Precise Control of Metal Active Sites of Metal–Organic Framework Nanozymes for Achieving Excellent Enzyme‐Like Activity and Efficient Pancreatitis Therapy

Abstract Acute pancreatitis (AP) is a potentially life‐threatening inflammatory disease that can lead to the development of systemic inflammatory response syndrome and its progression to severe acute pancreatitis. Hence, there is an urgent need for the rational design of highly efficient antioxidants to treat AP. Herein, an optimized Cu‐based metal–organic framework (MOF) nanozyme with exceptional antioxidant activity is introduced, designed to effectively alleviate AP, by engineering the metal coordination centers in MN2Cl2 (M = Co, Ni, Cu). Specifically, the Cu MOF, which benefits from a Cu active center similar to that of natural superoxide dismutase (SOD), exhibited at least four times higher SOD‐like activity than the Ni/Co MOF. Theoretical analyses further demonstrate that the CuN2Cl2 site not only has a moderate adsorption effect on the substrate molecule •OOH but also reduces the dissociation energy of the product H 2 O 2 . Additionally, the Cu MOF nanozyme possesses the excellent catalase‐like activity and •OH removal ability. Consequently, the Cu MOF with broad‐spectrum antioxidant activity can efficiently scavenge reactive oxygen species to alleviate arginine‐induced AP. More importantly, it can also mitigate apoptosis and necrosis of acinar cells by activating the PINK1/PARK2‐mediated mitophagy pathway. This study highlights the distinctive functions of tunable MOF nanozymes and their potential bio‐applications.