Lepidium meyenii Walp (Maca)‐derived extracellular vesicles ameliorate depression by promoting 5‐HT synthesis via the modulation of gut–brain axis

, which were significantly restored by administration of Maca-EVs. The effects of Maca-EVs on the altered microbial and fecal metabolites in UCMS mice were mapped to biotin, pyrimidine, and amino acid (tyrosine, alanine, aspartate, and glutamate) metabolisms, which were closely associated with the serotonin (5-HT) production. Maca-EVs were able to increase serum monoamine neurotransmitter levels in UCMS mice, with 5-HT showing the most significant changes. We further demonstrated that 5-HT improved the expression of brain-derived neurotrophic factor, a key regulator of neuronal plasticity, and its subsequent activation of TrkB/p-AKT signaling by regulating the GTP-Cdc42/ERK pathway. These findings suggest that Maca-EVs enhance 5-HT release, possibly by modulating the gut-brain axis, to improve depression behavior. Our study sheds light on a novel approach to depression treatment using plant-derived EVs.