Amino acid-based zwitterionic interfaces for transporter-mediated drug delivery

Whereas antifouling hydration is a general property shared by several classes of zwitterionic materials, amino acid-derived interfaces offer the conditional possibility of coupling such interfacial hydration with recognition by endogenous nutrient transporters. When appropriately presented, amino acid-derived motifs may reduce nonspecific interactions during circulation while promoting transporter-dependent interactions with cancer cells, tumor-associated endothelium, or brain capillary endothelial cells. However, these two functions are mechanistically distinct and require independent experimental validation. This review critically examines amino acid transporter-targeted prodrugs, polymer conjugates, and nanoparticle systems, with emphasis on ligand identity and conjugation, multivalency, ligand density, spacer architecture, conditional ligand presentation, and off-target transporter expression. EPR- and ATR-related processes are treated as potentially coexisting delivery steps rather than mutually exclusive mechanisms. We further propose standardized reporting frameworks for ligand presentation and stealth behavior and a graded evidence hierarchy for transporter involvement. Representative applications in cancer therapy, brain delivery, and oral administration illustrate both the potential and the current mechanistic limitations of the field. This design- and evidence-oriented framework aims to support more reproducible development and interpretation of amino acid transporter-targeted DDSs.