Self-Assembled Nanobodies as Selectively Targeted, Nanostructured, and Multivalent Materials

Laura Sánchez-García, Eric Voltà-Durán, Eloi Parladé, Elisa Mazzega, Alejandro Sánchez-Chardi, Naroa Serna, Hèctor López-Laguna, Mara Mitstorfer, Ugutz Unzueta, Esther Vázquez, Antonio Villaverde*, Ario De Marco

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Nanobodies represent valuable tools in advanced therapeutic strategies but their small size (∼2.5 × ∼4 nm) and limited valence for interactions might pose restrictions for in vivo applications, especially regarding their modest capacity for multivalent and cooperative interaction. In this work, modular protein constructs have been designed, in which nanobodies are fused to protein domains to provide further functionalities and to favor oligomerization into stable self-assembled nanoparticles. The nanobody specificity for their targets is maintained in such supramolecular complexes. Also, their diameter around 70 nm and multivalent interactivity should favor binding and penetrability into target cells via solvent-exposed receptor. These concepts have been supported by unrelated nanobodies directed against the ricin toxin (A3C8) and the Her2 receptor (EM1), respectively, that were modified with the addition of a reporter protein and a hexa-histidine tag at the C-terminus that promotes self-assembling. The A3C8-based nanoparticles neutralize the ricin toxin efficiently, whereas the EM1-based nanoparticles enable to selective imaging Her2-positive cells. These findings support the excellent extracellular and intracellular functionality of nanobodies organized in form of oligomeric nanoscale assemblies.

Original languageEnglish
Pages (from-to)29406-29415
Number of pages10
JournalACS Applied Materials and Interfaces
Volume13
Issue number25
DOIs
Publication statusPublished - 30 Jun 2021

Keywords

  • biomaterials
  • controlled delivery
  • nanobodies
  • nanoparticles
  • ricin
  • self-assembling

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