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We demonstrate a potent and broad-spectrum strategy that employs hybrid biomaterials of Urumin (a host defense peptide) and a honeycomb (HC) DNA origami through spatially organized multivalent presentation for enhanced antiviral efficacy. Molecular dynamics simulations reveal that Urumin penetrates and destabilizes the hemagglutinin (HA) trimer core, disrupting influenza A viral (IAV) entry. Arranging Urumin in trimeric clusters on the HC enables potent multivalent binding to trimeric HAs on IAV, enhancing antiviral efficacy at nanomolar concentrations, \u223c1,000-fold more effective than free Urumin. In vitro assays confirm HC-Urumin outperforms free Urumin in blocking viral entry and preserving cell viability in more IAV subtypes. In vivo studies show that compared to free Urumin, HC-Urumin treatment reduces disease severity, preserves physiological behavior, and decreases mortality in infected mice, while maintaining virus-specific adaptive immune responses without altering humoral immunity. Our study offers an advanced and effective materials platform and strategy for broad-spectrum, low-dose intervention against human and animal IAVs, which can be adapted to combat other viruses by patterning corresponding host defense peptides on custom designed DNA nanostructures.<\/jats:p>","DOI":"10.1101\/2025.07.21.666049","type":"posted-content","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T20:05:21Z","timestamp":1753473921000},"source":"Crossref","is-referenced-by-count":0,"title":["Hybrid peptide DNA nanomaterials enable potent and broad-spectrum virus neutralization"],"prefix":"10.64898","author":[{"given":"Saurabh","family":"Umrao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhisek","family":"Dwivedy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Payton L","family":"Haak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhanush","family":"Gandavadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurie A","family":"Rund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3662-0006","authenticated-orcid":false,"given":"Chi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lifeng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinwei","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J","family":"Steelman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9930-3287","authenticated-orcid":false,"given":"Xing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025072815500859000_2025.07.21.666049v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2017.118"},{"key":"2025072815500859000_2025.07.21.666049v1.2","doi-asserted-by":"crossref","unstructured":"Ferreira, C. , M.-F.J. 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