Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation

  • Nat Commun. 2023 May 23;14(1):2950. doi: 10.1038/s41467-023-38601-7.
Kaiyuan Wang  #  1  2 ,  Yang Li  #  3  4 ,  Xia Wang  #  5 ,  Zhijun Zhang  6 ,  Liping Cao  1 ,  Xiaoyuan Fan  1 ,  Bin Wan  1 ,  Fengxiang Liu  1 ,  Xuanbo Zhang  1  2 ,  Zhonggui He  1 ,  Yingtang Zhou  7 ,  Dong Wang  8 ,  Jin Sun  9 ,  Xiaoyuan Chen  10  11  12  13
Affiliations
  • 1. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, P. R. China.
  • 2. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119074, Singapore.
  • 3. Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 350002, China.
  • 4. Department of Translational Medicine & Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare-Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen, 361021, P. R. China.
  • 5. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
  • 6. Center for AIE Research, College of Materials Science and Engineering, Shenzhen University, Shenzhen, 518060, China.
  • 7. National Engineering Research Center for Marine Aquaculture, Marine Science and Technology College, Zhejiang Ocean University, Zhoushan, Zhejiang Province, 316004, China. [email protected].
  • 8. Center for AIE Research, College of Materials Science and Engineering, Shenzhen University, Shenzhen, 518060, China. [email protected].
  • 9. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, P. R. China. [email protected].
  • 10. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119074, Singapore. [email protected].
  • 11. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore. [email protected].
  • 12. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. [email protected].
  • 13. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore. [email protected].
  • # Contributed equally.
PMID: 37221157 DOI: 10.1038/s41467-023-38601-7
Abstract

The immunologically "cold" microenvironment of triple negative breast Cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

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