MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Sun Yat-Sen University, Guangzhou, 510006, PR China; Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, Guangzhou, 510006, PR China.
State Key Laboratory of Molecular Reaction, Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, PR China.
Eur J Med Chem. 2024 Sep 5;275:116638. doi: 10.1016/j.ejmech.2024.116638. Epub 2024 Jun 28.
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.
cGAS（环状 GMP-AMP 合酶）-STING（干扰素基因刺激物）途径通过检测从细胞核和线粒体漏出的细胞质 DNA 片段来促进抗肿瘤免疫反应。在此，我们设计了一种带正电荷的钌光敏剂（Ru1），其配体为β-咔啉生物碱衍生物，用于激活 cGAS-STING 途径。由于形成了多种非共价的分子间相互作用，Ru1 可以自组装成无载体的纳米颗粒（NPs）。通过引入三苯基膦取代基，Ru1 可以靶向并光损伤线粒体 DNA（mtDNA），导致细胞质 DNA 泄漏以激活 cGAS-STING 途径。最后，Ru1 NPs 在体内表现出强大的抗肿瘤作用并引发强烈的免疫反应。总之，我们报告了第一个自组装的靶向 mtDNA 的光敏剂，它可以有效地激活 cGAS-STING 途径，从而为新型光免疫治疗剂的设计提供了创新。
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