Efficient SARS-CoV-2 infection antagonization by rhACE2 ectodomain multimerized onto the...

Area of Science:

• Biotechnology
• Nanomedicine
• Virology

Background:

• Traditional antiviral strategies require complementary tools.
• Lipid-based nanovesicles for receptor anchorage present manufacturing challenges.
• Alternative nanostructures are needed for viral receptor multimerization.

Purpose of the Study:

• To develop a semisynthetic self-assembling nanodecoy for SARS-CoV-2.
• To evaluate the efficacy of multimerized ACE2 receptors on nanoparticles against SARS-CoV-2.
• To assess the nanodecoy's potential for therapeutic applications.

Main Methods:

• Constructed a nanodecoy by multimerizing ACE2 ectodomain onto poly-avidin nanoparticles (ANANAS).
• Measured SARS-CoV-2 infection inhibition in human lung cells at various ACE2:nanoparticle ratios.
• Assessed ACE2:viral receptor-binding domain (RBD) affinity.
• Evaluated nanodecoy biodistribution and safety in mice via nasal instillation.

Main Results:

• Achieved 90% SARS-CoV-2 inhibition at nanomolar ACE2 concentrations with optimal ACE2 density (30:1 ratio).
• Demonstrated ten-fold higher potency against Wuhan and Omicron variants compared to monomeric ACE2.
• Identified optimal geometrical relationships for nanoparticle-virus interactions.
• Showed promising biodistribution and safety profiles for nasal delivery in vivo.

Conclusions:

• ANANAS-based nanodecoys offer a potent and adaptable platform for antiviral therapies.
• Optimized receptor density is crucial for effective nanodecoy-virus recognition.
• The nanodecoy system is suitable for nasal instillation and potentially applicable to other viral infections.