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Among these, influenza viruses play a key role, as they potentially cause severe respiratory distress, representing a major threat to public health. Our study aims to develop new broad\u2010spectrum antivirals against influenza to improve the response to viral disease outbreaks. We engineered macromolecules (named CD\u2010SA) consisting of a \u03b2\u2010cyclodextrin scaffold modified with hydrophobic linkers in the primary face, onto which unitary sialic acid epitopes are covalently grafted to mimic influenza virus\u2212host receptors. We assessed the antiviral efficacy, mechanism of action, and the genetic barrier to resistance of this compound against influenza in vitro, ex vivo, and in vivo. We demonstrated that CD\u2010SA, with a unitary SA, without extensive polysaccharides or specific connectivity, acts as a potent virucidal antiviral against several human influenza A and B viruses. Additionally, CD\u2010SA displayed antiviral activity against SARS\u2010CoV\u20102, a virus that also relies on sialic acid for attachment. We then assessed the genetic barrier to resistance for CD\u2010SA. While resistance emerged after six passages with CD\u2010SA alone, the virus remained sensitive through eight passages when co\u2010treated with interferon\u2010\u03bb1 (IFN \u03bb1). Finally, we completed the characterization of the antiviral activity by conducting both ex vivo and in vivo studies, demonstrating a potent antiviral effect in human airway epithelia and in a mouse model of infection, higher than that of Oseltamivir, a currently approved anti\u2010influenza antiviral. The findings presented in this study support the potential therapeutic utility of a novel \u03b2\u2010cyclodextrin\u2010based nanomaterial for the treatment of influenza infections and potentially other sialic acid\u2010dependent viruses.<\/jats:p>","DOI":"10.1002\/jmv.70101","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T06:16:09Z","timestamp":1733120169000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Development of Broad\u2010Spectrum \u03b2\u2010Cyclodextrins\u2010Based Nanomaterials Against Influenza Viruses"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0713-1105","authenticated-orcid":false,"given":"Arnaud Charles\u2010Antoine","family":"Zwygart","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Medicine University of Geneva Geneva 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