Engineering Cylindrical Macromolecular Assemblies With Zwitterionic Amino Acids for Concurrent Prolonged Circulation and Tumor Targeting

ABSTRACT The rational design of drug delivery systems requires strategies that address the inherent trade‐off between active targeting and immune evasion. Here, we present a molecular design that integrates a zwitterionic amino acid interface with morphological control via graft polymer self‐assembly enabling both functions to be incorporated within a single carrier. The amphiphilic graft polymers, composed of hydrophilic backbones bearing zwitterionic amino acids and hydrophobic poly(propylene oxide) side chains, spontaneously assemble into short cylindrical micelles. These micelles exhibit preferential uptake by amino acid transporter‐expressing tumor cells while minimizing macrophage internalization, resulting in prolonged blood circulation and substantial tumor accumulation. The cylindrical morphology and zwitterionic surface contribute to reduced nonspecific uptake and enhanced transporter‐associated interactions. Upon loading with the photosensitizer IR780, the micelles generate reactive oxygen species and heat under near‐infrared irradiation, inducing apoptosis and significant tumor growth inhibition. This study demonstrates a molecular design strategy that resolves the trade‐off between tumor targeting and immune evasion through the integration of interfacial chemistry and morphology control. By establishing this structure–function coupling, our work offers a new direction in the design of drug delivery carriers that achieve selective accumulation and prolonged circulation through molecular‐level architecture.