Nanovesicles derived from bispecific CAR-T cells targeting the spike protein of SARS-CoV-2 for treating COVID-19.

BACKGROUND: Considering the threat of the COVID-19 pandemic, caused by SARS-CoV-2, there is an urgent need to develop effective treatments. At present, neutralizing antibodies and small-molecule drugs such as remdesivir, the most promising compound to treat this infection, have attracted considerable attention. However, some potential problems need to be concerned including viral resistance to antibody-mediated neutralization caused by selective pressure from a single antibody treatment, the unexpected antibody-dependent enhancement (ADE) effect, and the toxic effect of small-molecule drugs. RESULTS: Here, we constructed a type of programmed nanovesicle (NV) derived from bispecific CAR-T cells that express two single-chain fragment variables (scFv), named CR3022 and B38, to target SARS-CoV-2. Nanovesicles that express both CR3022 and B38 (CR3022/B38 NVs) have a stronger ability to neutralize Spike-pseudovirus infectivity than nanovesicles that express either CR3022 or B38 alone. Notably, the co-expression of CR3022 and B38, which target different epitopes of spike protein, could reduce the incidence of viral resistance. Moreover, the lack of Fc fragments on the surface of CR3022/B38 NVs could prevent ADE effects. Furthermore, the specific binding ability to SARS-CoV-2 spike protein and the drug loading capacity of CR3022/B38 NVs can facilitate targeted delivery of remdesiver to 293 T cells overexpressing spike protein. These results suggest that CR3022/B38 NVs have the potential ability to target antiviral drugs to the main site of viral infection, thereby enhancing the antiviral ability by inhibiting intracellular viral replication and reducing adverse drug reactions. CONCLUSIONS: In summary, we demonstrate that nanovesicles derived from CAR-T cells targeting the spike protein of SARS-COV-2 have the ability to neutralize Spike-pseudotyped virus and target antiviral drugs. This novel therapeutic approach may help to solve the dilemma faced by neutralizing antibodies and small-molecule drugs in the treatment of COVID-19.

Bacterial community diversity associated with different levels of dietary nutrition in the rumen of sheep.

The sheep rumen microbial community plays an important role in animal performance and the environment. Few studies have paid close attention to the impact of different levels of dietary nutrition on rumen microbial populations. A total of 112 healthy Tan sheep were selected and randomly allotted to one of four dietary treatments (groups I, II, III, and IV). Each treatment included four replicated pens with seven sheep each for a total of 28 sheep per treatment. The sheep were fed four diets with nutrient levels that were 84, 96, 108, or 120% of the recommendation. In this study, a next-generation sequencing strategy and quantitative real-time PCR analysis were applied to investigate changes in whole ruminal bacteria with increased dietary energy and protein levels. The study observed 133 genera belonging to 16 phyla distributed throughout the rumen samples, with Firmicutes and Bacteroidetes predominating. Additionally, the higher nutritional dietary level linearly increased (P < 0.05) the number of Bacteroidetes and Proteobacteria but linearly decreased (P < 0.05) the Firmicutes richness. At the species level, the abundance of Prevotella ruminicola, Ruminococcus flavefaciens, and Succinivibrio dextrinosolvens linearly increased (P < 0.05), whereas the abundance of Selenomonas ruminantium and Veillonella parvula did not (P > 0.05). Furthermore, we predicted the potential functions of rumen bacteria. In particular, the relative abundances of the genes related to carbohydrates were overrepresented, and the genes involved in amino acid metabolism linearly increased (P < 0.05). These findings provide the first deep insights into the rumen microbial composition and the targeted improvement of dietary protein and energy use efficiency in Tan sheep.

Fabrics Attached with Highly Efficient Aggregation-Induced Emission Photosensitizer: Toward Self-Antiviral Personal Protective Equipment.

Personal protective equipment (PPE) is vital for the prevention and control of SARS-CoV-2. However, conventional PPEs lack virucidal capabilities and arbitrarily discarding used PPEs may cause a high risk for cross-contamination and environmental pollution. Recently reported photothermal or photodynamic-mediated self-sterilizing masks show bactericidal-virucidal abilities but have some inherent disadvantages, such as generating unbearable heat during the photothermal process or requiring additional ultraviolet light irradiation to inactivate pathogens, which limit their practical applications. Here, we report the fabrication of a series of fabrics (derived from various PPEs) with real-time self-antiviral capabilities, on the basis of a highly efficient aggregation-induced emission photosensitizer (namely, ASCP-TPA). ASCP-TPA possesses facile synthesis, excellent biocompatibility, and extremely high reactive oxygen species generation capacity, which significantly outperforms the traditional photosensitizers. Meanwhile, the ASCP-TPA-attached fabrics (ATaFs) show tremendous photodynamic inactivation effects against MHV-A59, a surrogate coronavirus of SARS-CoV-2. Upon ultralow-power white light irradiation (3.0 mW cm-2), >99.999% virions (5 log) on the ATaFs are eliminated within 10 min. Such ultralow-power requirement and rapid virus-killing ability enable ATaFs-based PPEs to provide real-time protection for the wearers under indoor light irradiation. ATaFs' virucidal abilities are retained after 100 washings or continuous exposure to office light for 2 weeks, which offers the benefits of reusability and long-term usability. Furthermore, ATaFs show no toxicity to normal skin, even upon continuous high-power light illumination. This self-antiviral ATaFs-based strategy may also be applied to fight against other airborne pathogens and holds huge potential to alleviate global PPE supply shortages.

Glycyrrhizic Acid Nanoparticles as Antiviral and Anti-inflammatory Agents for COVID-19 Treatment.

COVID-19 has been diffusely pandemic around the world, characterized by massive morbidity and mortality. One of the remarkable threats associated with mortality may be the uncontrolled inflammatory processes, which were induced by SARS-CoV-2 in infected patients. As there are no specific drugs, exploiting safe and effective treatment strategies is an instant requirement to dwindle viral damage and relieve extreme inflammation simultaneously. Here, highly biocompatible glycyrrhizic acid (GA) nanoparticles (GANPs) were synthesized based on GA. In vitro investigations revealed that GANPs inhibit the proliferation of the murine coronavirus MHV-A59 and reduce proinflammatory cytokine production caused by MHV-A59 or the N protein of SARS-CoV-2. In an MHV-A59-induced surrogate mouse model of COVID-19, GANPs specifically target areas with severe inflammation, such as the lungs, which appeared to improve the accumulation of GANPs and enhance the effectiveness of the treatment. Further, GANPs also exert antiviral and anti-inflammatory effects, relieving organ damage and conferring a significant survival advantage to infected mice. Such a novel therapeutic agent can be readily manufactured into feasible treatment for COVID-19.

Cascaded Electrochemiluminescence Signal Amplifier for the Detection of Telomerase Activity from Tumor Cells and Tissues.

Telomerase is closely linked to the physiological transformation of tumor cells and is commonly overexpressed in most types of tumor cells. Therefore, telomerase has become a potential biomarker for the process of tumorigenesis, progression, prognosis and metastasis. Thus, it is important to develop a simple, accurate and reliable method for detecting telomerase activity. As a high signal-to-noise ratio mode, electrochemiluminescence (ECL) has been widely applied in the field of biomedical analysis. Here, our objective was to construct an improved ECL signal amplifier for the detection of telomerase activity. Methods: A cascaded ECL signal amplifier was constructed to detect telomerase activity with high selectivity via controllable construction of a lysine-based dendric Ru(bpy)32+ polymer (DRP). The sensitivity, specificity and performance index were simultaneously evaluated by standard substance and cell and tissue samples. Results: With this cascaded ECL signal amplifier, high sensitivities of 100, 50, and 100 cells for three tumor cell lines (A549, MCF7 and HepG2 cell lines) were simultaneously achieved, and desirable specificity was also obtained. Furthermore, the excellent performance of this platform was also demonstrated in the detection of telomerase in tumor cells and tissues. Conclusion: This cascaded ECL signal amplifier has the potential to be a technological innovation in the field of telomerase activity detection.

Zika Virus Liquid Biopsy: A Dendritic Ru(bpy)3 2+-Polymer-Amplified ECL Diagnosis Strategy Using a Drop of Blood.

Zika virus (ZIKV) is a mosquito-borne flavivirus that leads to devastating consequences for fetal development. However, accurate diagnosis of ZIKV is made difficult by the fact that most infected patients are asymptomatic or present with symptoms similar to those of other febrile illnesses. Thus, the development of a simple, accurate, highly sensitive, and reliable method for the biomedical analysis and diagnosis of ZIKV is needed. Herein, a novel ZIKV liquid biopsy system was constructed via a dendritic Ru(bpy)3 2+-polymer-amplified electro-chemiluminescence (ECL) strategy. This system accomplished amplification-free analysis of ZIKV using a drop of blood, and simultaneously achieved a high sensitivity of 500 copies and superior specificity. This strategy adopted the humoral biomarker as the diagnostic index, which greatly simplified the analysis process, and established a nondestructive detection mode. Furthermore, the performance index for biomedical analysis of clinical ZIKV samples was investigated, and the results indicated that the dendritic Ru(bpy)3 2+-polymer-amplified ECL strategy reliably responded to ZIKV from the body fluid (blood, saliva, and urine). Hence, this system suitably met the strict clinical requirements for ZIKV detection and thus has the potential to serve as a new paradigm for the biomedical analysis and diagnosis of ZIKV.