COVID-19 News: Researchers Develop Cell Membrane Nanoparticles Rich In ACE2 To Inhibit SARS-CoV-2 Entry Into Host Cells
: Researchers from Chongqing, China have developed membrane nanoparticles from ACE2-rich cells with a potent capability to block potential SARS-CoV-2 infections.
When developing therapeutic drugs or agents, one of the prime targets for researchers is the angiotensin-converting enzyme 2 (ACE2), the primary receptor for SARS-CoV-2 spike glycoprotein (S1 subunit), which mediates viral entry into host cells.
Prior research has already shown that ACE2 is pervasive in lung alveolar epithelial cells, renal tubular epithelium, and enterocytes of the small intestine, as demonstrated by large-scale immunohistochemistry, transcriptomics, and proteomics analysis.
As a result of the natural positioning of ACE2 on the cell membrane, and considering how membrane with active ingredients can be used to expand the antiviral arsenal, the study team from the Third Military Medical University in Chongqing attempted to apply the membrane of human cells abundant with ACE2 to prevent SARS-CoV-2 infections.
The study findings are published on a preprint server and is yet to have been peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.08.12.247338v1
During the research, cell membrane-based nanoparticles were designed to overcome the shortcoming of the uneven membrane size in the living organism.
Simply by taking advantage of functional elements on human platelet membranes, the study team developed cell membrane-based nanoparticles capable of targeting tumor cells and immune escape.
The team chose the membrane of human embryonic kidney-239T cells that typically express high amounts of human ACE2 receptor (HEK-293T-hACE2) to prepare cell membrane-based nanoparticles after analyzing the ACE2 content in five different human cells.
The HEK-293T-hACE2 cells were processed by repeated freezing and thawing in order to separate the membrane, which was broken by sonication, and subsequently applied to fabricate cell membrane-based nanoparticles using a classical extrusion method.
In order to assess the bioactivity of HEK-293T-hACE2 nanoparticles, the team had initially immobilized biotinylated SARS-CoV-2 S1-RBD on Sartorius streptavidin biosensors and then analyzed the recruitment of cell membrane-based nanoparticles by biolayer interferometry.
In addition, the antiviral activity and mechanism of action of this nanomaterial were explored in depth with the use of pseudovirus neutralization assay, spike adhesion experiment, as well as proteomics analysis. Finally, the toxicity of HEK-293T-hACE2 nanoparticles has been evaluated by a mouse experiment.
The exact content of ACE2 in HEK-293T-hACE2 nanoparticles (as determined by the enzyme-linked immunosorbent assay or ELISA) was 265.1 ng/mg, which was 3.2-fold higher than that in HEK-293T nanoparticles.
With targeted inhibition at play, the HEK-293T-hACE2 nanoparticles bound to SARS-CoV-2 S1 and subsequently blocked the viral ligand adhering to human renal tubular epithelial cells in a dose-dependent manner. The effect of SARS-CoV-2 S1 on cellular metabolism was suppressed by HEK-293T-hACE2 na
noparticles as well.
Co-researcher Professor Dr Jinghong Zhao from the department of Nephrology, Xinqiao Hospital, Third Military Medical University-Chongqing told Thailand Medical News, "Interestingly, SARS-CoV-2 S1 can translocate to the cytoplasm and affect the cell metabolism, which is also inhibited by HEK-293T-hACE2 nanoparticles. This biocompatible membrane nanomaterial is sufficient to block the adherence of SARS-CoV-2 D614G-S1 mutant to sensitive cells.”
In the study it was found that as a result of the spike recruitment, the HEK-293T-hACE2 nanoparticles adsorbed SARS-CoV-2 S pseudovirions on the material surface. These nanoparticles successfully blocked viral entry into the cytoplasm enabling a rather encouraging type of host cell protection from the viral infection.
Dr Zhao added, "This research demonstrates an efficient nano-antagonist that can be easily prepared in general laboratories against SARS-CoV-2, which is a feasible solution to resolve the shortage of effective measures to treat COVID-19"
Furthermore the study demonstrated that the overexpression of membrane receptors does not affect the biocompatibility of human cell membrane-based nanoparticles, while the demonstrated lack of toxicity in experimental animals laid a solid foundation for the application of HEK-293T-hACE2 nanoparticles as an antagonist to SARS-CoV-2.
Currently there is an acute lack of effective measures to treat COVID-19, this novel type of biocompatible and easy-to-achieve nano-antagonist may be a rather convenient therapeutic candidate for halting SARS-CoV-2 spread but further studies and research and clinical trials are warranted.
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