Biomimetic Design of Mitochondria‐Targeted Hybrid Nanozymes as Superoxide Scavengers

Development of enzyme mimics for the scavenging of excessive mitochondrial superoxide (O2•−) can serve as an effective strategy in the treatment of many diseases. Here, protein reconstruction technology and nanotechnology is taken advantage of to biomimetically create an artificial hybrid nanozyme. These nanozymes consist of ferritin‐heavy‐chain‐based protein as the enzyme scaffold and a metal nanoparticle core as the enzyme active center. This artificial cascade nanozyme possesses superoxide dismutase‐ and catalase‐like activities and also targets mitochondria by overcoming multiple biological barriers. Using cardiac ischemia‐reperfusion animal models, the protective advantages of the hybrid nanozymes are demonstrated in vivo during mitochondrial oxidative injury and in the recovery of heart functionality following infarction via systemic delivery and localized release from adhesive hydrogels (i.e., cardiac patch), respectively. This study illustrates a de novo design strategy in the development of enzyme mimics and provides a promising therapeutic option for alleviating oxidative damage in regenerative medicine. The key factor for de novo design of a metalloenzyme mimetic includes a suitable protein scaffold and enzyme active centers. A biomimetic cascade nanozyme is artificially created based on the hybridization of a recombinant ferritin‐heavy‐chain‐based protein scaffold modified for mitochondria‐targeting and a Mn‐based nanoparticle as the core of the enzymatic activity.