An ischemic area-targeting, peroxynitrite-responsive, biomimetic carbon monoxide nanogenerator for preventing myocardial ischemia-reperfusion injury

Jinyan Zhang; Liwei Liu; Zhen Dong; Xicun Lu; Wenxuan Hong; Jin Liu; Xiaoyi Zou; Jinfeng Gao; Hao Jiang; Xiaolei Sun; Kai Hu; Youjun Yang; Junbo Ge; Xiao Luo; Aijun Sun

doi:10.1016/j.bioactmat.2023.05.017

An ischemic area-targeting, peroxynitrite-responsive, biomimetic carbon monoxide nanogenerator for preventing myocardial ischemia-reperfusion injury

Bioact Mater. 2023 Jun 25:28:480-494. doi: 10.1016/j.bioactmat.2023.05.017. eCollection 2023 Oct.

Authors

Jinyan Zhang^{1

2

3

4}, Liwei Liu^{1

2

3

4}, Zhen Dong^{1

2

3

4}, Xicun Lu⁵, Wenxuan Hong^{1

2

3

4}, Jin Liu^{1

2

3

4}, Xiaoyi Zou^{1

2

3

4}, Jinfeng Gao^{1

2

3

4}, Hao Jiang^{1

2

3

4}, Xiaolei Sun^{1

2

3

4}, Kai Hu^{1

2}, Youjun Yang⁵, Junbo Ge^{1

2

6

3

4}, Xiao Luo⁷, Aijun Sun^{1

2

6

3

4}

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, China.
² Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
³ NHC Key Laboratory of Viral Heart Diseases, Shanghai, China.
⁴ Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China.
⁵ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
⁶ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁷ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.

Abstract

Myocardial ischemia-reperfusion (MI/R) injury is common in patients who undergo revascularization therapy for myocardial infarction, often leading to cardiac dysfunction. Carbon monoxide (CO) has emerged as a therapeutic molecule due to its beneficial properties such as anti-inflammatory, anti-apoptotic, and mitochondrial biogenesis-promoting properties. However, its clinical application is limited due to uncontrolled release, potential toxicity, and poor targeting efficiency. To address these limitations, a peroxynitrite (ONOO^-)-triggered CO donor (PCOD585) is utilized to generate a poly (lactic-co-glycolic acid) (PLGA)-based, biomimetic CO nanogenerator (M/PCOD@PLGA) that is coated with the macrophage membrane, which could target to the ischemic area and neutralize proinflammatory cytokines. In the ischemic area, local produced ONOO^- triggers the continuous release of CO from M/PCOD@PLGA, which efficiently ameliorates MI/R injury by clearing harmful ONOO^-, attenuating the inflammatory response, inhibiting cardiomyocyte apoptosis, and promoting mitochondrial biogenesis. This study provides a novel insight into the safe therapeutic use of CO for MI/R injury by utilizing a novel CO donor combined with biomimetic technology. The M/PCOD@PLGA nanogenerator offers targeted delivery of CO to the ischemic area, minimizing potential toxicity and enhancing therapeutic efficacy.

Keywords: Inflammation; Ischemia-reperfusion injury; Macrophage membrane; Mitochondria; Peroxynitrite.