Gold nanoparticles for central nervous system drug delivery in depression: nanobiological mechanisms, pharmacokinetics and translational perspectives

Abstract Gold nanoparticles have attracted increasing interest as nanocarriers for central nervous system drug delivery due to their tunable physicochemical properties, adaptable surface chemistry and ability to cross or bypass the blood–brain barrier. These features are particularly relevant for depression, a disorder in which a substantial proportion of patients fail to achieve adequate therapeutic response to conventional antidepressants, partly due to limited drug exposure within the brain. This review synthesises current knowledge on the nanobiological mechanisms governing gold nanoparticle transport across the blood–brain barrier, their pharmacokinetics and biodistribution, and their potential to deliver neuroactive compounds relevant to depression therapy. Preclinical studies demonstrate that gold nanoparticles can access the central nervous system through multiple pathways, including passive diffusion, receptor-mediated transcytosis and transporter-associated mechanisms. Quantitative biodistribution analyses consistently report low absolute brain accumulation, typically below 1% of the injected dose per gram of tissue, although ligand-functionalised systems achieve several-fold higher uptake compared with non-targeted formulations. Beyond delivery, gold nanoparticles have been shown to modulate neuroinflammatory, oxidative and neurotrophic signalling pathways that are implicated in depressive pathophysiology. However, significant translational challenges remain, including limited brain bioavailability, slow systemic clearance, long-term organ retention and insufficient data on safety during repeated or chronic administration. Overall, gold nanoparticles represent a promising but still experimental platform for central nervous system–targeted drug delivery in depression. Their modular surface engineering, compatibility with controlled-release strategies and potential for precision targeting offer opportunities for improved and personalised therapeutic approaches. Nevertheless, advancement toward clinical application will require robust depression-relevant preclinical models, comprehensive pharmacokinetic and biodistribution profiling, and early-phase clinical studies to establish safety and translational feasibility. By integrating nanobiological mechanisms with central nervous system pharmacokinetics, this review positions gold nanoparticles as a versatile platform in health nanotechnology, using depression as a clinically relevant model to illustrate broader challenges and opportunities in neurotherapeutic delivery.