Mechanistically, ODEXs mediated transcellular delivery of SIRT2, targeting AKT deacetylation and AKT/GSK-3β signaling to regulate neuroplasticity.<h4>Conclusion</h4>This study establishes how ODEXs improve depressive-like behaviors and hippocampal neuroplasticity and might provide a promising therapeutic approach for depression. Here, SIRT2 is linked to major depressive disorder.