Nanomedicine for Depression: From Blood–Brain Barrier Delivery to Neuroimmune–Barrier–Plasticity Network Reprogramming

Depression is a heterogeneous and recurrent brain disorder in which neuroinflammation, blood-brain barrier dysfunction, oxidative and mitochondrial stress, and impaired neuroplasticity interact within the neurovascular-glial-neuronal unit. This mechanism-oriented integrative review examines how engineered nanosystems may move beyond brain entry toward lesion-directed modulation of the neuroinflammation-barrier-neuroplasticity axis. We first synthesize the pathological nodes that sustain depression-related network dysfunction and then classify current nanotherapeutic strategies into three categories: small-molecule nanodelivery systems, nucleic acid nanocarriers, and functional nanoplatforms, including lipid and polymeric nanoparticles, inorganic and nanozyme-based systems, biomimetic membrane-coated nanoparticles, and engineered extracellular vesicles, including exosomes. Unlike previous nanosynthesis-focused or catalogue-style nanocarrier reviews, this review organizes the field around a disease-mechanism framework rather than material type alone, emphasizing barrier-state navigation, glial-neuronal-subcellular targeting, stimulus-responsive release, and coordinated modulation of inflammation, vascular integrity, redox homeostasis, and synaptic plasticity. We further argue that nanoplatforms should be evaluated not only by brain accumulation but also by patient stratification, engagement of defined pathological nodes, multimodal biomarker evidence of network-level modulation, manufacturability, and safety under repeated administration. Major translational bottlenecks include insufficient subtype-specific patient selection, limited human relevance of current stress- and inflammation-based models, uncertain biodistribution and long-term neurotoxicity, constraints in scaling up nose-to-brain delivery, batch-to-batch variability, cargo instability, immunogenicity, and unclear regulatory classification of complex biologic or combination products. Finally, we propose a pathological-network-guided precision nanomedicine framework that integrates blood-brain barrier status assessment, liquid biopsy and imaging biomarkers, human-relevant validation models, and scalable quality control to guide future platform design and clinical translation. This review provides a disease-mechanism-centered roadmap for transforming nanomedicine for depression from delivery optimization into precision network-oriented intervention.