Engineering Elastin-Like Peptide-Based Nanoparticles displaying Variable Domain of the Heavy Chain of Heavy-Chain-Only Antibodies for SARS-CoV-2 Neutralization

Biomacromolecules. 2026 Feb 9;27(2):1446-1458. doi: 10.1021/acs.biomac.5c02042. Epub 2026 Jan 21.

Abstract

Elastin-like polypeptides (ELPs) are self-assembling recombinant biopolymers that can be precisely engineered to display functional targeting ligands. In this study, we developed ELP-based nanoparticles (NPs) displaying the variable domain of the heavy chain of heavy-chain-only antibodies (VHHs) targeting the SARS-CoV-2 spike protein. By tuning VHH selection, multivalency, and surface display density, we created targeted ELP NPs capable of blocking entry of spike-protein-presenting virus-like particles (VLPs) and live viruses, with subnanomolar IC50 values, significantly outperforming the monovalent VHH equivalents. Notably, optimizing multivalency and VHH density unlocked broad virus-neutralizing potency against multiple variants, including Omicron variants resistant against the monovalent VHH equivalents. Confocal imaging further revealed that VHH-ELP NPs formed aggregates with VLPs, enhancing uptake by M1 macrophages, suggesting potential for eliciting vaccinal effects. Overall, this work highlights the versatility of ELP NPs as a tunable antiviral platform and provides design principles for next-generation nanotherapeutics against evolving viral threats.

MeSH terms

  • Animals
  • Antibodies, Neutralizing* / chemistry
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Viral* / chemistry
  • Antibodies, Viral* / immunology
  • COVID-19 / immunology
  • COVID-19 / prevention & control
  • COVID-19 / virology
  • Elastin* / chemistry
  • Humans
  • Immunoglobulin Heavy Chains* / chemistry
  • Immunoglobulin Heavy Chains* / immunology
  • Nanoparticles* / chemistry
  • Peptides* / chemistry
  • SARS-CoV-2* / immunology
  • Spike Glycoprotein, Coronavirus / immunology
  • Vero Cells

Substances

  • Elastin
  • Spike Glycoprotein, Coronavirus
  • Antibodies, Neutralizing
  • Peptides
  • spike protein, SARS-CoV-2
  • Antibodies, Viral
  • Immunoglobulin Heavy Chains