DNA Nanostructure-Templated Multivalency Enables Broad-Spectrum Virus Inhibition

Area of Science:

• Biotechnology
• Virology
• Nanotechnology

Background:

• Influenza A viruses (IAVs) rapidly evolve, challenging current antiviral strategies.
• Monomeric nanobodies and aptamers targeting hemagglutinin (HA) show limited efficacy due to monomeric binding.
• Broadly effective and modular therapeutic platforms are needed.

Purpose of the Study:

• To develop a programmable antiviral platform using designer DNA nanostructures.
• To engineer multivalency and precise ligand display for enhanced viral neutralization.
• To evaluate the efficacy of geometry-matched nanostructures against IAVs.

Main Methods:

• Synthesis of honeycomb-shaped designer DNA nanostructures (HC-DDN) displaying HA-targeting ligands (nanobodies and aptamers).
• Formation of trimeric clusters to match native HA trimer geometry.
• In vitro and in vivo evaluation using murine and porcine IAV models (H1N1, H3N2).

Main Results:

• Both HC-Nanobody and HC-Aptamer constructs significantly outperformed free ligands in viral neutralization and cytoprotection.
• HC-Nanobody achieved >99% inhibition of viral entry and 35-45% increase in cell viability in murine models.
• High antiviral efficacy (>97% inhibition) and improved cell viability (30-55%) were observed in a porcine IAV model, demonstrating cross-species performance.

Conclusions:

• Geometry-matched multivalency significantly enhances viral neutralization and antiviral efficacy.
• The HC-DDN platform provides a rational blueprint for designing broad-spectrum antivirals against rapidly evolving respiratory viruses.
• This approach holds promise for developing next-generation therapeutics against influenza and other viral pathogens.