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.

Altered oral and gut microbiota and its association with SARS-CoV-2 viral load in COVID-19 patients during hospitalization.

The human oral and gut commensal microbes play vital roles in the development and maintenance of immune homeostasis, while its association with susceptibility and severity of SARS-CoV-2 infection is barely understood. In this study, we investigated the dynamics of the oral and intestinal flora before and after the clearance of SARS-CoV-2 in 53 COVID-19 patients, and then examined their microbiome alterations in comparison to 76 healthy individuals. A total of 140 throat swab samples and 81 fecal samples from these COVID-19 patients during hospitalization, and 44 throat swab samples and 32 fecal samples from sex and age-matched healthy individuals were collected and then subjected to 16S rRNA sequencing and viral load inspection. We found that SARS-CoV-2 infection was associated with alterations of the microbiome community in patients as indicated by both alpha and beta diversity indexes. Several bacterial taxa were identified related to SARS-CoV-2 infection, wherein elevated Granulicatella and Rothia mucilaginosa were found in both oral and gut microbiome. The SARS-CoV-2 viral load in those samples was also calculated to identify potential dynamics between COVID-19 and the microbiome. These findings provide a meaningful baseline for microbes in the digestive tract of COVID-19 patients and will shed light on new dimensions for disease pathophysiology, potential microbial biomarkers, and treatment strategies for COVID-19.

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.