Engineering non-antibody human proteins as efficient scaffolds for selective, receptor-targeted drug delivery

Naroa Serna, Victor Pallarès, Ugutz Unzueta, Annabel Garcia-Leon, Eric Voltà-Durán, Alejandro Sánchez-Chardi, Eloi Parladé, Ariana Rueda, Isolda Casanova, Aïda Falgàs, Lorena Alba-Castellón, Jorge Sierra, Antonio Villaverde, Esther Vázquez, Ramón Mangues

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)


Self-assembling non-immunoglobulin scaffold proteins are a promising class of nanoscale carriers for drug delivery and interesting alternatives to antibody-based carriers that are not sufficiently efficient in systemic administration. To exploit their potentialities in clinics, protein scaffolds need to be further tailored to confer appropriate targeting and to overcome their potential immunogenicity, short half-life in plasma and proteolytic degradation. We have here engineered three human scaffold proteins as drug carrier nanoparticles to target the cytokine receptor CXCR4, a tumoral cell surface marker of high clinical relevance. The capability of these scaffolds for the selective delivery of Monomethyl auristatin E has been comparatively evaluated in a disseminated mouse model of human, CXCR4+ acute myeloid leukemia. Monomethyl auristatin E is an ultra-potent anti-mitotic drug used against a range of hematological neoplasias, which because of its high toxicity is not currently administered as a free drug but as payload in antibody-drug conjugates. The protein nanoconjugates generated here offer a collective strength of simple manufacturing process, high proteolytic and structural stability and multivalent ligand receptor interactions that result in a highly efficient and selective delivery of the payload drug and in a potent anticancer effect. The approach shown here stresses this class of human scaffold proteins as promising alternatives to antibodies for targeted drug delivery in the rapidly evolving drug development landscape.

Original languageEnglish
Pages (from-to)277-287
Number of pages11
Publication statusPublished - Mar 2022


  • Animals
  • Antineoplastic Agents
  • Drug Carriers
  • Drug Delivery Systems
  • Humans
  • Immunoconjugates/chemistry
  • Mice
  • Nanoconjugates
  • Proteins
  • Scaffold proteins
  • Drug delivery
  • Biomaterials
  • Nanoparticles
  • Self-assembling


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