In SituRecovery of Serotonin Synthesis by a TryptophanHydroxylase-Like Nanozyme for the Treatment of Depression

Depression is one of the most common mental disorders. The inactivation of tryptophan hydroxylase and the resulting serotonin decrease are the key factors in depression pathology. Herein, we report for the first time that Fe₃O₄ nanoparticles exhibit tryptophan hydroxylase-like activity and successfully verify their ability to restore serotonin synthesis in the brain for the treatment of depression. To achieve better biocompatibility and brain delivery, the Fe₃O₄ nanoparticles were functionalized with chitosan (CS) (Fe₃O₄@CS), enabling their delivery from the nose to the brain. Fe₃O₄@CS catalyzes the transformation of tryptophan into 5-hydroxytryptophan with the participation of high levels of endogenous ascorbic acid and hydrogen peroxide in stressed neurons, thus compensating for the deactivated tryptophan hydroxylase in the brain. In vivo Fe₃O₄@CS treatment results in the recovery of 5-hydroxytryptophan and serotonin levels and improvement of neuronal signal transduction ability in a depression mouse model, thus ameliorating depressive-like behaviors. The presented strategy of restoring serotonin synthesis in situ based on a tryptophan hydroxylase-like nanozyme provides a more accurate and efficient approach for the treatment of depression.