Self‐Assembled Nanoconjugates with Aggregation‐Induced Emission for Near‐Infrared II Imaging and Transcytosis‐Driven Cancer Therapy

Abstract Nanomedicine holds immense potential to revolutionize cancer therapy, yet its clinical translation remains hampered by insufficient tumor accumulation and an inability to dynamically monitor therapeutic penetration. While transcytosis‐mediated transport offers a promising strategy to overcome biological barriers, existing carriers lack real‐time imaging capabilities, particularly in the near‐infrared II window, to guide optimization. Herein, we address this dual challenge through a multifunctional poly[L‐γ‐[2‐( N ‐oxide‐ N,N ‐dimethylamino)ethyl]glutamine]‐paclitaxel (OPGAX) conjugate integrated with aggregation‐induced emission (AIE) luminogens. The OPGAX conjugate self‐assembled into uniform nanoparticles (NPs) with a high drug‐loading capacity (42.5%) and intense near‐Infrared II (NIR‐II) fluorescence (1000–1350 nm). The zwitterionic tertiary amine oxide (TAO) moiety endowed OPGAX with protein resistance and cell membrane affinity, leading to prolonged blood circulation and enhanced tumor accumulation. OPGAX NPs performed NIR‐II imaging to visualize whole‐body vasculature and dynamically track tumor penetration. In 4T1 tumor‐bearing mice, OPGAX NPs achieved deep tumor infiltration via transcytosis, visualized dynamically by NIR‐II imaging, and suppressed tumor growth. This platform bridges diagnostic certainty with therapeutic efficacy, offering a translatable strategy for image‐guided precision oncology.