Antioxidant\nCarbon Dots Nanozymes Alleviate Stress-induced\nDepression by Modulating Gut Microbiota

Depression\nis a debilitating mental illness that severely\nthreatens\nmillions of individuals and public health. Because of the multifactorial\netiologies, there is currently no cure for depression; thus, it is\nurgently imperative to find alternative antidepressants and strategies.\nGrowing evidence underscores the prominent role of oxidative stress\nas key pathological hallmarks of depression, making oxidative stress\n a potential therapeutic target. In this study, we report a N-doped\ncarbon dot nanozyme (CDzyme) with excellent antioxidant capacity for\ntreating depression by remodeling redox homeostasis and gut microbiota.\nThe CDzymes prepared via microwave-assisted fast polymerization of\nhistidine and glucose exhibit superior biocompatibility. Benefiting\nfrom the unique structure, CDzymes can provide abundant electrons,\nhydrogen atoms, and protons for reducing reactions, as well as catalytic\nsites to mimic redox enzymes. These mechanisms collaborating endow\nCDzymes with broad-spectrum antioxidant capacity to scavenge reactive\noxygen and nitrogen species (<sup>•</sup>OH, O<sub>2</sub><sup>–•</sup>, H<sub>2</sub>O<sub>2</sub>, ONOO<sup>–</sup>), and oxygen/nitrogen centered free radicals. A depression animal\nmodel was established by chronic unpredictable mild stress (CUMS)\nto evaluate the therapeutic efficacy of CDzymes from the behavioral,\nphysiological, and biochemical index and intestinal flora assessments.\nCDzymes can remarkably improve depression-like behaviors and key neurotransmitters\nproduced in hippocampus tissues and restore the gut microbiota compositions\nand the amino acid metabolic functions, proving the potential in treating\ndepression through the intestinal-brain axis system. This study will\nfacilitate the development of intestinal flora dysbiosis nanomedicines\nand treatment strategies for depression and other oxidative stress\nrelated multifactorial diseases.