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 O₂^−• 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.

Keywords

hepatocellular carcinoma / hypoxia-adaptive strategy / oxygen heterogeneity / pyroptosis / Type I photodynamic therapy

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2026 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.