Surface Avidity of Anionic Polypeptide Coatings on Layer‐by‐Layer Nanoparticles Target Cancer‐Associated Amino Acid Transporters
Abstract
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 (NP) 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.
Article Details
Authors (11)
Ivan S. Pires
Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology 500 Main Street Cambridge Massachusetts 02139 USA
Margaret M. Billingsley
Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology 500 Main Street Cambridge Massachusetts 02139 USA
Ezra Gordon
Department of Chemical Engineering Massachusetts Institute of Technology 21 Ames Street Cambridge Massachusetts 02139 USA
Andrew J. Pickering
Department of Chemical Engineering
Eva Cai
Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology 500 Main Street Cambridge Massachusetts 02139 USA
Gonzalo J. Esparza
Department of Chemical Engineering Massachusetts Institute of Technology 21 Ames Street Cambridge Massachusetts 02139 USA
Mae L. Pryor
Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology 500 Main Street Cambridge Massachusetts 02139 USA
Alexander D. Stoneman
Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology 500 Main Street Cambridge Massachusetts 02139 USA
Aidan Kindopp
Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology 500 Main Street Cambridge Massachusetts 02139 USA
Darrell J. Irvine
Paula T. Hammond
Department of Chemical Engineering