteine metabolism in living cells is still lacking due to its low metabolite concentration and rapid reaction kinetics. Herein, a cyanine moiety based ratiometric fluorescence probe was developed for highly selective and sensitive detection of sulfite in aqueous solution and living cells. The free probe exhibited an orange emission color, and the fluorescence color would gradually change to blue once sulfite anions selectively reacted with the unsaturated carbon double bonds in the probe molecule. This ratiometric fluorescence manner endowed the probe excellent sensitivity with a detection limit of 0.78 nM, which was then explored to image the kinetic process of sulfite release in hepatic BRL cells after incubating with an excess amount of cysteine. This strategy opens new opportunities for revealing thiol-containing species metabolism and even quantitatively tracking their distributions in live cells or organelles.

Zinc-Dithizone Complex Engineered Upconverting Nanosensors for the Detection of Hypochlorite in Living Cells.

Current chemo/biosensors for hypochlorous acid or hypochlorite detections are usually limited to the submicromolar level because of their insufficient sensitivity, which is a problem because the concentrations in biological matrices is generally on the nanomolar scale or even lower. Developing a probe with a high enough sensitivity remains a challenge. Using the minimal background fluorescence of upconversion nanocrystals to our advantage, we herein report on an energy-transfer mechanism-based upconversion luminescent nanosensor for the sensitive and selective detection of hypochlorite in aqueous solution. In this nanosensor water-dispersible upconversion nanoparticles act as the energy donor and a novel hypochlorite-responsive coordination complex Zn(DZ)3 is employed as the energy acceptor. The quenched upconversion luminescence, induced by the Zn(DZ)3 complex, can be efficiently recovered after addition of hypochlorite through the selective oxidative breakage of the Zn-S-C bonds in the Zn(DZ)3 complex, which was verified by mass spectrometry. The detection limit for hypochlorite of this sensing system is as low as 3 nM. Furthermore, this newly coordination-complex engineered upconversion nanosensor is successfully applied to image different amounts of exogenous hypochlorite in living HeLa cells.

Inkjet-printed silver nanoparticle paper detects airborne species from crystalline explosives and their ultratrace residues in open environment.

An electronic nose can detect highly volatile chemicals in foods, drugs, and environments, but it is still very much a challenge to detect the odors from crystalline compounds (e.g., solid explosives) with a low vapor pressure using the present chemosensing techniques in such way as a dog's olfactory system can do. Here, we inkjet printed silver nanoparticles (AgNPs) on cellulose paper and established a Raman spectroscopic approach to detect the odors of explosive trinitrotoluene (TNT) crystals and residues in the open environment. The layer-by-layer printed AgNP paper was modified with p-aminobenzenethiol (PABT) for efficiently collecting airborne TNT via a charge-transfer reaction and for greatly enhancing the Raman scattering of PABT by multiple spectral resonances. Thus, a Raman switch concept by the Raman readout of PABT for the detection of TNT was proposed. The AgNPs paper at different sites exhibited a highly uniform sensitivity to TNT due to the layer-by-layer printing, and the sensitive limit could reach 1.6 × 10(-17) g/cm(2) TNT. Experimentally, upon applying a beam of near-infrared low-energy laser to slightly heat (but not destruct) TNT crystals, the resulting airborne TNT in the open environment was probed at the height of 5 cm, in which the concentration of airborne species was lower than 10 ppt by a theoretical analysis. Similarly, the odors from 1.4 ppm TNT in soil and 7.2, 2.9, and 5.7 ng/cm(2) TNT on clothing, leather, and envelope, respectively, were also quickly sensed for 2 s without destoying these inspected objects.

Nano-optogenetics for Disease Therapies.

Optogenetic, known as the method of 21 centuries, combines optic and genetic engineering to precisely control photosensitive proteins for manipulation of a broad range of cellular functions, such as flux of ions, protein oligomerization and dissociation, cellular intercommunication, and so on. In this technique, light is conventionally delivered to targeted cells through optical fibers or micro light-emitting diodes, always suffering from high invasiveness, wide-field illumination facula, strong absorption, and scattering by nontargeted endogenous substance. Light-transducing nanomaterials with advantages of high spatiotemporal resolution, abundant wireless-excitation manners, and easy functionalization for recognition of specific cells, recently have been widely explored in the field of optogenetics; however, there remain a few challenges to restrain its clinical applications. This review summarized recent progress on light-responsive genetically encoded proteins and the myriad of activation strategies by use of light-transducing nanomaterials and their disease-treatment applications, which is expected for sparking helpful thought to push forward its preclinical and translational uses.

Glucose-lightened upconversion nanoprobes for accurate cellular-discrimination based on Warburg effect.

Accurate cellular-recognition based disease therapy is of significance for precision medicine. However, except of specific antibody-coupling strategy, very few probes have been reported to efficiently discriminate normal cells and lesion cells through cellular microenvironment. Herein, we proposed a glucose selectively-lightened upconversion nanoprobe to recognize cancer cells from a pile of normal cells based on Warburg effect, that indicated a heightened demand for glucose intake for cancer cells. The nanoprobes were constructed by mesoporous silica-coated upconversion nanoparticles (UCNP@mSiO2) with the crucial incorporation of a glucose-responsive modality, benzoboric acid (BA)-modified fluorescein molecules (FITC-BA). In cancer cells, the presence of elevated glucose concentrations triggered the transformation of FITC-BA to FITC-Glucose to recover nanoprobes' luminescence, however, the nanoprobes exhibited a shielded luminescent effect in healthy cells. To validate the hypothesis of accurate cellular-discrimination, a photodynamic therapy modality, riboflavin, with a specific ratio were also loaded into above UCNP@mSiO2 nanoprobes for effective production of reactive oxygen species to kill cells. It was found that 97.8% of cancer cells were cleaned up, but normal cells retained a nearly 100% viability after 10 min laser illumination. By leveraging the metabolic disparity from Warburg effect, the nanoprobes offer a highly accurate cellular discrimination, and significantly mitigate "off-target" damage commonly associated with conventional therapies.

Tether-free optogenetic control of insulin secretion using an upconversion nanoparticle-doped hydrogel platform.

Glucagon-like peptide-1 (GLP-1), as a molecular therapeutic, induces glucose-dependent stimulation of insulin secretion, which has drawn significant attention in treating type II diabetes. However, it always suffers from hurdles such as short half-lives or instability. Thus, producing such therapeutics endogenously, as and when needed, is beneficial. Optogenetics-based production of GLP-1 offers an attractive alternative, wherein, the cell lines such as HEK293T can be genetically modified to bring the expression of the gene of interest under visible light control. However, the need for blue light for activation necessitates the implantation of invasive optical fibers owing to high tissue scattering and low depth of penetration through biological tissue at this wavelength. Here, we overcome this problem by proposing an upconversion nanoparticle (UCNP)-based system. HEK293T cells, rewired to produce GLP-1 under blue light illumination, were co-encapsulated with UCNPs in a hydrogel. The UCNPs act as near-infrared (NIR) to blue light nano-transducers, allowing deep penetration toward implementing a tether-free optogenetic gene expression platform. This platform is particularly powerful for thick gel implants (>3 mm) that cannot be illuminated throughout using a blue light source. Moreover, the GLP-1 produced in this platform was sufficient to increase insulin secretion in rat insulinoma cells, providing a powerful and controllable therapeutic tool for diabetes.

Chemiluminescence switching on peroxidase-like Fe3O4 nanoparticles for selective detection and simultaneous determination of various pesticides.

To achieve selectivity in direct chemiluminescence (CL) detection is very significant and a great challenge as well. Here, we report a novel concept of developing intrinsically selective CL switching at the surface of Fe(3)O(4) nanoparticles for the sensitive detection and simultaneous determination of various pesticides. Fe(3)O(4) nanoparticles have peroxidase-like catalytic activity and catalyze the decomposition of dissolved oxygen to generate superoxide anions, so that the CL intensity of luminol was amplified by at least 20 times. The CL signals can be quenched by the addition of ethanol because ethanol readily reacts with superoxide anions as a radical scavenger. However, the quenching effect can be inhibited through the specific binding of target molecules on Fe(3)O(4) nanoparticles, leading to CL "turn-on" in the presence of ethanol. The novel CL "switching-on" concept demonstrated unique advantages in the detection of pesticide residues. Using the surface coordinative reactions, nonredox pesticide ethoprophos were sensitively detected with a detection limit of 0.1 nM and had a very wide detection range of 0.1 nM to 100 µM. More importantly, the selectivity of CL switching is tunable through the special surface modification of Fe(3)O(4) nanoparticles, and these Fe(3)O(4) nanoparticles with different surface groups can generate unique CL response pattern for the simultaneous determination of various pesticides. Meanwhile, the superparamagnetic properties of Fe(3)O(4) nanoparticles provide a simple magnetic separation approach to attain interference-free measurement for real detection. The very facile and versatile strategy reported here should open a new window to exploration of selective CL molecular switching and application of magnetic nanoparticles for chemo/biodetection.