Computational Screening-Assisted Design of Bioinspired Artificial Metalloenzymes with Efficient Cascade Biocatalysis...

Ischemic stroke is a life-threatening cerebrovascular condition in which reperfusion, although critical for restoring cerebral blood flow, often induces severe oxidative stress and exacerbates tissue injury. The development of effective antioxidant therapies remains a formidable challenge. Here, through computational screening of ten metal centers, we introduce the design of bioinspired artificial metalloenzymes with efficient cascade biocatalysis to alleviate cerebral ischemia-reperfusion injury. The optimized artificial metalloenzymes are constructed using iridium-cluster-doped Mn-organic complexes (Ir-MnOC), which function as artificial antioxidases with cascade biocatalytic properties to efficiently eliminate reactive oxygen species (ROS), thereby mitigating inflammation and protecting against cerebral ischemia-reperfusion injury. Combined experimental and theoretical analyses reveal strong electronic coupling within the Ir-Mn organic complex, which optimizes the orbital energy levels of the metal centers, while Mn-coordinated ligands modulate oxygen species adsorption, collectively enhancing biocatalytic kinetics. As a result, the Ir-MnOC reduces ROS-mediated neuronal apoptosis by alleviating oxidative stress and exerts anti-inflammatory effects by suppressing lipid peroxidation and inhibiting microglial and astrocytic activation. Ultimately, this multienzyme-inspired biomimetic system promotes functional recovery after cerebral ischemia reperfusion, offering a promising therapeutic strategy for ischemic stroke.