Microglia-Targeted Nanotherapeutics in Major Depressive Disorder: An Integrative Perspective on Neuroinflammation and Drug Delivery.

Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by complex neurobiological mechanisms, including oxidative stress and neuroinflammation, with microglial activation playing a key role in its pathophysiology. Conventional antidepressants, though widely used, often fail to achieve remission due to limited efficacy, adverse effects, and poor patient adherence. In this context, nanotechnology-based drug delivery systems have emerged as promising strategies to overcome pharmacological limitations, enhance blood-brain barrier (BBB) penetration, and target neuroinflammatory pathways. This narrative review explores the role of microglia as both mediators of neuroinflammation and potential therapeutic targets in MDD. We examine different nanocarriers and their ability to modulate microglial activation, promote a shift from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype, and enhance antidepressant efficacy. Preclinical studies have demonstrated that nanoparticle-based systems not only improve drug bioavailability and brain targeting but also potentiate neuroprotective effects by reducing oxidative stress, promoting neurogenesis, and restoring synaptic plasticity. These findings highlight the potential of nanotechnology as a novel approach to precision neuropsychopharmacology. This review aims to provide an integrative perspective on how nanocarrier-based strategies targeting microglia could redefine future therapeutic paradigms for MDD.