Rational Design of Genetically Engineered Mitochondrial-Targeting Nanozymes for Alleviating Myocardial Ischemic-Reperfusion Injury
Xiangyun Zhang, Qiqi Liu, Rongping Zhao, Zhihua Pang, Weiyu Zhang, Tianyi Qi, Mingsheng Zhu, Helong Kang, Meng Qian, Yajuan Wan, Rui Wang, Shufang Wang, Xinglu Huang, Jie Zhuang
Abstract
The development of mitochondria-targeting nanozymes holds significant promise for treating myocardial ischemia-reperfusion (IR) injury but faces significant biological barriers. To overcome these obstacles, we herein utilized genetically engineered ferritin nanocages (i.e., imFTn) to develop mitochondria-targeting nanozymes consisting of three ferritin subunit assembly modules: an IR-injured cardiomyocyte-targeting module, a lysosome-escaping module, and a mitochondria-targeting module. Using imFTn as a nanozyme platform, we developed nanozymes capable of efficiently catalyzing the l -Arg substrate to produce NO. The imFTn-Ru exhibits NO-generating activities, reduces mitochondrial reactive oxygen species generation, inhibits mitochondrial permeability transition pore opening, and enhances mitochondrial membrane potential. Furthermore, imFTn-Ru provides synergistic effects by specifically targeting myocardial IR-injured tissues, facilitating their accumulation in mitochondria, and protecting mitochondria against myocardial IR-induced injury in both in vitro and in vivo models. This study underscores a rational approach to designing nanozymes for targeting specific subcellular organelles in the treatment of IR injury.