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What are nano-bubbles and how they block SAR-COV 2 infection

In preclinical studies, researchers from Northwestern Medicine and The University of Texas MD Anderson Cancer Center discovered natural nano-bubbles containing the ACE2 protein (evACE2) in the blood of COVID-19 patients, and found that these nano-sized particles can block infection from broad strains of SARS-CoV-2 virus.

The evACE2 functions as a decoy in the body and might be used as a therapy for the prevention and treatment of existing and future SARS-CoV-2 strains, as well as future coronaviruses, according to the researchers. Once established as a therapeutic substance, it can be used as a biological treatment for humans with low side effects.

The research is the first to show that evACE2 proteins can combat novel SARS-CoV-2 variants with the same or higher efficacy than inhibiting the original strain. These evACE2 micro bubbles were discovered in human blood as a natural anti-viral response, according to the researchers. The higher the amounts of evACE2 discovered in the patient's blood, the more serious the condition.

The study was  published in the journal Nature Communications.

Dr. Huiping Liu, an associate professor of pharmacology and medicine at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician, said, "Whenever a new mutant strain of SARS-CoV-2 emerges, the original vaccine and therapeutic antibodies may lose power against alpha, beta, delta, and the most recent omicron variants."

"However, the beauty of evACE2 is its ability to prevent broad strains of coronaviruses from infecting people, including the current SARS-CoV-2 and even future SARS coronaviruses."

"When administered to the airway via droplets, our mice trials reveal the therapeutic potential of evACE2 in preventing or blocking SARS-CoV-2 infection," Liu added.

The evACE2 proteins are nanoparticle-sized lipid (fat) bubbles that express the ACE2 protein, acting as grips for the virus to grab. The SARS-CoV-2 virus is lured away from the ACE2 protein on cells by these bubbles, which is how the virus infects cells. Instead of cellular ACE2, the virus spike protein grabs the handle of evACE2, stopping it from entering the cell. The virus will either float around harmlessly or be removed by a macrophage immune cell once it has been trapped. It can no longer cause infection at that moment.

Dr. Raghu Kalluri, chair of cancer biology at MD Anderson, said, "The key takeaway from this study is the identification of naturally occurring extracellular vesicles in the body that express the ACE2 receptor on their surface and serve as part of the normal adaptive defence against COVID-19-causing viruses." "Based on this, we've discovered a way to use this natural defence as a new possible therapeutic for this deadly infection."

A continually changing virus, SARS-CoV-2, has expanded and challenged the COVID-19 epidemic. The changing target of pathogenic coronavirus, which constantly changes into new virus strains (variants) with mutations, is one of the most difficult difficulties. Due to vaccine inefficiencies and resistance to therapeutic monoclonal antibodies, these novel viral strains have diverse alterations in the viral spike protein, resulting in high infection rates and greater breakthroughs.

"It's still critical to find new therapies," Liu said. "We believe evACE2 will be able to meet the challenges and fight broad strains of SARS-CoV-2 and future emerging coronaviruses to protect the immunocompromised (at least 2.7 percent of U.S. adults), unvaccinated (94 percent in low-income countries and more than 30 percent in the United States), and even vaccinated from breakthrough infections."

A patent on evACE2 has been filed by Northwestern University and MD Anderson Cancer Center. The goal is to work with business partners to create evACE2 as a biological therapeutic solution for COVID-19 prevention and treatment (nasal spray or injectable therapies). Exomira, a startup company founded by Liu and another co-senior author, Deyu Fang of Northwestern's pathology department, will take this patent and develop evACE2 as a treatment.

This work was co-authored by a group of more than 30 people. Lamiaa El-Shennawy, Andrew Hoffmann, and Nurmaa Dashzeveg, all of the Liu lab at Northwestern, and Kathleen McAndrews, of MD Anderson's Raghu Kalluri lab, are among the four lead co-first authors.


Lamiaa El-Shennawy, Andrew D. Hoffmann, Nurmaa Khund Dashzeveg, Kathleen M. McAndrews, Paul J. Mehl, Daphne Cornish, Zihao Yu, Valerie L. Tokars, Vlad Nicolaescu, Anastasia Tomatsidou, Chengsheng Mao, Christopher J. Felicelli, Chia-Feng Tsai, Carolina Ostiguin, Yuzhi Jia, Lin Li, Kevin Furlong, Jan Wysocki, Xin Luo, Carolina F. Ruivo, Daniel Batlle, Thomas J. Hope, Yang Shen, Young Kwang Chae, Hui Zhang, Valerie S. LeBleu, Tujin Shi, Suchitra Swaminathan, Yuan Luo, Dominique Missiakas, Glenn C. Randall, Alexis R. Demonbreun, Michael G. Ison, Raghu Kalluri, Deyu Fang, Huiping Liu. Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2. Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-021-27893-2

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