Lithium-Charged Gold Nanoparticles: A New Powerful Tool for Lithium Delivery and Modulation of Glycogen Synthase Kinase 3 Activity

“A Trojan Horse for Lithium Delivery”. Lithium has important pharmacological applications, although its use is severely limited due to its narrow therapeutic window of administrable concentrations. This study presents a novel nanocarrier for this metal cation based on glutathione-stabilized gold nanoparticles (LiG-AuNPs), which enable targeted release of lithium. LiG-AuNPs are easily synthesized, with dimensions of ≈2 nm, with a lithium loading of 2 wt%. These particles show a tendency to aggregate and a narrow size distribution. Aggregates of LiG-AuNPs (a-LiG-AuNPs) are non-toxic to cells at concentrations lower than 2 mg mL−1 and are rapidly internalized into cells, where they release lithium in the cytosol through cation exchange, effectively modulating Glycogen Synthase Kinase-3 (GSK-3β) activity, especially the β isoform. Administration of a-LiG-AuNPs in murine models increased the inhibitory phosphorylation of GSK-3β at Ser9. Intranasal administration of a-LiG-AuNPs modulated GSK-3β activity in the brain, particularly in the hippocampus, without significantly altering plasma lithium levels, even when the administration lasted several months. LiG-AuNPs thus represent a powerful tool for the targeted administration of lithium, enhancing its therapeutic effects in modulating GSK-3β. They have potential applications for treating illnesses depending on GSK-3β (hyper)activation, such as mood disorders, Alzheimer's disease, and viral infections.