Nrf2 silencing amplifies DNA photooxidative damage to activate the STING pathway for synergistic tumor immunotherapy

• Published in: Biomaterials 2023-05, Vol.296, p.122068-122068, Article 122068
• Main Authors: Sun, Shengjie, Yu, Mian, Yu, Liu, Huang, Wenxin, Zhu, Meishu, Fu, Yanan, Yan, Lingchen, Wang, Qiang, Ji, Xiaoyuan, Zhao, Jing, Wu, Meiying
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; DNA - metabolism; DNA oxidative damage; Glutathione - metabolism; Immunogenic cell death; Immunotherapy; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Photoimmunotherapy; Reactive Oxygen Species - metabolism; siRNA delivery; STING pathway
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2023.122068

Photodynamic therapy (PDT)-mediated antitumor immune response depends on oxidative stress intensity and subsequent immunogenic cell death (ICD) in tumor cells, yet the inherent antioxidant system restricts reactive oxygen species (ROS)-associated oxidative damage, which is highly correlated with the upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream products, such as glutathione (GSH). Herein, to overcome this dilemma, we designed a versatile nanoadjuvant (RI@Z-P) to enhance the sensitivity of tumor cells to oxidative stress via Nrf2-specific small interfering RNA (siNrf2). The constructed RI@Z-P could significantly amplify photooxidative stress and achieve robust DNA oxidative damage, activating the stimulator of interferon genes (STING)-dependent immune-sensing to produce interferon-β (IFN-β). Additionally, RI@Z-P together with laser irradiation reinforced tumor immunogenicity by exposing or releasing damage-associated molecular patterns (DAMPs), showing the prominent adjuvant effect for promoting dendritic cell (DC) maturation and T-lymphocyte activation and even alleviating the immunosuppressive microenvironment to some extent.