Biomimetic Design of Manganese-Doped Carbon Dot Nanozymes with Ultrahigh SOD-Like Activity for ALS Management

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease without cure. Mitochondrial dysfunction and reactive oxygen species (ROS)-induced oxidative stress are considered critical factors in ALS pathogenesis. Here, we design carbon dot superoxide dismutase (SOD) nanozymes with manganese doping (Mn@CDs) by screening for the optimal active site according to the special structures of natural SODs. Mn interacts with N and O in the CD scaffold, optimizing its structure, enhancing electron transfer and superoxide anion binding, and achieving superhigh specific activity of more than 7×104 U/mg. Theoretical calculations reveal the SOD-like activity of Mn@CDs from both kinetic and thermodynamic perspectives, identifying MnN₂O₂ (with amide-derived N) as the most likely active center. After being applied in ALS therapy, Mn@CDs which target and accumulate in mitochondria, effectively prevent oxidative stress and protect mitochondria from abnormalities in morphology, quantity, and function. Hence, administration of Mn@CDs prolonged survival by 14.5 days, with a 93% increase over the effect of edaravone. These results suggest that Mn@CD hold significant potential as a promising therapeutic candidate for ALS treatment.