A Novel Drug Candidate for Sepsis Targeting Heparanase by Inhibiting Cytokine Storm.

Sepsis is an infection-triggered, rapidly progressive systemic inflammatory syndrome with a high mortality rate. Currently, there are no promising therapeutic strategies for managing this disease in the clinic. Heparanase plays a crucial role in the pathology of sepsis, and its inhibition can significantly relieve related symptoms. Here, a novel heparanase inhibitor CV122 is rationally designed and synthesized, and its therapeutic potential for sepsis with Lipopolysaccharide (LPS) and Cecal Ligation and Puncture (CLP)-induced sepsis mouse models are evaluated. It is found that CV122 potently inhibits heparanase activity in vitro, protects cell surface glycocalyx structure, and reduces the expression of adhesion molecules. In vivo, CV122 significantly reduces the systemic levels of proinflammatory cytokines, prevents organ damage, improves vitality, and efficiently protects mice from sepsis-induced death. Mechanistically, CV122 inhibits the activity of heparanase, reduces its expression in the lungs, and protects glycocalyx structure of lung tissue. It is also found that CV122 provides effective protection from organ damage and death caused by Crimean-Congo hemorrhagic fever virus (CCHFV) infection. These results suggest that CV122 is a potential drug candidate for sepsis therapy targeting heparanase by inhibiting cytokine storm.

Near-Infrared Nanophosphors Based on CuInSe2 Quantum Dots with Near-Unity Photoluminescence Quantum Yield for Micro-LEDs Applications.

Highly efficient near-infrared (NIR) luminescent nanomaterials are urgently required for portable mini or micro phosphors-converted light-emitting diodes (pc-LEDs). However, most existing NIR-emitting phosphors are generally restricted by their low photoluminescence (PL) quantum yield (QY) or large particle size. Herein, a kind of highly efficient NIR nanophosphors is developed based on copper indium selenide quantum dots (CISe QDs). The PL peak of these QDs can be exquisitely manipulated from 750 to 1150 nm by altering the stoichiometry of Cu/In and doping with Zn2+ . Their absolute PLQY can be significantly improved from 28.6% to 92.8% via coating a ZnSe shell. By combining the phosphors with a commercial blue chip, an NIR pc-LED is fabricated with remarkable photostability and a record-high radiant flux of 88.7 mW@350 mA among the Pb/Cd-free QDs-based NIR pc-LEDs. Particularly, such QDs-based nanophosphors acted as excellent luminescence converter for NIR micro-LEDs with microarray diameters below 5 µm, which significantly exceeds the resolutions of current commercial inkjet display pixels. The findings may open new avenues for the exploration of highly efficient NIR micro-LEDs in a variety of applications.

Ultra-broad Near-Infrared Emitting Phosphor LiInF4: Cr3+ with Extremely Weak Crystal Field.

Recent decades have witnessed a major development in broadband near-infrared (NIR)-emitting phosphors because of their potential applications in real-time nondestructive examination. These applications require the emission spectra of phosphors to be as broad as possible for efficient performance. Therefore, a blue-light excited LiInF4: Cr3+ phosphor with a NIR emission covering 700-1400 nm is successfully synthesized. Under 470 nm excitation, it shows broadband emission peaked at 980 nm with the full-width at half maximum of 210 nm. The structure and crystal field environment are investigated in detail, and the LiInF4: Cr3+ possesses a weak crystal field strength and strong electron-phonon coupling. An efficient NIR phosphor-converted light-emitting diode (pc-LED) is fabricated by the prepared LiInF4: Cr3+ phosphor and commercial blue diode chip, generating a NIR radiant flux of 5.54 mW at 150 mA drive current. Finally, the NIR pc-LED is successfully applied to identify the blood vessel distribution of the hand. This work suggests the potential of LiInF4: Cr3+ phosphor in applications.

In Vivo NIR-II Fluorescence Lifetime Imaging of Whole-Body Vascular Using High Quantum Yield Lanthanide-Doped Nanoparticles.

Second near infrared (NIR-II, 1000-1700 nm) fluorescence lifetime imaging is a powerful tool for biosensing, anti-counterfeiting, and multiplex imaging. However, the low photoluminescence quantum yield (PLQY) of fluorescence probes in NIR-II region limits its data collecting efficiency and accuracy, especially in multiplex molecular imaging in vivo. To solve this problem, lanthanide-doped nanoparticles (NPs) ß-NaErF4 : 2%Ce@NaYbF4 @NaYF4 with high PLQY and tunable PL lifetime through multi-ion doping and core-shell structural design, are presented. The obtained internal PLQY can reach up to 50.1% in cyclohexane and 9.2% in water under excitation at 980 nm. Inspired by the above results, a fast NIR-II fluorescence lifetime imaging of whole-body vascular in mice is successfully performed by using the homebuilt fluorescence lifetime imaging system, which reveals a murine abdominal capillary network with low background. A further demonstration of fluorescence lifetime multiplex imaging is carried out in molecular imaging of atherosclerosis cells and different organs in vivo through NPs conjugating with specific peptides and different injection modalities, respectively. These results demonstrate that the high PLQY NPs combined with the homebuilt fluorescence lifetime imaging system can realize a fast and high signal-to-noise fluorescence lifetime imaging; thus, opening a road for multiplex molecular imaging of atherosclerosis.

Resveratrol-loaded macrophage exosomes alleviate multiple sclerosis through targeting microglia.

Despite exosome promise as endogenous drug delivery vehicles, the current understanding of exosome may be insufficient to develop their various applications. Here we synthesized five sialic acid analogues with different length N-acyl side chains and screened out the optimal metabolic precursor for exosome labeling via bio-orthogonal click chemistry. In proof-of-principle labeling experiments, exosomes derived from macrophages (RAW-Exo) strongly co-localized with central nervous system (CNS) microglia. Inspired by this discovery, we developed a resveratrol-loaded RAW-Exo formulation (RSV&Exo) for multiple sclerosis (MS) treatment. Intranasal administration of RSV&Exo significantly inhibited inflammatory responses in the CNS and peripheral system in a mouse model of MS and effectively improved the clinical evolution of MS in vivo. These findings suggested the feasibility and efficacy of engineered RSV&Exo administration for MS, providing a potential therapeutic strategy for CNS diseases.

Achieving stable photoluminescence by double thiacalix[4]arene-capping: the lanthanide-oxo cluster core matters.

Luminescence stability is a critical consideration for applying phosphors in practical devices. In this work, we report two categories of double p-tert-butylthiacalix[4]arene (H4TC4A) capped clusters that exhibit characteristic lanthanide luminescence. Specifically, {[Ln4(µ4-OH)(TC4A)2(DMF)6(CH3OH)3(HCOO)Cl2]}·xCH3OH (Ln = Eu (1), Tb (2); x = 0-1) with square-planar [Ln4(µ4-OH)] cluster cores and {[Ln9(µ5-OH)2(µ3-OH)8(OCH3) (TC4A)2 (H2O)24Cl9]}·xDMF (Ln = Gd (3), Tb (4), Dy (5); x = 2-6) with hourglass-like [Ln9(µ5-OH)2(µ3-OH)8] cluster cores are synthesized and characterized. By comparing 2 and 4, we find that several critical luminescence properties (such as quantum efficiency and luminescence stabilities) depend directly on the cluster core structure. With the square-planar [Ln4(µ4-OH)] cluster cores, 2 demonstrates high quantum yield (∼65%) and excellent luminescence stability against moisture, high temperature, and UV-radiation. A white light-emitting diode (LED) with ultrahigh color quality is successfully fabricated by mixing 2 with commercial phosphors. These results imply that high quality phosphors might be achieved by exploiting the double thiacalix[4]arene-capping strategy, with an emphasis on the cluster core structure.

Not Just Anticoagulation-New and Old Applications of Heparin.

In recent decades, heparin, as the most important anticoagulant drug, has been widely used in clinical settings to prevent and treat thrombosis in a variety of diseases. However, with in-depth research, the therapeutic potential of heparin is being explored beyond anticoagulation. To date, heparin and its derivatives have been tested in the protection against and repair of inflammatory, antitumor, and cardiovascular diseases. It has also been explored as an antiangiogenic, preventive, and antiviral agent for atherosclerosis. This review focused on the new and old applications of heparin and discussed the potential mechanisms explaining the biological diversity of heparin.

Ultrastable Photoluminescence Enabled by 1D Rare-Earth Metal-Organic Frameworks Based on Double Thiacalix[4]arene-Capped Nodes.

Luminescent stability is a vital factor that dictates the application of lanthanide luminescent materials. Designing luminescent lanthanide cluster nodes that form an extended framework with predictable linking patterns may help enhance the structural stability of the lanthanide complexes and hence lead to improved luminescent stability. Herein, we report a series of one-dimensional (1D) rare-earth metal-organic framework compounds, {Ln4(µ4-OH)(TC4A)2(H2O)2(CH3O)(HCOO)2(HCOOH)}·xCH3OH (Ln = Sm (1), Eu (2), Tb (3), Dy (4); x = 1-5), based on double thiacalix[4]arene-capped Ln4(µ4-OH)(TC4A)2 nodes. The axially capped Ln4(µ4-OH)(TC4A)2 nodes are connected equatorially by formate bridges to form zigzag 1D-metal-organic framework (MOF) chains, which further assemble into a quasi-two-dimensional (2D) structure via hydrogen bonding. These unique features result in a stable structure and therefore superior luminescent stability. For example, the Tb-based 1D-MOF (3) exhibits intensive green photoluminescence with a quantum yield of 53% and an average decay time of 1.33 × 106 ns. It maintains its integrated emission intensity at 96.5, 94.5, and 89.4% of the original value after being exposed to moisture (soaking in water for 10 days), elevated temperature (150 °C), and UV (15 days of continuous radiation), respectively, demonstrating excellent luminescent stability. We adopt the Tb-based 1D-MOF (3) as the green phosphor and successfully fabricate a prototype white-light-emitting diode (LED) with stable emission under long-term operation. Our synthetic strategy allows control over the linking pattern of lanthanide nodes, providing a predictive route to obtain lanthanide MOFs with improved luminescent stability.

Suppression of Photoinduced Phase Segregation in Mixed-Halide Perovskite Nanocrystals for Stable Light-Emitting Diodes.

Halide segregation is a critical bottleneck that hampers the application of mixed-halide perovskite nanocrystals (NCs) in both electroluminescent and down-conversion red-light-emitting diodes. Herein, we report a strategy that combines precursor and surface engineering to obtain pure-red-emitting (peaked at 624 nm) NCs with a photoluminescence quantum yield of up to 92% and strongly suppresses the halide segregation of mixed-halide NCs under light irradiation. Red-light-emitting diodes (LED) using these mixed-halide NCs as phosphors exhibit color-stable emission with a negligible peak shift and spectral broadening during operation over 240 min. By contrast, a dramatic peak shift and spectral broadening were observed after 10 min of operation in LEDs based on mixed-halide NCs synthesized by a traditional method. Our strategy is critical to achieving photo- and band-gap-stable mixed-halide perovskite NCs for a variety of optoelectronic applications such as micro-LEDs.

An efficient and safe MUC1-dendritic cell-derived exosome conjugate vaccine elicits potent cellular and humoral immunity and tumor inhibition in vivo.

Antitumor vaccines are a promising strategy for preventing or treating cancers by eliciting antitumor immune responses and inducing protective immunity against specific antigens expressed on tumor cells. Vaccine formulations that enhance the humoral and cellular immune responses of vaccine candidates would be highly beneficial but are still limited. Here we developed an antitumor vaccine candidate by conjugating a MUC1 glycopeptide antigen to dendritic cell-derived exosomes (Dex). In vivo, the MUC1-Dex construct induced high MUC1-specific IgG antibody titers with strong binding affinities for MUC1-positive tumor cells and promoted cytokine secretion. Moreover, CD8+ T cells from immunized mice exhibited strong cytotoxicity against MUC1-positive tumor cells. Importantly, in both preventative and therapeutic tumor-bearing mouse models, the construct inhibited tumor growth and prolonged survival. Collectively, these results demonstrate that Dex is a promising vaccine carrier that can be used as adjuvant to enhance the immunological efficacy of tumor vaccines. STATEMENT OF SIGNIFICANCE.

The Structural and Dynamical Properties of the Hydration of SNase Based on a Molecular Dynamics Simulation.

The dynamics of protein-water fluctuations are of biological significance. Molecular dynamics simulations were performed in order to explore the hydration dynamics of staphylococcal nuclease (SNase) at different temperatures and mutation levels. A dynamical transition in hydration water (at ~210 K) can trigger larger-amplitude fluctuations of protein. The protein-water hydrogen bonds lost about 40% in the total change from 150 K to 210 K, while the Mean Square Displacement increased by little. The protein was activated when the hydration water in local had a comparable trend in making hydrogen bonds with protein- and other waters. The mutations changed the local chemical properties and the hydration exhibited a biphasic distribution, with two time scales. Hydrogen bonding relaxation governed the local protein fluctuations on the picosecond time scale, with the fastest time (24.9 ps) at the hydrophobic site and slowest time (40.4 ps) in the charged environment. The protein dynamic was related to the water's translational diffusion via the relaxation of the protein-water's H-bonding. The structural and dynamical properties of protein-water at the molecular level are fundamental to the physiological and functional mechanisms of SNase.

The Adjuvant of α-Galactosylceramide Presented by Gold Nanoparticles Enhances Antitumor Immune Responses of MUC1 Antigen-Based Tumor Vaccines.

BACKGROUND: Therapeutic tumor vaccines are one of the most promising strategies and have attracted great attention in cancer treatment. However, most of them have shown unsatisfactory immunogenicity, there are still few available vaccines for clinical use. Therefore, there is an urgent demand to develop novel strategies to improve the immune efficacy of antitumor vaccines. PURPOSE: This study aimed to develop novel adjuvants and carriers to enhance the immune effect of MUC1 glycopeptide antigen-based antitumor vaccines. METHODS: An antitumor vaccine was developed, in which MUC1 glycopeptide was used as tumor-associated antigen, α-GalCer served as an immune adjuvant and AuNPs was a multivalent carrier. RESULTS: Immunological evaluation results indicated that the constructed vaccines enabled a significant antibody response. FACS analysis and immunofluorescence assay showed that the induced antisera exhibited a specific binding with MUC1 positive MCF-7 cells. Moreover, the induced antibody can mediate CDC to kill MCF-7 cells. Besides stimulating B cells to produce MUC1-specific antibodies, the prepared vaccines also induced MUC1-specific CTLs in vitro. Furthermore, the vaccines significantly delayed tumor development in tumor-bearing mice model. CONCLUSION: These results showed that the construction of vaccines by presenting α-GalCer adjuvant and an antigen on gold nanoparticles offers a potential strategy to improve the antitumor response in cancer immunotherapy.

Multiple emission bands NIR-persistent luminescence mSiO2@Zn0.6Ca0.4Ga2O4:Cr3+,Yb3+ nanoparticles for biological applications.

Persistent luminescence nanoparticles (PLNPs) emitting in the NIR window (700-1700 nm) have shown great promise in the field of fluorescence imaging due to their unique properties, including the absence of in situ excitation and low optical scattering in tissues. However, they are still facing some challenges, such as irregular shape, wide size distribution and poor persistent luminescence performance. Here, we report a facile mesoporous template method for synthesizing mSiO2@Zn0.6Ca0.4Ga2O4:Cr3+,Yb3+ (mSiO2@ZCGO) persistent luminescent nanoparticles, which show a regular morphology and a size of about 69 nm. In addition, these nanocrystals exhibit persistent luminescence in multi-NIR windows, the first infrared window (∼696 nm of Cr3+ emission) and second infrared window (∼1000 nm of Yb3+ emission). Under illumination of a 254 nm UV lamp for 10 min, the persistent time of Cr3+ ions and Yb3+ ions lasted more than 120 min and 10 min, respectively. In particular, the NIR persistent emission of mSiO2@ZCGO could be stimulated by soft X-ray, which is beneficial to long-term imaging in deep tissues. The optical penetration length of Yb3+ ions persistent luminescence was evaluated to be 2.8 mm. These results demonstrate the great promise of mSiO2@ZCGO for deep-tissue bio-imaging.

Theoretical and Experimental Optimization of the Graft Density of Functionalized Anti-Biofouling Surfaces by Cationic Brushes.

Diseases and complications related to catheter materials are severe problems in biomedical material applications, increasing the infection risk and medical expenses. Therefore, there is an enormous demand for catheter materials with antibacterial and antifouling properties. Considering this, in this work, we developed an approach of constructing antibacterial surfaces on polyurethane (PU) via surface-initiated atom transfer radical polymerization (SI-ATRP). A variety of cationic polymers were grafted on PU. The biocompatibility and antifouling properties of all resulting materials were evaluated and compared. We also used a theoretical algorithm to investigate the anticoagulant mechanism of our PU-based grafts. The hemocompatibility and anti-biofouling performance improved at a 86-112 µg/cm2 grafting density. The theoretical simulation demonstrated that the in vivo anti-fouling performance and optimal biocompatibility of our PU-based materials could be achieved at a 20% grafting degree. We also discuss the mechanism responsible for the hemocompatibility of the cationic brushes fabricated in this work. The results reported in this paper provide insights and novel ideas on material design for applications related to medical catheters.

Design, Synthesis, and Preliminary Immunological Studies of MUC1-Based Antitumor Vaccines Adjuvanted with R- and S-FSL-1.

Fibroblast stimulating lipopeptide 1 (FSL-1) is the ligand of TLR2 and TLR6 and can be used as the vaccine adjuvant to prepare antitumor vaccines. However, FSL-1 is a stereoisomeric mixture that contains the R stereoisomer and S stereoisomer, and it is still unclear which stereoisomer has better adjuvant activities. In this work, we designed and synthesized MUC1-based antitumor vaccines adjuvanted with the stereoisomers R-FSL-1 and S-FSL-1, which were synthesized from the stereoisomeric building blocks R-Fmoc-Pam2Cys-OH and S-Fmoc-Pam2Cys-OH, respectively. Immunological evaluation indicated that both R-FSL-1 and S-FSL-1 can be used as adjuvants for the construction of MUC1-based antitumor vaccines, with R-FSL-1 showing a better adjuvant effect than S-FSL-1.

Synthesis and optical properties of a Y3(Al/Ga)5O12:Ce3+,Cr3+,Nd3+ persistent luminescence nanophosphor: a promising near-infrared-II nanoprobe for biological applications.

Persistent luminescence nanophosphors (PLNPs) emitting in the second near-infrared window (1000-1700 nm, NIR-II) are emerging as one promising class of in vivo bio-imaging agents due to their unique advantages including non-autofluorescence and low optical scattering in tissues. Currently, it remains a great challenge to synthesize nanosized lanthanide-doped inorganic NIR-II phosphors with a good persistent luminescence performance. Herein, we present a salt microemulsion method for synthesizing Ce3+, Cr3+, Nd3+ codoped Y3(Al/Ga)5O12 nanocrystals, which generate multi-wavelength persistent luminescence in the visible (∼508 nm, 5d1→ 4f of Ce3+), the first near-infrared window (∼890 nm, 4F3/2→4I9/2 of Nd3+) and NIR-II (∼1063 nm, 4F3/2→4I11/2 of Nd3+) regions. Under illumination of a 410 nm diode (3 W) for 10 min, the observed duration time of NIR-II persistent luminescence is as long as 60 min at room temperature. Moreover, the persistent luminescence can be excited efficiently by multiple excitation sources including a blue diode, white LEDs and an X-ray generator, which is crucial for deep tissue imaging applications. By comparing the penetration depth between NIR-I and NIR-II persistent luminescence through chicken breast, we prove that NIR-II photons exhibit a deeper optical penetration length (3.9 mm) than that of the NIR-I ones (2.5 mm). In addition, the NIR signals can still be detected 3 min after ceasing the excitation source by a small animal imaging system (InGaAs detector) when the thickness of the covering chicken breast is 20 mm. These results show great promise for Y3(Al/Ga)5O12:Ce3+,Cr3+,Nd3+ nanocrystals as a PLNP for bio-imaging applications with deep penetration depth and a high signal-to-noise ratio.

Factors of Importance for Arsenic Migration/Separation under Coffee-Ring Effect on Silver Nanofilms.

Surface-enhanced Raman spectroscopy (SERS) has been recognized as a promising analytical technique owing to its merit of nondestructive and fast detection capabilities. However, SERS usually suffers signal interferences from different analytes or a complicated matrix. Separation is an effective approach to solve the signal interference in the application of SERS. It was proposed that two concentric coffee rings could serve as a simple separation platform; however, there are still many questions to be answered for in-depth understanding. In this study, critical parameters during the formation of two concentric coffee rings are characterized for a better understanding of this phenomenon, including surface tension, surface morphology, and surface energy. Two arsenicals, including arsenate (AsV) and cacodylic acid (DMAV), are chosen to study the arsenicals' separation/migration mechanism due to their significant difference in chemical properties. In the typical coffee ring, these two arsenicals have signal interference and only DMAV is detected via SERS; however, they are detected along the radius of the two concentric coffee rings. The distribution of arsenicals on the two concentric coffee rings is further verified by the chromatographic method. Under this simple platform, interactions between the arsenicals and the surface of the silver nanofilm are pivotal to their migration/separation. By surface modification of silver nanofilm with small molecules, the surface polarity and surface ζ potential are manipulated. The signal dynamics of these two arsenicals are studied on these modified silver nanofilms. It is clear that the electrostatic interaction plays a more important role than the polarity in the arsenicals' migration. This study reveals the mechanism of small molecule migration/separation in the two concentric coffee rings and provides insights for future study of employing this simple platform.

Integrating temporal and spatial control of electronic transitions for bright multiphoton upconversion.

The applications of lanthanide-doped upconversion nanomaterials are limited by unsatisfactory brightness currently. Herein, a general strategy is proposed for boosting the upconversion efficiency in Er3+ ions, based on combined use of a core-shell nanostructured host and an integrated optical waveguide circuit excitation platform. A NaErF4@NaYF4 core-shell nanoparticle is constructed to host the upconversion process for minimizing non-radiative dissipation of excitation energy by surface quenchers. Furthermore, an integrated optical microring resonator is designed to promote absorption of excitation light by the nanoparticles, which alleviates quenching of excited states due to cross-relaxation and phonon-assisted energy transfer. As a result, multiphoton upconversion emission with a large anti-Stokes shift (greater than 1150 nm) and a high energy conversion efficiency (over 5.0%) is achieved under excitation at 1550 nm. These advances in controlling photon upconversion offer exciting opportunities for important photonics applications.

Polyurethane-Cardiolipin Nanoparticle-Modified Decellularized Scaffold-Based Vascular Patches for Tissue Engineering Applications.

Vascular patches based on a decellularized scaffold (DCS) have received considerable attention for the treatment of vascular defects caused by cardiovascular diseases. In this work, we fabricated a polyurethane-cardiolipin/polyurethane composite film (PU-CL/PU) by cosedimentating PU-CL nanoparticles in a PU-saturated ethanol solution onto a PU film and evaluated the biocompatibility of the composite film. We also fabricated a PU-CL/PU/DCS vascular patch (CLVP) and investigated its in vivo performance in a mouse model. The PU-CL/PU film showed improved biocompatibility features, such as a prolonged in vitro coagulation time, improved nonhemolytic properties, enhanced resistance to platelet adhesion, reduced cytotoxicity, and enhanced affinity for endothelial progenitor cells. The B ultrasound and the Doppler spectrum results indicated that the CLVP maintained blood vessel patency 30 days after implantation. In addition, endothelialization at the surgical site was achieved. Therefore, the CLVP may have great potential for the treatment of diseased or damaged blood vessels.

Moisture-Resistant Mn4+ -Doped Core-Shell-Structured Fluoride Red Phosphor Exhibiting High Luminous Efficacy for Warm White Light-Emitting Diodes.

K2 TiF6 :Mn4+ is a highly efficient narrow-band emission red phosphor with promising applications in white light-emitting diodes (LEDs) and wide-gamut displays. Nevertheless, the poor moisture-resistant properties of this material hinder commercialization. A convenient reverse cation-exchange strategy is introduced for constructing a core-shell-structured K2 TiF6 :Mn4+ @K2 TiF6 phosphor. The outer K2 TiF6 shell acts as a shield for preventing moisture in the air from hydrolyzing the internal MnF6 2- group, while effectively cutting off the path of energy migration to surface defects, thereby increasing the emission efficiency (especially for the phosphors doped with high concentrations of Mn4+ ). Employed as a red phosphor, the packaged white LED exhibits an extraordinarily high luminous efficacy of 162 lm W-1 , a correlated color temperature (CCT) of 3510 K, and a color rendering index of 93 (Ra ). Aging tests performed on this device at 85 °C and 85 % humidity for 480 h retain up to 89 % luminous efficacy. The findings could facilitate commercial application of K2 TiF6 :Mn4+ @K2 TiF6 phosphor.