C-176 loaded Ce DNase nanoparticles synergistically inhibit the cGAS-STING pathway for ischemic stroke treatment

Zhixin Zhu; Haipeng Lu; Lulu Jin; Yong Gao; Zhefeng Qian; Pan Lu; Weijun Tong; Pik Kwan Lo; Zhengwei Mao; Haifei Shi

doi:10.1016/j.bioactmat.2023.07.002

C-176 loaded Ce DNase nanoparticles synergistically inhibit the cGAS-STING pathway for ischemic stroke treatment

Bioact Mater. 2023 Jul 18:29:230-240. doi: 10.1016/j.bioactmat.2023.07.002. eCollection 2023 Nov.

Authors

Zhixin Zhu^{1

2}, Haipeng Lu², Lulu Jin², Yong Gao², Zhefeng Qian², Pan Lu¹, Weijun Tong², Pik Kwan Lo³, Zhengwei Mao², Haifei Shi¹

Affiliations

¹ Department of Orthopedics, 1st Affiliated Hospital of Zhejiang University School of Medicine, Qingchun Road 79, Hangzhou, 31000, China.
² MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
³ Department of Chemistry and State Key Laboratory of Marine Pollution, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong.

Abstract

The neuroinflammatory responses following ischemic stroke cause irreversible nerve cell death. Cell free-double strand DNA (dsDNA) segments from ischemic tissue debris are engulfed by microglia and sensed by their cyclic GMP-AMP synthase (cGAS), which triggers robust activation of the innate immune stimulator of interferon genes (STING) pathway and initiate the chronic inflammatory cascade. The decomposition of immunogenic dsDNA and inhibition of the innate immune STING are synergistic immunologic targets for ameliorating neuroinflammation. To combine the anti-inflammatory strategies of STING inhibition and dsDNA elimination, we constructed a DNase-mimetic artificial enzyme loaded with C-176. Nanoparticles are self-assembled by amphiphilic copolymers (P[CL₃₅-b-(OEGMA_20.7-co-NTAMA_14.3)]), C-176, and Ce⁴⁺ which is coordinated with nitrilotriacetic acid (NTA) group to form corresponding catalytic structures. Our work developed a new nano-drug that balances the cGAS-STING axis to enhance the therapeutic impact of stroke by combining the DNase-memetic Ce⁴⁺ enzyme and STING inhibitor synergistically. In conclusion, it is a novel approach to modulating central nervus system (CNS) inflammatory signaling pathways and improving stroke prognosis.

Keywords: Anti-inflammation; Ce-based nano-nuclease; Ischemic stroke; The cGAS-STING signaling pathway.