Engineering Advanced Nanomedicine Against Depression: From Treatment Challenges to Delivery Strategies.

Depression is a leading global health burden, yet current pharmacotherapy remains constrained by depression-specific challenges that extend beyond simple blood-brain barrier (BBB) penetration, including delayed onset of action, poor regional brain specificity, and the inability to deliver emerging biologics. Engineered nanomedicine offers a paradigm-shifting platform to address these limitations through precise designs such as receptor-mediated transport and cell-mimetic carriers, enabling targeted modulation of depression-related neural circuits. This review critically evaluates advanced nanoengineering strategies for antidepressant delivery, distinguishing proof-of-concept systems from platforms with realistic translational potential. We further provide a decision-oriented framework to guide future clinical development. By moving beyond generic strategies for BBB penetration to address the distinctive pharmacotherapeutic shortcomings of depression, engineered nanomedicine holds great promise for advancing next-generation antidepressant therapies that achieve rapid onset, precise intervention, and comprehensive improvement in patient quality of life.