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bioRxiv · 10.1101/2025.07.21.666049

Hybrid peptide DNA nanomaterials enable potent and broad-spectrum virus neutralization

Umrao, S.·Dwivedy, A.·Haak, P. L.·Gandavadi, D.·Rund, L.·Chen, C.·Zhou, L.·Duan, J.·Fang, Y.·Steelman, A.·Wang, X.
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Abstract

The continued emergence of antigenic drift and drug-resistant viral strains highlights the need for antiviral strategies that deliver robust efficacy, broad subtype coverage, and minimal off-target toxicity. 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, [~]1,000-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.

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Umrao, S., Dwivedy, A., Haak, P. L., Gandavadi, D., Rund, L., Chen, C., Zhou, L., Duan, J., Fang, Y., Steelman, A., Wang, X.. 2025-07-25. Hybrid peptide DNA nanomaterials enable potent and broad-spectrum virus neutralization. https://doi.org/10.1101/2025.07.21.666049

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