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. Overall design: In order to investigate the regulation of Mn@CDs in ALS , RNA-seq was performed on mouse spinal cord tissues to elucidate the therapeutic mechanism of Mn@CDs in ALS. We collected four groups of RNA-seq data, abbreviated as H, C, E, and P. P refers to data obtained from ALS model mice fed with PBS, which can be considered as the negative control group; H represents data from healthy WT mice; C corresponds to data from ALS model mice treated with the material we developed, which can be regarded as the experimental group; and D refers to data from ALS model mice treated with the representative ALS drug Edaravone. Each group of data includes three replicates, with the numbers following the abbreviated letters representing different biological duplication.