Sun Shengjie, Yu Mian, Yu Liu, Huang Wenxin, Zhu Meishu, Fu Yanan, Yan Lingchen, Wang Qiang, Ji Xiaoyuan, Zhao Jing, Wu Meiying
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China.
Department of Burn and Plastic Surgery, Department of Wound Repair, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.
Biomaterials. 2023 May;296:122068. doi: 10.1016/j.biomaterials.2023.122068. Epub 2023 Feb 27.
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.
光动力疗法（PDT）介导的抗肿瘤免疫反应取决于肿瘤细胞中的氧化应激强度和随后的免疫原性细胞死亡（ICD），然而，固有的抗氧化系统会限制活性氧（ROS）相关的氧化损伤，这与上调的核因子红细胞2相关因子2（Nrf2）及其下游产物如谷胱甘肽（GSH）高度相关。在此，为克服这一困境，我们设计了一种多功能纳米佐剂（RI@Z-P），通过Nrf2特异性小干扰RNA（siNrf2）增强肿瘤细胞对氧化应激的敏感性。构建的RI@Z-P可显著放大光氧化应激并实现强大的DNA氧化损伤，激活干扰素基因刺激物（STING）依赖性免疫传感以产生干扰素-β（IFN-β）。此外，RI@Z-P与激光照射一起通过暴露或释放损伤相关分子模式（DAMPs）增强肿瘤免疫原性，显示出促进树突状细胞（DC）成熟和T淋巴细胞活化的显著佐剂作用，甚至在一定程度上缓解免疫抑制微环境。
