Green-synthesized Nanoparticles as Emerging Antidepressant and Anxiolytic Candidates: A Critical Review of Preclinical Evidence and Translational Prospects.

The high incidence of depression and anxiety disorders worldwide, with figures of depression > 300 million and anxiety > 264 million, poses a serious challenge to health and wellness. Treatment is still limited by existing pharmacotherapies with delayed onset, adverse side effects, poor entry into the blood-brain barrier (BBB), and resistance in approximately 30% of patients. Green-synthesized nanoparticles (NPs) obtained via phytochemicals, microorganisms, and biomolecules are a promising sustainable route for neurotherapeutic applications. This critical review explores preclinical studies on the antidepressant and anxiolytic effects of green NPs, discussing their underlying mechanisms, translatability, and safety concerns in the context of the period 2015-2025. A comprehensive literature search on green synthesis, nanoparticles, Depression, Anxiety and Neurobehavioral outcomes was conducted using the Boolean operator in PubMed, Scopus, Web of Science, and Google Scholar. Evidence suggests that green NPs can facilitate both serotonergic and dopaminergic signal modulation, minimize neuroinflammation, recruit NFκB, activate antioxidant activity via the Nrf2/ HO-1 axis and induce neuroplasticity (Akt/CREB/BDNF axis). Their biogenic characteristics on the surface may enhance BBB transport and biocompatibility and reduce cytotoxicity and environmental persistence. However, there is still inadequate evidence regarding chronic toxicity, biodistribution, synthesis reproducibility, mechanistic validation and clinical evidence. Nano optimization by AI (as well as characterizing nanomaterials in a standardized manner), nanoinformatics and personalized nano-neuropharmacology in the future are required. Green NPs have promising therapeutic potential; however, this has mainly been demonstrated in preclinical studies.