{"doi":"10.1002/anie.202519203","title":"Surface Avidity of Anionic Polypeptide Coatings on Layer‐by‐Layer Nanoparticles Target Cancer‐Associated Amino Acid Transporters","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.","journal":"Angewandte Chemie International Edition","year":2025,"id":535874,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9474,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":103471,"name":"Margaret M. Billingsley","orcid":"0000-0003-4499-9066","position":1,"is_corresponding":false},{"id":1254544,"name":"Ezra Gordon","orcid":"0009-0002-6023-2789","position":2,"is_corresponding":false},{"id":1255004,"name":"Andrew J. Pickering","orcid":null,"position":3,"is_corresponding":false},{"id":1054031,"name":"Eva Cai","orcid":"0009-0006-0024-6969","position":4,"is_corresponding":false},{"id":1420596,"name":"Gonzalo J. Esparza","orcid":null,"position":5,"is_corresponding":false},{"id":1420085,"name":"Mae L. Pryor","orcid":"0000-0002-7211-8150","position":6,"is_corresponding":false},{"id":1420086,"name":"Alexander D. Stoneman","orcid":"0000-0002-5662-6542","position":7,"is_corresponding":false},{"id":1073931,"name":"Aidan Kindopp","orcid":"0009-0002-7560-8611","position":8,"is_corresponding":false},{"id":236278,"name":"Darrell J. Irvine","orcid":"0000-0002-8637-1405","position":9,"is_corresponding":false},{"id":263335,"name":"Paula T. Hammond","orcid":"0000-0002-9835-192X","position":10,"is_corresponding":false},{"id":399197,"name":"Ivan S. Pires","orcid":"0000-0002-4035-0027","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41431241","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}