A Cationic Metal-Organic Framework to Scavenge Cell-Free DNA for Severe Sepsis Management.

Circulating cell-free DNA (cfDNA) released by damaged cells causes inflammation and has been associated with the progression of sepsis. One proposed strategy to treat sepsis is to scavenge this inflammatory circulating cfDNA. Here, we develop a cfDNA-scavenging nanoparticle (NP) that consists of cationic polyethylenimine (PEI) of different molecular weight grafted to zeolitic imidazolate framework-8 (PEI-g-ZIF) in a simple one-pot process. PEI-g-ZIF NPs fabricated using PEI 1800 and PEI 25k but not PEI 600 suppressed cfDNA-induced TLR activation and subsequent nuclear factor kappa B pathway activity. PEI 1800-g-ZIF NPs showed greater inhibition of cfDNA-associated inflammation and multiple organ injury than naked PEI 1800 (lacking ZIF), and had greater therapeutic efficacy in treating sepsis. These results indicate that PEI-g-ZIF NPs acts as a "nanotrap" that improves upon naked PEI in scavenging circulating cfDNA, reducing inflammation, and reversing the progression of sepsis, thus providing a novel strategy for sepsis treatment.

A Mononuclear Iron(II) Spin-Crossover Molecule Decorated by Photochromic Azobenzene Group.

Aiming at constructing photoresponsive spin crossover (SCO) behavior, herein we designed a new ligand Abtz (Abtz = (E)-N-(4-((E)-phenyldiazenyl)phenyl)-1-(thiazol-4-yl)methanimine) which was decorated by a photochromic azobenzene group. Based on this photochromic ligand, a mononuclear Fe(II) SCO molecule [Fe(Abtz)3](BF4)2·(EAC)2 (1, EAC = ethyl acetate) was successfully synthesized and showed a complete one-step SCO behavior. Under continuous UV light and blue-light exposure, the cis-trans photoisomerization of both ligand Abtz and compound 1 in the liquid phase was confirmed through UV-Vis spectra. Moreover, the 1H-NMR spectra of Abtz reveal a trans-cis conversion ratio of 37%. Although the UV-Vis spectra reveal the photochromic behavior for 1 in the solution phase, the SCO behavior in the liquid state is absent according to the variable-temperature Evans method, suggesting the possible decomposition. Moreover, in the solid state, the cis-trans photoisomerization of both Abtz and 1 was not observed, due to the steric hindrance.

Subcellular distribution and cellular self-repair ability of fluorescent quantum dots emitting in the visible to near-infrared region.

Semiconductor II-VI quantum dots (QDs), as high-performance fluorescent biological probes, have garnered significant attention due to their superior optical properties. To enable QDs for wide-ranging bioapplications, concerns about their in vitro behavior need to be fully addressed. Herein, for the first time, cellular behaviors of aqueous synthesized-QDs (aqQDs), whose maximum emission wavelength (λ emission) covers the visible to near-infrared spectral window, are systematically investigated. Our results demonstrate that three different sized aqQDs feature distinct cellular distributions, i.e. aqQD530 (aqQDs whose λ emission is 530 nm) and aqQD620 (aqQDs whose λ emission is 620 nm) mainly distribute in the cytoplasm and nucleus, while aqQD730 (aqQDs whose λ emission is 730 nm) mainly accumulates in the cytoplasm. Most significantly, the phenomenon that cellular self-repair ability is dependent on diameters of aqQDs is revealed for the first time. In particular, small-sized QDs (e.g. aqQD530 and aqQD620) severely deteriorate cellular self-repair ability, leading to an irreversible decrease in cell viability. In striking contrast, large-sized QDs (e.g. aqQD730) have little effect on cellular self-repair ability, and the cell viability is restored after removal of aqQD730 from the culture medium. Our results provide invaluable information for QD-relevant biosafety analysis, as well as suggest available guidance for the design of biocompatible QDs for wide utilization in biological and biomedical studies.

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.

Linking Subcellular Disturbance to Physiological Behavior and Toxicity Induced by Quantum Dots in Caenorhabditis elegans.

The wide-ranging applications of fluorescent semiconductor quantum dots (QDs) have triggered increasing concerns about their biosafety. Most QD-related toxicity studies focus on the subcellular processes in cultured cells or global physiological effects on whole animals. However, it is unclear how QDs affect subcellular processes in living organisms, or how the subcellular disturbance contributes to the overall toxicity. Here the behavior and toxicity of QDs of three different sizes in Caenorhabditis elegans (C. elegans) are systematically investigated at both the systemic and the subcellular level. Specifically, clear size-dependent distribution and toxicity of the QDs in the digestive tract are observed. Short-term exposure of QDs leads to acute toxicity on C. elegans, yet incurring no lasting, irreversible damage. In contrast, chronic exposure of QDs severely inhibits development and shortens lifespan. Subcellular analysis reveals that endocytosis and nutrition storage are disrupted by QDs, which likely accounts for the severe deterioration in growth and longevity. This work reveals that QDs invasion disrupts key subcellular processes in living organisms, and may cause permanent damage to the tissues and organs over long-term retention. The findings provide invaluable information for safety evaluations of QD-based applications and offer new opportunities for design of novel nontoxic nanoprobes.

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.

Peptide-Conjugated Fluorescent Silicon Nanoparticles Enabling Simultaneous Tracking and Specific Destruction of Cancer Cells.

We herein introduce a kind of fluorescent silicon nanoparticles (SiNPs) bioprobes, that is, peptides-conjugated SiNPs, which simultaneously feature small sizes (<10 nm), biological functionality, and stable and strong fluorescence (photoluminescent quantum yield (PLQY): ∼28%), as well as favorable biocompatibility. Taking advantage of these merits, we further demonstrate such resultant SiNPs bioprobes are superbly suitable for real-time immunofluorescence imaging of cancer cells. Meanwhile, malignant tumor cells could be specifically destroyed by the peptides-conjugated SiNPs, suggesting potential promise of simultaneous detection and treatment of cancer cells.

Silicon nanomaterials platform for bioimaging, biosensing, and cancer therapy.

Silicon nanomaterials are an important class of nanomaterials with great potential for technologies including energy, catalysis, and biotechnology, because of their many unique properties, including biocompatibility, abundance, and unique electronic, optical, and mechanical properties, among others. Silicon nanomaterials are known to have little or no toxicity due to favorable biocompatibility of silicon, which is an important precondition for biological and biomedical applications. In addition, huge surface-to-volume ratios of silicon nanomaterials are responsible for their unique optical, mechanical, or electronic properties, which offer exciting opportunities for design of high-performance silicon-based functional nanoprobes, nanosensors, and nanoagents for biological analysis and detection and disease treatment. Moreover, silicon is the second most abundant element (after oxygen) on earth, providing plentiful and inexpensive resources for large-scale and low-cost preparation of silicon nanomaterials for practical applications. Because of these attractive traits, and in parallel with a growing interest in their design and synthesis, silicon nanomaterials are extensively investigated for wide-ranging applications, including energy, catalysis, optoelectronics, and biology. Among them, bioapplications of silicon nanomaterials are of particular interest. In the past decade, scientists have made an extensive effort to construct a silicon nanomaterials platform for various biological and biomedical applications, such as biosensors, bioimaging, and cancer treatment, as new and powerful tools for disease diagnosis and therapy. Nonetheless, there are few review articles covering these important and promising achievements to promote the awareness of development of silicon nanobiotechnology. In this Account, we summarize recent representative works to highlight the recent developments of silicon functional nanomaterials for a new, powerful platform for biological and biomedical applications, including biosensor, bioimaging, and cancer therapy. First, we show that the interesting photoluminescence properties (e.g., strong fluorescence and robust photostability) and excellent biocompatibility of silicon nanoparticles (SiNPs) are superbly suitable for direct and long-term visualization of biological systems. The strongly fluorescent SiNPs are highly effective for bioimaging applications, especially for long-term cellular labeling, cancer cell detection, and tumor imaging in vitro and in vivo with high sensitivity. Next, we discuss the utilization of silicon nanomaterials to construct high-performance biosensors, such as silicon-based field-effect transistors (FET) and surface-enhanced Raman scattering (SERS) sensors, which hold great promise for ultrasensitive and selective detection of biological species (e.g., DNA and protein). Then, we introduce recent exciting research findings on the applications of silicon nanomaterials for cancer therapy with encouraging therapeutic outcomes. Lastly, we highlight the major challenges and promises in this field, and the prospect of a new nanobiotechnology platform based on silicon nanomaterials.

Large-scale aqueous synthesis of fluorescent and biocompatible silicon nanoparticles and their use as highly photostable biological probes.

A large-scale synthetic strategy is developed for facile one-pot aqueous synthesis of silicon nanoparticles (SiNPs) yielding ∼0.1 g SiNPs of small sizes (∼2.2 nm) in 10 min. The as-prepared SiNPs feature strong fluorescence (photoluminescence quantum yield of 20-25%), favorable biocompatibility, and robust photo- and pH-stability. Moreover, the SiNPs are naturally water dispersible, requiring no additional post-treatment. Such SiNPs can serve as highly photostable bioprobes and are superbly suitable for long-term immunofluorescent cellular imaging.

Surface-enhanced Raman scattering-based sensing in vitro: facile and label-free detection of apoptotic cells at the single-cell level.

Surface-enhanced Raman scattering (SERS) is well recognized as a powerful analytical tool, enabling ultrahigh sensitive detection of analytes at low concentrations, even down to single-molecule level. Of particular note, in comparison to sufficient investigations on SERS-based detection of biomolecules (e.g., DNA and protein), there has been relatively scanty information regarding in vitro and in vivo detection. In this Article, we demonstrate a kind of SERS-active substrate, i.e., AgNPs-decorated silicon wafer (AgNPs@Si), as a high-performance in vitro sensing platform for single-cell detection of apoptotic cells. The AgNPs@Si yields highly reproducible SERS signals with an enhancement factor of ∼10(7). Remarkably, cellular experiments show that facile, noninvasive, label-free, and sensitive detection of apoptotic cells is readily realized using the high-performance SERS-active platform. Three kinds of apoptotic cells treated with apoptosis inducer are facilely and sensitively detected at the single-cell level, suggesting the exciting potential of AgNPs@Si for SERS-based in vitro analysis and detection.

Aqueous synthesized near-infrared-emitting quantum dots for RGD-based in vivo active tumour targeting.

Over the past two decades, fluorescent quantum dots (QDs) have been highly attractive for a myriad of bioapplications due to their unique optical properties. For bioimaging applications, QD-based in vivo specific tumour targeting is vitally important in the biological and biomedical fields. Aqueous synthesized QDs (aqQDs) exhibit excellent aqueous dispersibility without requiring any post-treatment and have small hydrodynamic diameters (generally <5 nm), which are highly useful for bioimaging applications. We herein present the first example of in vivo active tumour targeting using water-dispersed near-infrared-emitting aqQDs modified with Arg-Gly-Asp (RGD) peptides. In vitro and in vivo studies (e.g., tumour cell labelling, histological analysis, and active tumour targeting) demonstrate that the prepared RGD-decorated aqQDs exhibit highly bio-specific properties, enabling sensitive and specific targeting of tumour sites in both cells and living animals. Our results suggest that the new class of RGD-decorated aqQDs are highly promising as fluorescent bioprobes for a wide range of biological applications.

A silicon-based electrochemical sensor for highly sensitive, specific, label-free and real-time DNA detection.

We herein present a new kind of silicon-based electrochemical sensor using a gold nanoparticles-decorated silicon wafer (AuNPs@Si) as a high-performance electrode, which is facilely prepared via in situ AuNPs growth on a silicon wafer. Particularly significantly, the resultant electrochemical sensor is efficacious for label-free DNA detection with high sensitivity due to the unique merits of the prepared silicon-based electrode. Typically, DNA at remarkably low concentrations (1-10 fM) could be readily detected without requiring additional signal-amplification procedures, which is better than or comparable to the lowest DNA concentration ever detected via well-studied signal-amplification-assisted electrochemical sensors. Moreover, the silicon-based sensor features high specificity, allowing unambiguous discrimination of single-based mismatches. We further show that real-time DNA assembly is readily monitored via recording the intensity changes of current signals due to the robust thermal stability of the silicon-based electrode. The unprecedented advantages of the silicon-based electrochemical sensor would offer new opportunities for myriad sensing applications.

Gold nanoparticles-decorated silicon nanowires as highly efficient near-infrared hyperthermia agents for cancer cells destruction.

Near-infrared (NIR) hyperthermia agents are of current interest because they hold great promise as highly efficacious tools for cancer photothermal therapy. Although various agents have been reported, a practical NIR hyperthermia agent is yet unavailable. Here, we present the first demonstration that silicon nanomaterials-based NIR hyperthermia agent, that is, gold nanoparticles-decorated silicon nanowires (AuNPs@SiNWs), is capable of high-efficiency destruction of cancer cells. AuNPs@SiNWs are found to possess strong optical absorbance in the NIR spectral window, producing sufficient heat under NIR irradiation. AuNPs@SiNWs are explored as novel NIR hyperthermia agents for photothermal ablation of tumor cells. In particular, three different cancer cells treated with AuNPs@SiNWs were completely destructed within 3 min of NIR irradiation, demonstrating the exciting potential of AuNPs@SiNWs for NIR hyperthermia agents.

Comparative Analysis of Nucleic Acid-Binding Polymers as Potential Anti-Inflammatory Nanocarriers.

Conventionally, nanocarriers are used to regulate the controlled release of therapeutic payloads. Increasingly, they can also be designed to have an intrinsic therapeutic effect. For example, a positively charged nanocarrier can bind damage-associated molecular patterns, inhibiting toll-like receptor (TLR) pathway activation and thus modulating inflammation. These nucleic acid-binding nanomaterials (NABNs), which scavenge pro-inflammatory stimuli, exist in diverse forms, ranging from soluble polymers to nanoparticles and 2D nanosheets. Unlike conventional drugs that primarily address inflammation symptoms, these NABPs target the upstream inflammation initiation pathway by removing the agonists responsible for inflammation. Many NABNs have demonstrated effectiveness in murine models of inflammatory diseases. However, these scavengers have not been systematically studied and compared within a single setting. Herein, we screen a subset of the most potent NABNs to define their relative efficiency in scavenging cell-free nucleic acids and inhibiting various TLR pathways. This study helps interpret existing in vivo results and provides insights into the future design of anti-inflammatory nanocarriers.

Microwave-assisted synthesis of biofunctional and fluorescent silicon nanoparticles using proteins as hydrophilic ligands.

Protective shell: A microwave-assisted method allows rapid production of biofunctional and fluorescent silicon nanoparticles (SiNPs), which can be used for cell labeling. Such SiNPs feature excellent aqueous dispersibility, are strongly fluorescent, storable, photostable, stable at different pH values, and biocompatible. The method opens new avenues for designing multifunctional SiNPs and related silicon nanostructures.

Design of therapeutic biomaterials to control inflammation.

Inflammation plays an important role in the response to danger signals arising from damage to our body and in restoring homeostasis. Dysregulated inflammatory responses occur in many diseases, including cancer, sepsis and autoimmunity. The efficacy of anti-inflammatory drugs, developed for the treatment of dysregulated inflammation, can be potentiated using biomaterials, by improving the bioavailability of drugs and by reducing side effects. In this Review, we first outline key elements and stages of the inflammatory environment and then discuss the design of biomaterials for different anti-inflammatory therapeutic strategies. Biomaterials can be engineered to scavenge danger signals, such as reactive oxygen and nitrogen species and cell-free DNA, in the early stages of inflammation. Materials can also be designed to prevent adhesive interactions of leukocytes and endothelial cells that initiate inflammatory responses. Furthermore, nanoscale platforms can deliver anti-inflammatory agents to inflammation sites. We conclude by discussing the challenges and opportunities for biomaterial innovations in addressing inflammation.

Mining, expression, and phylogenetic analysis of volatile terpenoid biosynthesis-related genes in different tissues of ten Elsholtzia species based on transcriptomic analysis.

We sequenced the leaf and inflorescence transcriptomes of 10 Elsholtzia species to mine genes related to the volatile terpenoid metabolic pathway. A total of 184.68 GB data and 1,231,162,678 clean reads were obtained from 20 Elsholtzia samples, and 333,848 unigenes with an average length of at least 1440 bp were obtained by Trinity assembly. KEGG pathway analysis showed that there were three pathways related to volatile terpene metabolism: terpenoid backbone biosynthesis (No. ko00900), monoterpenoid biosynthesis (No. ko00902), and sesquiterpenoid and triterpenoid biosynthesis (No. ko00909), with 437, 125, and 121 related unigenes, respectively. The essential oil content and composition in 20 Elsholtzia samples were determined by gas chromatography-mass spectrometry. The results showed that there were obvious interspecific differences among the 10 Elsholtzia species, but there were no significant differences between the different tissues among species. The expression levels of seven candidate genes involved in volatile terpenoid biosynthesis in Elsholtzia were further analyzed by quantitative real-time PCR. The results showed that HMGS had the highest expression among all genes, followed by GGPS4. In addition, there was not a significant correlation between the seven genes and the components with high essential oil contents. Combined with the essential oil components detected in this study, the possible biosynthetic pathway of the characteristic components in Elsholtzia plants was speculated to be a metabolic pathway with geraniol as the starting point and elsholtzione as the end product. Phylogenetic analysis was conducted using the nucleotide sequences of the geranyl diphosphate synthase candidate genes, and the results showed that genes related to the volatile terpenoid biosynthetic pathway may be more suitable gene fragments for resolving the Elsholtzia phylogeny.

Therapeutic Nanocarriers Inhibit Chemotherapy-Induced Breast Cancer Metastasis.

Chemotherapy, although effective against primary tumors, may promote metastasis by causing the release of proinflammatory factors from damaged cells. Here, polymeric nanoparticles that deliver chemotherapeutics and scavenge proinflammatory factors simultaneously to inhibit chemotherapy-induced breast cancer metastasis are developed. The cationic nanoparticles can adsorb cell-free nucleic acids (cfNAs) based on charge-charge interaction, which downregulates the expression of Toll-like receptors and then reduces the secretion of inflammatory cytokines. Through in vitro structural optimization, cationic polyamidoamine (PAMAM) dendrimers modified with drug-binding dodecyl groups and diethylethanolamine surface groups (PAMAM-G3-C125 -DEEA20 ) exhibit the most desirable combination of nanoparticle size (≈140 nm), drug loading, cytotoxicity, cfNA binding, and anti-inflammatory activity. In the mouse models of breast cancer metastasis, paclitaxel-loaded nanoparticles reduce serum levels of cfNAs and inflammatory cytokines compared with paclitaxel treatment alone and inhibit both primary tumor growth and tumor metastasis. Additionally, no significant side effects are detected in the serum or major organs. These results provide a strategy to deliver chemotherapeutics to primary tumors while reducing the prometastatic effects of chemotherapy.

Targeting Proinflammatory Molecules Using Multifunctional MnO Nanoparticles to Inhibit Breast Cancer Recurrence and Metastasis.

Photothermal therapy (PTT) is an effective treatment modality that is highly selective for tumor suppression and is a hopeful alternative to traditional cancer therapy. However, PTT-induced inflammatory responses may result in undesirable side effects including increased risks of tumor recurrence and metastasis. Here we developed multifunctional MnO nanoparticles as scavengers of proinflammatory molecules to alleviate the PTT-induced inflammatory response. The MnO nanoparticles improve the PTT therapy by (1) binding and scavenging proinflammatory molecules to inhibit the proinflammatory molecule-induced Toll-like receptors (TLR) activation and nuclear factor kappa B (NF-κB) signaling; (2) inhibiting activated macrophage-induced macrophage recruitment; and (3) inhibiting tumor cell migration and invasion. In vivo experimental results showed that further treatment with MnO nanoparticles after laser therapy not only inhibited the PTT-induced inflammatory response and primary tumor recurrence but also significantly reduced tumor metastasis due to the scavenging activity. These findings suggest that MnO nanoparticles hold the potential for mitigating the therapy-induced severe inflammatory response and inhibiting tumor recurrence and metastasis.

DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.

Millions of COVID-19 patients have succumbed to respiratory and systemic inflammation. Hyperstimulation of toll-like receptor (TLR) signaling is a key driver of immunopathology following infection by viruses. We found that severely ill COVID-19 patients in the Intensive Care Unit (ICU) display hallmarks of such hyper-stimulation with abundant agonists of nucleic acid-sensing TLRs present in their blood and lungs. These nucleic acid-containing Damage and Pathogen Associated Molecular Patterns (DAMPs/PAMPs) can be depleted using nucleic acid-binding microfibers to limit the patient samples' ability to hyperactivate such innate immune receptors. Single-cell RNA-sequencing revealed that CD16+ monocytes from deceased but not recovered ICU patients exhibit a TLR-tolerant phenotype and a deficient anti-viral response after ex vivo TLR stimulation. Plasma proteomics confirmed such myeloid hyperactivation and revealed DAMP/PAMP carrier consumption in deceased patients. Treatment of these COVID-19 patient samples with MnO nanoparticles effectively neutralizes TLR activation by the abundant nucleic acid-containing DAMPs/PAMPs present in their lungs and blood. Finally, MnO nanoscavenger treatment limits the ability of DAMPs/PAMPs to induce TLR tolerance in monocytes. Thus, treatment with microfiber- or nanoparticle-based DAMP/PAMP scavengers may prove useful for limiting SARS-CoV-2 induced hyperinflammation, preventing monocytic TLR tolerance, and improving outcomes in severely ill COVID-19 patients.