Rational Design\nof Genetically Engineered Mitochondrial-Targeting\nNanozymes for Alleviating Myocardial Ischemic-Reperfusion Injury

The development of mitochondria-targeting nanozymes holds\nsignificant\npromise for treating myocardial ischemia-reperfusion (IR) injury but\nfaces significant biological barriers. To overcome these obstacles,\nwe herein utilized genetically engineered ferritin nanocages (i.e.,\nimFTn) to develop mitochondria-targeting nanozymes consisting of three\nferritin subunit assembly modules: an IR-injured cardiomyocyte-targeting\nmodule, a lysosome-escaping module, and a mitochondria-targeting module.\nUsing imFTn as a nanozyme platform, we developed nanozymes capable\nof efficiently catalyzing the l-Arg substrate to produce\nNO. The imFTn-Ru exhibits NO-generating activities, reduces mitochondrial\nreactive oxygen species generation, inhibits mitochondrial permeability\ntransition pore opening, and enhances mitochondrial membrane potential.\nFurthermore, imFTn-Ru provides synergistic effects by specifically\ntargeting myocardial IR-injured tissues, facilitating their accumulation\nin mitochondria, and protecting mitochondria against myocardial IR-induced\ninjury in both <i>in vitro</i> and <i>in vivo</i> models. This study underscores a rational approach to designing\nnanozymes for targeting specific subcellular organelles in the treatment\nof IR injury.