Real-world effectiveness and safety of nirmatrelvir-ritonavir (Paxlovid)-treated for COVID-19 patients with onset of more than 5 days: a retrospective cohort study.

Background: Nirmatrelvir-ritonavir (Paxlovid) has received emergency use authorization from the US Food and Drug Administration owing to its effectiveness and safety. However, data on the effectiveness and safety of Paxlovid use in COVID-19 patients with onset of more than 5 days are lacking. Methods: A real-world retrospective study was performed during the outbreak involving the SARS-CoV-2 BA.5.2 subvariant. Hospitalized COVID-19 patients (including mild, moderate, severe and critical cases) were divided into three groups: Paxlovid treatment within (Group A) or more than (Group B) 5 days of COVID-19 onset and no Paxlovid treatment during more than 5 days of COVID-19 onset with only basic symptomatic treatment (Group C). Endpoints were all-cause 28-day mortality, improvement in clinical classification, and a composite endpoint of disease progression, viral load and virus elimination time. Safety was assessed by comparing adverse events reported during treatment in each group. Results: During the period, 248 hospitalized COVID-19 patients, including 55 in Group A, 170 in Group B, and 23 in Group C, were enrolled. There were no significant differences in the clinical classification improvement rate [80.0% (16/20) vs. 81.3% (52/64), p = 1.000; 60.0% (21/35) vs. 55.7% (59/106), p = 0.653, respectively] or all-cause 28-day mortality [0% (0/20) vs. 1.6% (1/64), p = 1.000; 11.4% (4/35) vs. 6.6% (7/106), p = 0.576, respectively] between Groups A and B for nonsevere and severe cases. However, the clinical classification improvement rate in Group B was markedly higher than that in Group C [81.3% (52/64) vs. 50.0% (6/12), p = 0.049] among nonsevere cases. Cycle threshold values of the N and ORF genes in Group B were significantly increased after Paxlovid treatment [31.14 (IQR 26.81-33.93) vs. 38.14 (IQR 36.92-40.00), p < 0.001; 31.33 (IQR 26.00-33.47) vs. 38.62 (IQR 35.62-40.00), p < 0.001, respectively]. No significant differences in reported adverse events of neurological disease (p = 0.571), liver injury (p = 0.960) or kidney injury (p = 0.193) between Group A and Group B were found. Conclusion: Paxlovid treatment within 10 days of onset can shorten the disease course of COVID-19 by reducing the viral load. Paxlovid is effective and safe in treating COVID-19 with onset of more than five or even 10 days when patients have a high viral load.

Defect engineering to tailor structure-activity relationship in biodegradable nanozymes for tumor therapy by dual-channel death strategies.

Pursuing biodegradable nanozymes capable of equipping structure-activity relationship provides new perspectives for tumor-specific therapy. A rapidly degradable nanozymes can address biosecurity concerns. However, it may also reduce the functional stability required for sustaining therapeutic activity. Herein, the defect engineering strategy is employed to fabricate Pt-doping MoOx (PMO) redox nanozymes with rapidly degradable characteristics, and then the PLGA-assembled PMO (PLGA@PMO) by microfluidics chip can settle the conflict between sustaining therapeutic activity and rapid degradability. Density functional theory describes that Pt-doping enables PMO nanozymes to exhibit an excellent multienzyme-mimicking catalytic activity originating from synergistic catalysis center construction with the interaction of Pt substitution and oxygen vacancy defects. The peroxidase- (POD), oxidase- (OXD), glutathione peroxidase- (GSH-Px), and catalase- (CAT) mimicking activities can induce robust ROS output and endogenous glutathione depletion under tumor microenvironment (TME) response, thereby causing ferroptosis in tumor cells by the accumulation of lipid peroxide and inactivation of glutathione peroxidase 4. Due to the activated surface plasmon resonance effect, the PMO nanozymes can cause hyperthermia-induced apoptosis through 1064 nm laser irradiation, and augment multienzyme-mimicking catalytic activity. This work represents a potential biological application for the development of therapeutic strategy for dual-channel death via hyperthermia-augmented enzyme-mimicking nanocatalytic therapy.

Modulating the local coordination environment of cobalt single-atomic nanozymes for enhanced catalytic therapy against bacteria.

Single-atomic nanozymes (SANZs) characterized by atomically dispersed single metal atoms have recently contributed to breakthroughs in biomedicine due to their satisfactory catalytic activity and superior selectivity compared to their nanoscale counterparts. The catalytic performance of SANZs can be improved by modulating their coordination structure. Therefore, adjusting the coordination number of the metal atoms in the active center is a potential method for enhancing the catalytic therapy effect. In this study, we synthesized various atomically dispersed Co nanozymes with different nitrogen coordination numbers for peroxidase (POD)-mimicking single-atomic catalytic antibacterial therapy. Among the polyvinylpyrrolidone modified single-atomic Co nanozymes with nitrogen coordination numbers of 3 (PSACNZs-N3-C) and 4 (PSACNZs-N4-C), single-atomic Co nanozymes with a coordination number of 2 (PSACNZs-N2-C) had the highest POD-like catalytic activity. Kinetic assays and Density functional theory (DFT) calculations indicated that reducing the coordination number can lower the reaction energy barrier of single-atomic Co nanozymes (PSACNZs-Nx-C), thereby increasing their catalytic performance. In vitro and in vivo antibacterial assays demonstrated that PSACNZs-N2-C had the best antibacterial effect. This study provides proof of concept for enhancing single-atomic catalytic therapy by regulating the coordination number for various biomedical applications, such as tumor therapy and wound disinfection. STATEMENT OF SIGNIFICANCE: The use of nanozymes that contain single-atomic catalytic sites has been shown to effectively promote the healing of bacteria-infected wounds by exhibiting peroxidase-like activity. The homogeneous coordination environment of the catalytic site has been associated with high antimicrobial activity, which provides insight into designing new active structures and understanding their mechanisms of action. In this study, we designed a series of cobalt single-atomic nanozymes (PSACNZs-Nx-C) with different coordination environments by shearing the Co-N bond and modifying polyvinylpyrrolidone (PVP). The synthesized PSACNZs-Nx-C demonstrated enhanced antibacterial activity against both Gram-positive and Gram-negative bacterial strains, and showed good biocompatibility in both in vivo and in vitro experiments.

Local photothermal/photodynamic synergistic antibacterial therapy based on two-dimensional BP@CQDs triggered by single NIR light source.

Pathogenic bacteria-infected wound healing faces challenges even though many advanced antibiotics and antibacterial nanoagents have been developed. Herein, we established a two-dimensional antibacterial nanoplatform with synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) antibacterial capabilities mediated by a single 808 nm laser irradiation. The nanoplatform is constructed by combining black phosphorus (BP) obtained by liquid phase exfoliation and hydrothermally prepared tellurium-doped carbon quantum dots (CQDs) prepared by electrostatic interaction. As a result, the photothermal conversion of BP and hydroxyl radical (‧OH) production of CQDs under NIR laser makes the nanoplatform (BP@CQDs) possess an outstanding antibacterial performance against S. aureus and E. coli (as high as 92.7% and 98.4%, respectively), resulting in a faster wound closure ratio than another infected wound. Moreover, in vitro and in vivo researches showed that BP@CQDs have good hemocompatibility, cytocompatibility, and biocompatibility during the therapeutic process. This work demonstrates the broad application prospect of BP nanosheets in infectious microenvironments and develops a potential strategy for S. aureus-infected wound repair.

Dual enzyme-mimic nanozyme based on single-atom construction strategy for photothermal-augmented nanocatalytic therapy in the second near-infrared biowindow.

Nanozyme-based catalytic therapy, an emerging therapeutic pattern, has significantly incorporated in the advancement of tumor therapy by generating lethal reactive oxygen species. Nevertheless, most of the nanozymes have mono catalytic performances with H2O2 in the tumor microenvironment (TME), which lowers their therapeutic efficiency. Herein, we design a newly-developed single-atom Fe dispersed N-doped mesoporous carbon nanospheres (SAFe-NMCNs) nanozyme with high H2O2 affinity for photothermal-augmented nanocatalytic therapy. The SAFe-NMCNs nanozyme possesses dual enzyme-mimic catalytic activity which not only acts as a catalase-mimic role to achieve ultrasonic imaging in tumor site by O2 generation, but also exhibits the superior peroxidase-mimic catalytic performance to generate •OH for nanocatalytic therapy. Besides, the SAFe-NMCNs nanozyme with strong optical absorption in the second near-infrared (NIR-II) region shows excellent photothermal conversion performance. The peroxidase-mimic catalytic process of SAFe-NMCNs nanozyme is realized using density functional theory (DFT). Both in vitro and in vivo results indicate that the SAFe-NMCNs nanozyme can efficiently suppress tumor cells growth by a synergistic therapy effect with photothermal-augmented nanocatalytic therapy. The work developed a single-atom-coordinated nanozyme with dual-enzyme catalytic performance and achieve hyperthermia-augmented nanocatalytic therapy effect, can open a window for potential biological applications.

Antibacterial fluorescent nano-sized lanthanum-doped carbon quantum dot embedded polyvinyl alcohol for accelerated wound healing.

Bacteria is one of the main culprits that cause human diseases and pose long-term challenges to people's health. Rare earth elements have unique antibacterial advantages, but little research is available. In this paper, we reported an antibacterial composite film based on lanthanum-doped carbon quantum dot nanoparticles (La@N-P-CQDs) and polyvinyl alcohol (PVA) film for fluorescence of antibiotics and accelerating wound healing. PVA/La@N-P-CQDs composite film presented excellent hydrophilicity, biocompatibility, fluorescence intensity, and antibacterial effects. The antibacterial activity of La@N-P-CQDs was evaluated by employing antibacterial assay using Escherichia coli (E.coli)and Staphylococcus aureus (S.aureus) in vitro. La@N-P-CQDs showed enhanced antibacterial activity compared with N-P-CQDs. Moreover, the PVA/La@N-P-CQDs composite film with 0.5 mg/mL La@N-P-CQDs showed better antibacterial capability and wound healing performance than PVA and PVA/N-P-CQDs films in bacterial adhesion experiment. PVA/La@N-P-CQDs composite film could be used for wound dressing in vivo experiment and had no side effects on major organs in mice. The antibacterial composite film significantly promoted in vivo wound healing process because of its multifunctional properties. Therefore, it was an excellent candidate for wound dressing.

A ZIF-8 Host for Dendrite-Free Zinc Anodes and N,O Dual-doped Carbon Cathodes for High-Performance Zinc-Ion Hybrid Capacitors.

Zn is a promising anode for aqueous energy storage owing to it intrinsic superior properties such as large capacity, abundant reserves, low potential and safety. But, the growth of dendrites during charge and discharge leads to a decrease in reversibility. In addition, further development of zinc-ion hybrid capacitors (ZICs) is seriously challenging because of the lack of an exceptional cathode. Herein, we use ZIF-8 annealed at 500 °C (annealed ZIF-8) as a host material for stable and dendrite-free Zn anodes. Utilization of annealed ZIF-8 results in dendrite-free Zn deposition and stripping as a result of its porous construction, which contains trace Zn. Furthermore, we firstly proposed innovative N,O dual-doped carbon which was designed by the derived ZIF-8 (ZIF-8 derived C) as cathode for high-energy and power-density ZICs. The new ZIC assembled by Zn@annealed ZIF-8 anode and ZIF-8 derived C cathode provides a capacity of 135.5 mAh g-1 and an energy density of 108.4 Wh kg-1 with a power density of 800 W kg-1 at 1.0 A g-1 . In addition, it shows outstanding cycling stability of 91% capacity retention after 6000 cycles at 5.0 A g-1 . Moreover, the solid-state ZICs can drive LEDs and smart watches. This ZIC holds promise for the practical application of supercapacitors.

Tumor Microenvironment-Activatable Cyclic Cascade Reaction to Reinforce Multimodal Combination Therapy by Destroying the Extracellular Matrix.

The optimal therapy effect of tumors is frequently restricted by the dense extracellular matrix (ECM) and anoxia. Herein, an intelligent BPNs-Arg-GOx@MnO2 (BAGM) nanozyme is innovatively designed as a multimodal synergistic therapeutic paradigm that possesses both nitric oxide (NO) self-supplying and ECM degradation properties to reinforce the therapy effect by a tumor microenvironment (TME)-activatable cyclic cascade catalytic reaction. This theranostic nanoplatform is constructed by using polyethyleneimine-modified black phosphorus nanosheets as a "fishnet" to attach l-Arginine (l-Arg) and glucose oxidase (GOx) and then depositing mini-sized MnO2 nanosheets (MNs) on the surface by a facile situ biomineralization method. As an intelligent "switch", the MNs can effectively trigger the cascade reaction by disintegrating intracellular H2O2 to release O2. Then, the conjugated GOx can utilize O2 production to catalyze intracellular glucose to generate H2O2, which not only starves the tumor cells but also promotes oxidation of l-Arg to NO. Thereafter, matrix metalloproteinases will be activated by NO production to degrade the dense ECM and transform matrix collagen into a loose state. In turn, a loose ECM can enhance the accumulation of the BAGM nanozyme and thereby reinforce synergistic photothermal therapy/starvation therapy/NO gas therapy. Both in vitro and in vivo results indicate that the TME-tunable BAGM therapeutic nanoplatform with cascade anticancer property and satisfactory biosecurity shows potential in nanomedicine.

A hydrothermal route to multicolor luminescent carbon dots from adenosine disodium triphosphate for bioimaging.

In this work, phosphor and nitrogen co-doped carbon dots (N-P-doped CDs) were developed for bioimaging. The as-synthesized N-P-doped CDs emit a bright blue coloured fluorescence after exposure to a 365nm UV-lamp illumination. It is also demonstrated that the fluorescence of CDs is resistant to the interference of metal ions, saline solution, and high ionic strength environments. The bright fluorescence nature of the N-P-doped CDs has proven them to be excellent probes for cellular imaging. And this guess is further confirmed by using a laser scanning confocal microscope (LSCM). The viability study was carried out by MTT assay, suggesting the high biocompatibility of N-P-doped CDs. The results demonstrated that N-P-doped CDs may be considered as a safe material for bio-imaging and drug delivery in cancer cells.

Carboxylated graphene oxide functionalized with ß-cyclodextrin-Engineering of a novel nanohybrid drug carrier.

In this paper, we selected biocompatible carboxylated graphene oxide (GeneO-COOH) as a base material. The nanohybrid drug carriers composed of GeneO-COOH and cyclodextrin (ß-CD), have been successfully synthesized through esterification and self-assembly technique. The nanohybrid drug carriers of GeneO-COO-ß-CD were characterized by X-ray diffraction (XRD), fourier infrared spectroscopy (FTIR), thermogravimetric analysis (TG), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and solubility experiments. Results indicated that the nanohybrid was obtained with GeneO-COOH forming the core and a large number of ß-CD molecules forming the shell with a special structure. In the nanohybrid, the westerification between GeneO-COOH and ß-CD led to the formation of covalent bonds, while adjacent ß-CD molecules engineer an outer shell composed of 100 ß-CD molecules (ca. 800nm of thickness) in the form of a layer-by-layer self-assembly due to hydrogen-bonding interaction. The obtained novel nanohybrid drug carriers of GeneO-COO-ß-CD possessed good dispersibility in water media and the solutions were found to remain stable for 12 months，providing a possibility for further applications in biology, medicine, agriculture and other fields.

Hydroxypropyl-ß-cyclodextrin-graphene oxide conjugates: Carriers for anti-cancer drugs.

A novel drug carrier based on hydroxypropyl-ß-cyclodextrin (HP-ß-CD) modified carboxylated graphene oxide (GO-COOH) was designed to incorporate anti-cancer drug paclitaxel (PTX). The formulated nanomedicines were characterized by Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Results showed that PTX can be incorporated into GO-COO-HP-ß-CD nanospheres successfully, with an average diameter of about 100 nm. The solubility and stability of PTX-loaded GO-COO-HP-ß-CD nanospheres in aqueous media were greatly enhanced compared with the untreated PTX. The results of hemolysis test demonstrated that the drug-loaded nanospheres were qualified with good blood compatibility for intravenous use. In vitro anti-tumor activity was measured and results demonstrated that the incorporation of PTX into the newly developed GO-COO-HP-ß-CD carrier could confer significantly improved cytotoxicity to the nanosystem against tumor cells than single application of PTX. GO-COO-HP-ß-CD nanospheres may represent a promising formulation platform for a broad range of therapeutic agent, especially those with poor solubility.