Ting-ting Zhu, Pan‑miao Liu, Kenji Hashimoto, Jian-jun Yang
Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy. Lipid, polymeric, inorganic, and hybrid NPs can be engineered to traverse the blood-brain barrier (BBB) via receptor/transporter pathways, target specific cell types, and deliver sustained or stimuli-responsive release. Beyond drug delivery, NPs improve imaging, enable gene/RNA therapeutics, and support anti-inflammatory and neuroprotective strategies, advancing precision medicine. Preclinical studies in depression, schizophrenia, Alzheimer's disease, and Parkinson's disease show superior exposure, target engagement, and behavioral or cognitive benefits versus free drugs, including photothermal/photodynamic and nanobody-based approaches. Clinically, translation remains early: a handful of CNS-directed candidates (e.g., gold-based bioenergetic agents, intranasal lipid formulations, liposomal modulators) are in trials, while approvals largely lie outside CNS indications. Key hurdles include variable BBB integrity, immunogenicity and protein-corona effects, manufacturing and stability constraints, and limited effect-site exposure-response data in humans. This review outlines a translational playbook: model-informed development linking formulation to brain interstitial exposure; Quality-by-Design chemistry, manufacturing, and controls (CMC); stratified, adaptive trials with population PK/PD and harmonized biomarkers; and proactive safety monitoring with long-term registries. We also highlight NP strategies targeting the gut-brain axis-delivering probiotics, metabolites, or antimicrobials-as complementary routes to modulate neuroinflammation and circuit function. With rigorous clinical science, manufacturing quality, and safety governance embedded from the outset, nanotechnology is positioned to deliver safer, more effective, and potentially disease-modifying therapies for CNS disorders.