Small Extracellular Vesicles with Engineered Receptors as Decoys for SARS-CoV-2Update 02.03.2023
February 15, 2023
Small Extracellular Vesicles with Engineered Receptors as Decoys for SARS-CoV-2
Scientists from Korea develop a novel therapeutic platform that could potentially pave the way for a cure for COVID-19
The SARS-CoV-2 virus infects us by binding with the angiotensin-converting enzyme 2 (ACE2) receptor on our cell surface. In a recent study, scientists tested whether small extracellular vesicles bearing engineered variants of ACE2 could act as decoys for the virus. Their experiments in cell cultures and live mice showcase the effectiveness of this approach in protecting cells from SARS-CoV-2, opening doors to potential therapeutic strategies against COVID-19 and other viral diseases.
Caption: Small extracellular vesicles bearing specially engineered variants of the ACE2 receptor could be used as decoys for SARS-CoV-2 viral particles, keeping them away from the actual ACE2 receptor on our cells and greatly reducing their infectivity.
Courtesy: Kateryna kon from Shutterstock.
The ongoing COVID-19 pandemic has claimed hundreds of millions of lives despite our best efforts to mitigate the spread of the disease through social distancing, improved hygiene, and vaccination. This is primarily because we are still lacking an effective cure for the disease once the infection sets in. The best we can do in such a scenario is provide supportive care as the body fights the infection by itself.
Scientists have been focusing on the angiotensin-converting enzyme 2 (ACE2) receptor, the cell membrane protein that binds to the spike (S) protein enveloping SARS-CoV-2 and grants it access to the interior of the cell. One possible way to neutralize the virus is by injecting the patient with a soluble variant of ACE2, called “sACE2,” such that sACE2 would work as a decoy receptor, binding to the S proteins before they can bind to the real ACE2 receptor on the cell membrane. Although clinical trials of sACE2 as a therapeutic drug are ongoing, the relatively short half-life of this protein inside the body is a likely limitation, as it would necessitate stronger and more frequent doses.
To address this problem, a research team including Dr. Junhyung Cho from the National Institute of Health in Korea are testing a different approach for administering a more stable form of sACE2, namely by embedding it on small extracellular vesicles (sEVs), tiny bubble-like lipid structures that cells normally use for chemical signaling. As detailed in their study published in the , sACE2 can be combined with a modified CD9 protein (used as a scaffold) and “displayed” on artificially produced sEVs. “Owing to their lipophilic nature and excellent stability, sEVs can not only circulate in the blood but are also able to reach different cell populations, which is indicative of their potential for targeting specific cells,” explains Dr. Cho. “Together with their longer half-lives, this would allow for a greater in vivo efficacy of sEV-bound sACE2 compared to the bare sACE2 protein.”
In their work, the team first tested their strategy via an immunoprecipitation assay that measured how well sEVs displaying the CD9-sACE2 could bind to different variants of the S protein, including those found in the Beta and Delta strains. Further, in addition to testing for the wild-type sACE2 derived from the human protein, they also tested two different sACE2 variants specifically engineered to show a higher affinity for the S protein.
The team then employed cell cultures to assess whether sEVs displaying either sACE2 or its variants could provide protection against SARS-CoV-2. They found that sEVs bearing the engineered variants considerably reduce the infectivity of SARS-CoV-2, even at low concentrations. Moreover, the team employed genetically modified mice expressing the ACE2 protein to further verify their findings. To their delight, the mice model treated with sEVs containing the superior sACE2 variant showed reduced viral burden in the lungs along with lower weight loss and inflammatory response.
Together, the results of this study highlight the potential of sEVs as a revolutionary platform for delivering anti-COVID-19 drugs. In this regard, Dr. Cho highlights, “The sEVs containing sACE2 can be developed as a broad-spectrum corona treatment that is not affected by the S protein mutations, which are likely to continue.” Moreover, using sEVs to treat COVID-19 could set a precedent for treating other viral diseases with a similar strategy, including influenza and MERS-CoV.
Looks like we may finally be on the verge of finding a cure for COVID-19!
Title of original paper
Hark Kyun Kim1, Junhyung Cho2, Eunae Kim1, Junsik Kim1, Jeong-Sun Yang2, Kyung-Chang Kim2, Joo-Yeon Lee2, Younmin Shin2, Leon F. Palomera1, Jinsu Park1, Seung Hyun Baek1, Han-Gyu Bae1, Yoonsuk Cho1, Jihoon Han1, Jae Hoon Sul1, Jeongmi Lee1, Jae Hyung Park3,4,5,7, Yong Woo Cho6,7, Wonsik Lee1, and Dong-Gyu Jo1,3,4,7
Engineered small extracellular vesicles displaying ACE2 variants on
the surface protect against SARS-CoV-2 infection
Journal of Extracellular Vesicles
1School of Pharmacy, Sungkyunkwan University
2Division of Emerging Viral Diseases and Vector Research, Centre for Infectious Diseases Research, Korea National Institute of Health, Korea Centres for Disease Control and Prevention Agency
3Biomedical Institute for Convergence, Sungkyunkwan University
4Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University
5School of Chemical Engineering, Sungkyunkwan University, Suwon
6Department of Materials Science and Chemical Engineering, Hanyang University ERICA
About National Institute of Health in Korea
The Korea National Institute of Health (KNIH), one of the major operating components of the Ministry of Health and Welfare, leads the nation’s medical research. Over the past seven decades, the KNIH has made unwavering efforts to enhance the public’s health and innovate biomedical research. The KNIH seeks to eradicate diseases and make people healthier. The KNIH establishes a scientific basis and evidence underlying health policy as well as provides national research infrastructures. We also promote public health research. To this end, we make efforts to enrich a health research environment by granting funds to research projects and keeping our resources, data, and facilities more open and accessible to researchers.
About Dr. Junhyung Cho
Junhyung Cho works at the National Institute of Infectious Diseases, Emerging Virus and Vector Research Division of the National Institute of Health in Korea. His research focuses on establishing high-throughput screening platform technologies and the discovery of candidate therapeutic materials for new variants of viruses, including SARS-CoV-2. In addition, Emerging Virus and Vector Research Division carries out various other related tasks, such as providing development and commercialization support for antibody treatments and antiviral drugs for high-risk viral infectious diseases like COVID-19, MERS, and Ebola.