Conquering Oxygen Heterogeneity in Hepatocellular Carcinoma With a Dual‐Targeted Nanoplatform Integrating Type I Photodynamic Therapy/Starvation Therapy/Hypoxia‐Activated Chemotherapy

ABSTRACT Hepatocellular carcinoma (HCC) displays severe oxygen heterogeneity, which is regarded as a critical limitation to therapeutic efficacy. Herein, a targeted nanoplatform is engineered to overcome this barrier via a synergistic starvation/chemotherapy/Type I photodynamic therapy (PDT) strategy by co‐encapsulating glucose oxidase (GOx), tirapazamine (TPZ), and photosensitizer (sulfur‐substituted Nile Blue, ENBS) in galactose/biotin dual‐ligand‐modified liposomal nanoparticles (TGoE@BG‐Lipo). ENBS‐enabled Type I PDT provides oxygen‐independent photokilling, whereas GOx‐mediated glucose/oxygen depletion induces starvation and aggravates hypoxia to activate TPZ, together enabling efficient tumor eradication. TGoE@BG‐Lipo exhibits precise targeting with an 84‐fold higher uptake in HCC cells versus normal cells in a coculture model. In vitro, TGoE@BG‐Lipo/L generates O 2 −• through Type I PDT and produces robust reactive oxygen species (ROS) under both normoxic (3.1‐fold vs. untreated control) and hypoxic (2.1‐fold) conditions. This treatment induces both caspase‐3/GSDME‐dependent pyroptosis and immunogenic cell death (ICD) hallmarks upon irradiation. Thus, this synergistic treatment induces potent cell killing characterized by severe mitochondrial dysfunction (45.0% monomers) and achieves a tumor growth inhibition rate of 95.3 ± 1.1% in a hypoxic C5WN1 tumor model. Overall, this study presents a hypoxia‐adaptive nanoplatform for the precise eradication of oxygen‐heterogeneous HCC.