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These viruses have added to the existing respiratory infection burden along with respiratory syncytial virus (RSV) and influenza. There are limited therapies for respiratory viruses, with broad-spectrum treatment remaining an unmet need. Since gut fermentation of fiber produces short-chain fatty acids (SCFA) with antiviral potential, developing a fatty acid-based broad-spectrum antiviral was investigated. Molecular docking of fatty acids showed \u03b1-linolenic acid (ALA) is likely to interact with CoV-2-S, NL63-CoV-S, and RSV-F, and an ALA-containing liposome interacted with CoV-2 directly, degrading the particle. Furthermore, a combination of ALA and a SCFA-acetate synergistically inhibited CoV2-N expression and significantly reduced viral plaque formation and IL-6 and IL-1\u03b2 transcript expression in Calu-3 cells, while increasing the expression of IFN-\u03b2. A similar effect was also observed in RSV-infected A549 cells. Moreover, mice infected with a murine-adapted SARS-CoV-2 (MA10) and treated with an ALA\u2013liposome encapsulating acetate showed significant reductions in plaque-forming units present in lung tissue and in infection-associated lung inflammation and cytokines. Taken together, these results demonstrate that the ALA liposome-encapsulating acetate can be a promising broad antiviral therapy against respiratory infections.<\/jats:p>","DOI":"10.3390\/v15071429","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T02:05:02Z","timestamp":1687745102000},"page":"1429","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Acetate-encapsulated Linolenic Acid Liposomes Reduce SARS-CoV-2 and RSV Infection"],"prefix":"10.3390","volume":"15","author":[{"given":"Andrew R.","family":"McGill","sequence":"first","affiliation":[{"name":"James A. Haley Veterans Hospital, Tampa, FL 33612, USA"},{"name":"Center for Research and Education in Nanobioengineering, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"},{"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Markoutsa","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Tampa, FL 33612, USA"},{"name":"Center for Research and Education in Nanobioengineering, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"},{"name":"Taneja College of Pharmacy Graduate Programs, MDC30, 12908 USF Health Drive, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthick","family":"Mayilsamy","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Tampa, FL 33612, USA"},{"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Green","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Tampa, FL 33612, USA"},{"name":"Center for Research and Education in Nanobioengineering, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"},{"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavya","family":"Sivakumar","sequence":"additional","affiliation":[{"name":"Taneja College of Pharmacy Graduate Programs, MDC30, 12908 USF Health Drive, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhra","family":"Mohapatra","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Tampa, FL 33612, USA"},{"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-0681","authenticated-orcid":false,"given":"Shyam S.","family":"Mohapatra","sequence":"additional","affiliation":[{"name":"James A. Haley Veterans Hospital, Tampa, FL 33612, USA"},{"name":"Center for Research and Education in Nanobioengineering, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA"},{"name":"Taneja College of Pharmacy Graduate Programs, MDC30, 12908 USF Health Drive, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mannino, F., Bitto, A., and Irrera, N. (2020). 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