An amino acid cluster-inspired nanoplatform exhibits LAT1-mediated cell targeting for tumor delivery

Conventional tumor-targeted nanocarriers remain limited by heterogeneous intratumoral distribution, which arises from abnormal tumor vasculature, dense extracellular matrix barriers, and spatially variable receptor expression. These biological barriers restrict deep tumor penetration and prevent homogeneous nanocarrier accumulation. Although peptide-based targeting strategies can enhance tumor cell uptake, their complex synthesis, structural heterogeneity, and conformational constraints may compromise amino acid functionality and complicate scalable formulation. Here, we developed a series of amino acid cluster-inspired amphiphilic copolymers, termed DC₁₈-PR, as a metabolically recognizable platform for hydrophobic drug delivery. By presenting high-density amino acid groups at the nano-bio interface, DC₁₈-PR mimics endogenous metabolic substrates and exploits tumor metabolic reprogramming and amino acid transporter-associated recognition pathways to promote rapid tumor accumulation and improve intratumoral distribution. Among the tested copolymers, leucine-functionalized DC₁₈-PLeu showed the strongest cellular internalization and tumor accumulation. Pharmacological inhibition with the amino acid transport inhibitor BCH markedly reduced cellular uptake, supporting the involvement of an LAT1-associated metabolic recognition pathway rather than nonspecific passive accumulation. Systematic evaluation across multiple tumor models demonstrated that DC₁₈-PR achieved significantly higher intracellular delivery efficiency than polyoxyethylene-based poloxamer materials, resulting in nearly two-fold enhancement of intracellular payload accumulation. High-resolution near-infrared-II fluorescence imaging further demonstrated accelerated tumor accumulation, more homogeneous intratumoral fluorescence distribution, and superior spatiotemporal imaging performance across multiple tumor models. Overall, this study establishes amino acid cluster engineering as a general strategy for converting amphiphilic stabilizers into metabolically interactive nanocarrier interfaces, providing a promising design principle for homogeneous tumor drug delivery.