Abstract：
The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway promotes antitumor immune responses by sensing cytosolic DNA fragments leaked from nucleus and mitochondria. Herein, we designed a highly charged ruthenium photosensitizer (Ru1) with a β-carboline alkaloid derivative as the ligand for photo-activating of the cGAS-STING pathway. Due to the formation of multiple non-covalent intermolecular interactions, Ru1 can self-assemble into carrier-free nanoparticles (NPs). By incorporating the triphenylphosphine substituents, Ru1 can target and photo-damage mitochondrial DNA (mtDNA) to cause the cytoplasmic DNA leakage to activate the cGAS-STING pathway. Finally, Ru1 NPs show potent antitumor effects and elicit intense immune responses in vivo. In conclusion, we report the first self-assembling mtDNA-targeted photosensitizer, which can effectively activate the cGAS-STING pathway, thus providing innovations for the design of new photo-immunotherapeutic agents.
摘要：
cGAS（环GMP-AMP合酶）-STING（干扰素基因的刺激物）途径通过感测从细胞核和线粒体泄漏的胞质DNA片段来促进抗肿瘤免疫反应。在这里，我们设计了一种高电荷的钌光敏剂（Ru1），其β-咔啉生物碱衍生物作为配体，用于光活化cGAS-STING途径。由于多个非共价分子间相互作用的形成，Ru1可以自组装成无载体纳米粒子(NPs)。通过引入三苯基膦取代基，Ru1可以靶向和光损伤线粒体DNA（mtDNA），导致细胞质DNA泄漏，从而激活cGAS-STING途径。最后,Ru1NP显示出有效的抗肿瘤作用，并在体内引发强烈的免疫反应。总之,我们报道了第一个自组装mtDNA靶向光敏剂，可以有效激活cGAS-STING途径，从而为新的光免疫治疗剂的设计提供了创新。
