Scientists have developed tiny gold particles that work like molecular Trojan horses, sneaking lithium directly into the brain through the nose. The approach could sidestep the kidney damage and thyroid problems that have plagued lithium therapy for more than 150 years.
The nanoparticles, about 2 nanometers across and coated with glutathione, clump together into aggregates that cells readily swallow. Once inside, the aggregates break apart and release their lithium cargo through a simple ion exchange, much like trading one metal for another at the atomic level. Researchers at Universita Cattolica del Sacro Cuore in Rome and the University of Salerno demonstrated that mice given the particles intranasally showed increased inhibitory phosphorylation of an enzyme called glycogen synthase kinase-3 beta, or GSK-3β, particularly in the hippocampus.
That enzyme matters because its hyperactivity shows up in bipolar disorder, Alzheimer’s disease, and infections that affect the brain. Lithium has been used clinically since 1870 to calm manic episodes, but doctors have always had to balance its benefits against its tendency to harm other organs when circulating through the bloodstream. The therapeutic window remains narrow: plasma concentrations between 0.8 and 1.2 milliequivalents per liter provide relief, but anything higher risks toxicity.
Bypassing the Bloodstream
The nasal delivery changes that calculus entirely. In mice treated for five days with the gold nanoparticles, plasma lithium levels stayed essentially unchanged compared to controls, even as GSK-3β phosphorylation in the hippocampus more than doubled. The particles appear to travel along olfactory nerve axons directly into the brain, avoiding systemic circulation altogether.
“Our challenge was to develop a device that would allow us to exploit the therapeutic potential of lithium without causing adverse effects and that could be delivered in a site-specific manner, avoiding systemic administration.”
Roberto Piacentini, an associate professor of physiology who led the research, notes that the approach worked even when mice received treatments for five months. No signs of neuroinflammation appeared in the hippocampus, based on measurements of glial fibrillary acidic protein, a marker for astrocyte activation. The animals’ weight, coat condition, and behavior remained normal throughout.
The gold itself seems to leave through the kidneys. When researchers measured gold content in both brain and kidney tissue after two months of treatment, they found a positive correlation, suggesting renal clearance removes the nanoparticles over time. That matters because any therapeutic agent given repeatedly needs an exit strategy.
Memory Rescued in Alzheimer’s Model
The team tested whether the particles could reverse existing cognitive decline in 12-month-old 3xTg-AD mice, an established model of Alzheimer’s disease. These animals typically show severe memory deficits by that age. After two months of treatment with the lithium-loaded nanoparticles, the mice performed significantly better on novel object recognition tests, with their preference index jumping from 45.4 percent before treatment to 65.9 percent after. Control mice showed no improvement.
The behavioral changes tracked with molecular ones. Total tau protein in the hippocampus dropped by 48 percent in treated mice, and phosphorylated tau decreased proportionally. The researchers also found that extremely low concentrations of lithium delivered via nanoparticles (0.15 milliequivalents per liter) protected cultured hippocampal neurons from synaptic damage caused by toxic tau oligomers, while the same concentration of lithium chloride did nothing.
“We believe that our nanotechnological tool can enable the development of new therapeutic approaches not only for psychiatric disorders but also for neurodegenerative and viral diseases in which altered GSK-3β activity in the brain plays a key role.”
In cultured human neuroblastoma cells, the nanoparticles delivered lithium about 26.5 times more efficiently than lithium chloride at equivalent extracellular concentrations. The particles work because they aggregate into structures roughly 100 to 300 nanometers across, which cells internalize readily through clathrin-mediated endocytosis. The aggregation protects inner lithium from being released prematurely in the extracellular environment, but once inside, the particle clusters disaggregate in the presence of cellular proteins and other biomolecules.
The synthesis process is straightforward enough that it might scale to commercial production without extraordinary costs. Tetrachloroauric acid, reduced glutathione, and lithium hydroxide are mixed in a hydroalcoholic solution, then sodium borohydride reduces the gold to metallic nanoparticles. The particles precipitate out when lithium chloride is added, and the whole procedure takes about two days.
GSK-3β phosphorylates more than 100 different proteins, so inhibiting it has wide-ranging effects. The enzyme adds phosphate groups to tau protein at threonine 205 and serine 396, modifications that promote the neurofibrillary tangles characteristic of Alzheimer’s. It also phosphorylates amyloid precursor protein at threonine 668, leading to cleavage that produces amyloid-beta peptides. Both pathologies appeared to ease in the treated mice.
The approach has been patented in Italy and internationally, and the researchers are now working on safety assessments needed before human trials. The particles’ loading capacity of 2 weight percent lithium and the ability to reach the hippocampus preferentially over other brain regions suggest the targeting works better than anyone might have predicted from first principles. Whether that translates to human patients with psychiatric disorders or dementia remains an open question, but the preclinical data make a compelling case for finding out.
Advanced Materials: 10.1002/adma.202513858
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