Rational engineering of single-chain polypeptides into protein-only, BBB-targeted nanoparticles

Naroa Serna, María Virtudes Céspedes, Paolo Saccardo, Zhikun Xu, Ugutz Unzueta, Patricia Álamo, Mireia Pesarrodona, Alejandro Sánchez-Chardi, Mónica Roldán, Ramón Mangues, Esther Vázquez, Antonio Villaverde, Neus Ferrer-Miralles

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)


© 2016 Elsevier Inc. A single chain polypeptide containing the low density lipoprotein receptor (LDLR) ligand Seq-1 with blood-brain barrier (BBB) crossing activity has been successfully modified by conventional genetic engineering to self-assemble into stable protein-only nanoparticles of 30 nm. The nanoparticulate presentation dramatically enhances in vitro, LDLR-dependent cell penetrability compared to the parental monomeric version, but the assembled protein does not show any enhanced brain targeting upon systemic administration. While the presentation of protein drugs in form of nanoparticles is in general advantageous regarding correct biodistribution, this principle might not apply to brain targeting that is hampered by particular bio-physical barriers. Irrespective of this fact, which is highly relevant to the nanomedicine of central nervous system, engineering the cationic character of defined protein stretches is revealed here as a promising and generic approach to promote the controlled oligomerization of biologically active protein species as still functional, regular nanoparticles.
Original languageEnglish
Pages (from-to)1241-1251
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Publication statusPublished - 1 Jul 2016


  • Biodistribution
  • LDLR
  • Nanoparticles
  • Protein engineering
  • Self-assembling


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