2. Academic Validation
  3. Surface avidity of anionic polypeptide coatings target nanoparticles to cancer-associated amino acid transporters

Surface avidity of anionic polypeptide coatings target nanoparticles to cancer-associated amino acid transporters

  • bioRxiv. 2025 Jul 31:2025.07.28.667320. doi: 10.1101/2025.07.28.667320.
Ivan S Pires 1 2,  Margaret M Billingsley 1,  Ezra Gordon 2,  Andrew J Pickering 1 2,  Eva Cai 1 3,  Gonzalo J Esparza 2,  Mae L Pryor 1 4,  Alexander D Stoneman 1 2,  Darrell J Irvine 1 5 4 6 7,  Paula T Hammond 1 2
Affiliations

Affiliations

  • 1 Koch Institute for Integrative Cancer Research, MIT.
  • 2 Department of Chemical Engineering, MIT.
  • 3 Harvard-MIT Health Sciences and Technology, MIT.
  • 4 Department of Materials Science and Engineering, MIT.
  • 5 Department of Biological Engineering, MIT.
  • 6 Ragon Institute of MGH, MIT and Harvard University.
  • 7 Howard Hughes Medical Institute.
PMID: 40766676 DOI: 10.1101/2025.07.28.667320
Abstract

Tumor-targeted drug delivery enhances therapeutic efficacy while minimizing toxicity. Layer-by-layer nanoparticles (LbL-NPs) coated with anionic polypeptides selectively bind to Cancer cells, though the mechanisms have been unclear. Here, we integrated in silico and in vitro approaches-including gene expression analysis, receptor inhibition, and AI-based protein modeling-to show that poly(L-glutamate) (PLE)-coated LbL-NPs bind with high avidity to SLC1A5, a glutamine transporter overexpressed in Cancer. We also discovered that PLE clusters SLC1A5 on the cell membrane, promoting prolonged cell surface retention. Poly(L-aspartate) (PLD)-coated NPs similarly bind SLC1A5 but also interact with faster internalizing transporters of anionic Amino acids. Correlation analyses across Cancer cell lines confirmed a strong link between transporter expression and nanoparticle association. These findings demonstrate that dense glutamate or aspartate presentation through electrostatically adsorbed polypeptides enables selective targeting of overexpressed transporters, providing a mechanistic framework for receptor-targeted delivery that leverages metabolic characteristics of a range of solid tumor types.

Keywords

cancer; drug delivery; layer-by-layer; nanoparticles; polymer coating; targeting.

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