Biomimetic Hybrid‐Membrane Nanoreactor for Deep‐Seated Photodynamic Immunotherapy of Hepatocellular Carcinoma via Dual Catalysis‐Enhanced ROS Amplification and cGAS‐STING Activation

ABSTRACT Photodynamic therapy (PDT) is promising against hepatocellular carcinoma (HCC). However, its efficacy against deep‐seated HCC is severely restricted by limited light penetration, intratumoral hypoxia, and insufficient systemic antitumor immunity. Here, we developed a highly integrated biomimetic self‐oxygenating nanoreactor UCNP@MnO x ‐Hyp@HRM (denoted UMHM). Coated with a Hepa1‐6 tumor cell/red blood cell fused hybrid membrane, UMHM achieves homologous tumor targeting and immune evasion, ensuring effective nanoparticle accumulation in deep‐seated tumors. The manganese oxide shell catalyzes H 2 O 2 decomposition for in situ oxygen generation to mitigate hypoxia and improve upconversion nanoparticle‐mediated PDT outcomes, while PDT/CDT synergistically amplifies oxidative stress and induces immunogenic cell death (ICD). Crucially, cytoplasmic double‐stranded DNA released by ICD acts synergistically with Mn 2 + to activate the cGAS–STING pathway. In concert with ICD, this signaling pathway facilitates dendritic cell maturation and cytotoxic T lymphocyte recruitment, as well as remodeling of the immunosuppressive tumor microenvironment. In vivo, UMHM achieved an 86.4% tumor growth inhibition rate in a large‐volume subcutaneous HCC model and effectively suppressed tumor progression in an orthotopic HCC model. Furthermore, UMHM induced a marked abscopal effect, inhibiting the growth of distant tumors and lung metastases. This study provides a novel and multifunctional synergistic strategy for photodynamic immunotherapy of deep‐seated solid tumors.