The Role of Exosomes in the Regulation of Molecular Mechanisms Underlying Treatment Resistance-Linking Cellular Crosstalk to Clinical Implications in Depression.

Depressive disorders (DDs), especially treatment-resistant depression (TRD), pose a significant challenge worldwide, largely because their underlying biological mechanisms are complicated and treatments often fall short. There is growing evidence pointing to factors like disrupted neuroplasticity, neuroinflammation, irregularities in the hypothalamic-pituitary-adrenal (HPA) axis, and glutamatergic system imbalances as contributors to the onset and persistence of depressive symptoms. Exosomes (small extracellular vesicles involved in communication between cells) have recently gained attention for their potential role in connecting peripheral and central nervous system (CNS) changes. They carry proteins, lipids, and nucleic acids and are even capable of crossing the blood-brain barrier. Because of this, exosomes might provide a window into molecular changes in the brain and serve as accessible biomarkers of disease status and treatment response. Recent research points out that the contents of exosomes, especially microRNAs (miRNAs) and neurotrophic factors like brain-derived neurotrophic factor (BDNF), might play a part in disrupting synaptic plasticity and could be linked to resistance to antidepressants. At the same time, there is growing interest in using engineered exosomes as targeted drug carriers aimed at the CNS. That said, there are still quite a few hurdles to overcome. Methods vary widely between studies, protocols for isolating exosomes are not sufficiently standardized, safety data are limited, and we do not fully understand how drugs and exosomes interact or how they behave pharmacokinetically. This review brings together current findings regarding exosomes in DDs (with particular emphasis on TRD), highlights their promise for diagnosis and treatment, and sets out some of the main questions that need to be answered before clinical application becomes feasible.