Early-relief effects of tetrahedral DNA nanostructures-assisted depression therapy via modulates hippocampal neurogenesis and neuroplasticity

The delayed-onset effects of antidepressants may increase the risk of suicide in patients before they take full effect. Accumulating evidence indicates that the restriction of the blood–brain barrier (BBB), the inhibition of hippocampal neurogenesis, and the decrease in neuroplasticity play vital roles in this delayed response. This study utilizes tetrahedral DNA nanostructures (TDNs) as a drug delivery system, inherently facilitating the proliferation of neural precursor cells and effectively penetrating the BBB. The nanoscale complex, TDNs@FLX, is constructed by combining TDNs with the classic antidepressant fluoxetine (FLX). TDNs@FLX demonstrates the ability to alleviate depression symptoms in a mouse model during the early stages of treatment. In contrast, pure TDNs alone fail to provide long-lasting therapeutic benefits, and free FLX results in delayed therapeutic outcomes. The early efficacy of the TDNs@FLX complex in treating depression is closely related to the promotion of neural precursor cell proliferation, dendritic complexity, and spine density. Thus, this study addresses the limitations of classic antidepressants and presents exciting prospects for the application of DNA-based nanomedicine in the treatment of depressive disorders.