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It contains spike proteins on its envelope that bind to human angiotensin\u2010converting enzyme 2 (hACE2) expressed on airway cells, enabling entry of the virus, and causing infection. The soluble form of hACE2 binds SARS\u2010CoV\u20102 spike protein, prevents viral entry into target cells, and ameliorates lung injury; however, its short half\u2010life limits therapeutic utilities. Here, synthetic mRNA is engineered to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. A novel lipid nanoparticle (LNP) is used for packaging and delivering mRNA to cells to produce hsACE2 proteins. Intravenously administered LNP delivers mRNA to hepatocytes, leading to the production of circulatory hsACE2 initiated within 2\u00a0h and sustained over several days. Inhaled LNP results in lung transfection and secretion of mucosal hsACE2 to lung epithelia, the primary site of entry and pathogenesis for SARS\u2010CoV\u20102. Furthermore, mRNA\u2010generated hsACE2 binds to the receptor\u2010binding domain of the viral spike protein. Finally, hsACE2 effectively inhibits SARS\u2010CoV\u20102 and its pseudoviruses from infecting host cells. The proof of principle study shows that mRNA\u2010based nanotherapeutics can be potentially deployed to neutralize SARS\u2010CoV\u20102 and open new treatment opportunities for coronavirus disease 2019 (COVID\u201019).<\/jats:p>","DOI":"10.1002\/advs.202202556","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T21:29:38Z","timestamp":1665437378000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Rapid Generation of Circulating and Mucosal Decoy Human ACE2 using mRNA Nanotherapeutics for the Potential Treatment of SARS\u2010CoV\u20102"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1697-5107","authenticated-orcid":false,"given":"Jeonghwan","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University  Portland OR 97201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6249-2328","authenticated-orcid":false,"given":"Antony","family":"Jozic","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University  Portland OR 97201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anindit","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University  Portland OR 97201 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University  Portland OR 97201 USA"},{"name":"High\u2010Throughput Screening Services Laboratory College of Pharmacy Oregon State University  Corvallis OR 97331 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Chiem","sequence":"additional","affiliation":[{"name":"Disease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute  San Antonio TX 78227 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Siddiqur Rahman","family":"Khan","sequence":"additional","affiliation":[{"name":"Disease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute  San Antonio TX 78227 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7702-5941","authenticated-orcid":false,"given":"Jordi B.","family":"Torrelles","sequence":"additional","affiliation":[{"name":"Disease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute  San Antonio TX 78227 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7084-0804","authenticated-orcid":false,"given":"Luis","family":"Martinez\u2010Sobrido","sequence":"additional","affiliation":[{"name":"Disease Prevention and Intervention and Population Health Programs Texas Biomedical Research Institute  San Antonio TX 78227 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1071-0500","authenticated-orcid":false,"given":"Gaurav","family":"Sahay","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences College of Pharmacy Robertson Life Sciences Building Oregon State University  Portland OR 97201 USA"},{"name":"Department of Biomedical Engineering Robertson Life Sciences Building Oregon Health &amp; 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