Smart antioxidant function enhancing (SAFE) nucleic acid therapy for ROS-related chronic diseases and comorbidities

Zhiguo Lu; Ruichen Zhao; Yi Li; Jianze Wang; Jing Guo; Chaobo Bai; Jing Chen; Jun Yang; Yiwan Geng; Tianlu Zhang; Yanyue Wu; Xiyue Jiao; Yining Wang; Junliang Yuan; Xin Zhang

doi:10.1016/j.bioactmat.2023.09.004

Smart antioxidant function enhancing (SAFE) nucleic acid therapy for ROS-related chronic diseases and comorbidities

Bioact Mater. 2023 Sep 15:31:509-524. doi: 10.1016/j.bioactmat.2023.09.004. eCollection 2024 Jan.

Authors

Zhiguo Lu^{1

2

3}, Ruichen Zhao^{1

2

3}, Yi Li⁴, Jianze Wang¹, Jing Guo^{1

3}, Chaobo Bai⁵, Jing Chen⁵, Jun Yang^{1

2

3}, Yiwan Geng^{1

2

3}, Tianlu Zhang^{1

3}, Yanyue Wu^{1

2

3}, Xiyue Jiao^{1

3}, Yining Wang⁴, Junliang Yuan⁵, Xin Zhang^{1

2

3}

Affiliations

¹ State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China.
² School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing, 100049, PR China.
³ Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, PR China.
⁴ Department of Radiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, PR China.
⁵ Department of Neurology, Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, 100191, PR China.

Abstract

Reactive oxygen species (ROS)-mediated oxidative stress exacerbates chronic diseases such as organ damage and neurodegenerative disorders. The Keap1-Nrf2-ARE pathway is a widely distributed endogenous antioxidant system. However, ROS under redox homeostasis regulates a wide range of life activities. Therefore, smart scavenging of excess ROS under pathological conditions is essential to treat chronic diseases safely. This study reports a smart antioxidant function enhancement (SAFE) strategy. On-demand release of nucleic acid drugs in a pathological ROS environment smartly activates the endogenous antioxidant system, thereby smartly alleviating oxidative stress in an exogenous antioxidant-independent manner. Through structural modulation and ligand modification, we develop SAFE nanoparticles based on nanohybrid complexes (SAFE-complex) adapted to brain delivery of nucleic acid drugs. SAFE-complex with homogeneous monodisperse structure efficiently treat ROS-related neurodegenerative diseases while protecting the major organ from oxidative stress damage. Moreover, SAFE-complex can stabilize storage in the form of freeze-dried powder. These data indicate that SAFE nanoparticles hold promise for treating ROS-related chronic diseases and comorbidities through rational transformation.

Keywords: Keap1-Nrf2-ARE pathway; Nucleic acid drugs; ROS-Associated chronic diseases and comorbidities; Reactive oxygen species; Smart antioxidant function enhancing (SAFE) strategy.