5-Hydroxytryptophan artificial synaptic vesicles across the blood-brain barrier for the rapid-acting treatment of depressive disorder

Conventional antidepressants are slow to work and have serious side effects and poor response rates. As a precursor to 5-hydroxytryptamine (5-HT), 5-hydroxytryptophan (5-HTP) can be safely increased in concentration and rapidly metabolized into 5-HT in the brain, but the effectiveness of 5-HTP is severely limited due to its short half-life and lack of targeting. To traverse the blood-brain barrier (BBB) and achieve effective targeting, we designed a near-infrared (NIR) light-responsive artificial synaptic vesicles functionalized with an aptamer and loaded with 5-HTP and IR780. Photothermal approaches could improve the BBB permeability, and photothermal-triggered 5-HTP release could also be achieved. The ability to penetrate the BBB and enhance cerebral drug enrichment could be observed by fluorescence imaging. In addition, the nanoplatform incorporating the NIR laser considerably reduced depressive-like behaviors in chronic unpredictable moderate stress model mice in only 4 weeks, suggesting a potential approach for rapid-acting depression treatment.