Self-assembly of a ruthenium-based cGAS-STING photoactivator for carrier-free cancer immunotherapy

  • Eur J Med Chem. 2024 Sep 5:275:116638. doi: 10.1016/j.ejmech.2024.116638.
Yu-Yi Ling  1 ,  Zhi-Yuan Li  1 ,  Xia Mu  2 ,  Ya-Jie Kong  1 ,  Liang Hao  1 ,  Wen-Jin Wang  1 ,  Qing-Hua Shen  1 ,  Yue-Bin Zhang  3 ,  Cai-Ping Tan  4
Affiliations
  • 1. 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.
  • 2. State Key Laboratory of Molecular Reaction, Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, PR China.
  • 3. State Key Laboratory of Molecular Reaction, Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, PR China. Electronic address: [email protected].
  • 4. 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. Electronic address: [email protected].
PMID: 38950489 DOI: 10.1016/j.ejmech.2024.116638
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.

Keywords
DNA binding; Photoimmunotherapy; Ru(II) complexes; Self-assembly; cGAS-STING.
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