A Photothermally Triggered Cascade Nanodelivery Platform for On‐Demand Nitric Oxide Release in Targeted Hepatocellular Carcinoma Therapy

ABSTRACT Traditional nanoparticle delivery systems for hepatocellular carcinoma (HCC) rely on passive targeting and low drug release rates, limiting efficacy, while the biocompatible nitric oxide (NO) donor L‐Arginine (L‐Arg) is prone to systemic leakage, hindering precise HCC delivery. In the content, we constructed a cascade‐responsive nanoplatform based on porous hollow gold nanocages (GNCs) that integrates spatial targeting and temporal activation of multimodal treatment. By co‐loading the near‐infrared (NIR) photosensitizer indocyanine green (ICG) and the NO precursor L‐Arg into GNCs, and conjugating the HCC‐targeting peptide 9R‐P201 on the surface, we obtained the multifunctional nanoplatform GIL9R. Upon NIR irradiation, GIL9R nanoplatform simultaneously generated localized hyperthermia (photothermal therapy, PTT) and the resulting strong oxidizing agent. The resulting reactive oxygen species (ROS) catalyze L‐Arg oxidation via an enzyme‐mimetic pathway to produce NO, triggering gas therapy (GT) in situ. This PTT/PDT‐initiated NO release synchronizes three modalities, yielding potent synergistic cytotoxicity against HCC cells. In vitro, GIL9R nanoplatform showed high HCC affinity, effective photodynamic therapy (PDT), and robust NO‐mediated GT. In vivo, GIL9R nanoplatform selectively accumulated in tumors and significantly suppressed tumor growth. This rationally designed cascade platform leverages intrinsic synergy among PTT, PDT, and GT, offering a translatable strategy for precision liver cancer treatment.