Rational Design of Genetically Engineered Mitochondrial-Targeting Nanozymes for Alleviating Myocardial Ischemic-Reperfusion Injury

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.