Lithium-Loaded Gold Nanoparticle Nasal Spray to Treat Neuropsychiatric Diseases

Investigators have discovered a new nanotechnological device for the treatment and prevention of neuropsychiatric and neurodegenerative diseases: lithium-loaded gold nanoparticles in the form of a nasal spray that delivers treatment directly to the brain. This could be a revolutionary approach to neuropsychiatric diseases such as bipolar disorder, neurodegenerative diseases such as Alzheimer disease, and brain infections such as those caused by Herpes Simplex Virus type 1.^1,2

In the study, investigators demonstrated the effectiveness of this nanotechnology in inhibiting the activity of the glycogen synthase kinase-3 beta (GSK-3β) enzyme in the hippocampus and restoring memory already compromised in an experimental model of Alzheimer disease. This approach achieves the same effects as orally administered lithium but uses significantly lower concentrations of the ion and targets it specifically to the brain, reducing the risk of adverse effects. Studies are currently underway to verify other areas of application for this device and to complete its safety assessment in order to proceed quickly with its clinical application.

The nanotechnology was developed by scientists at the Università Cattolica Rome campus/Fondazione Policlinico Universitario A. Gemelli IRCCS, and has a patent in Italy and abroad. The research team is led by Roberto Piacentini, associate professor of physiology at Università Cattolica - Fondazione Policlinico Universitario A. Gemelli IRCCS; Antonio Buonerba, associate professor of inorganic chemistry at the University of Salerno; Alfonso Grassi, full professor of inorganic chemistry at the University of Salerno; and Claudio Grassi, professor of physiology and director of the department of neuroscience at the Università Cattolica/Fondazione Policlinico Universitario Agostino Gemelli IRCCS. The research was funded with an award by the Alzheimer's Association in the United States to Profs Piacentini and Buonerba and the support of the Agostino Gemelli IRCCS University Hospital Foundation.

“In this work we have shown that 5 days of administration of gold nanoparticles functionalized with glutathione and coated with lithium (called LiG-AuNPs) can significantly inhibit the activity of GSK-3β kinase in the hippocampus of mice, and that the same treatment repeated for 2 months leads to a significant regression of the memory deficit exhibited by a mouse model of Alzheimer's disease, analyzed at the behavioral and molecular levels," said Giulia Puliatti, one of the study’s authors.

GSK-3β is an enzyme that is essential for many cellular functions, with an estimated 100+ proteins targeted by this kinase. Abnormal activation of this enzyme can cause malfunctioning of the target proteins and promote the onset of various diseases. In the case of neurodegenerative diseases, such as Alzheimer disease, or neuropsychiatric disorders such as bipolar disorder, hyperactivation of the GSK-3β enzyme is observed. Investigators believe controlling the activation of this enzyme in specific areas of the brain could counteract the onset of diseases. Lithium, which is a potent inhibitor of GSK-3β, is already in use in the treatment of neuropsychiatric disorders such as bipolar disorder. Higher concentrations of lithium are needed to counteract the molecular mechanisms responsible for neurodegenerative diseases or viral infections affecting the central nervous system—higher than those considered acceptable in terms of risk/benefit ratio.

“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,” said Piacentini.

“Gold nanoparticles are the optimal tool for this type of strategy. They can be functionalized with glutathione, which, on the one hand, promotes the formation of aggregates that easily enter cells and, on the other, allows molecules or ions, such as lithium, to bind. Once the nanoparticle aggregates enter the cells, they are broken down and the lithium is released into the cells, allowing effective therapeutic concentrations of this ion to be obtained with low doses of administration,” shared Buonerba. “The versatility of this new pharmaceutical vector is extraordinary. The nanoparticles developed can be loaded with different pharmacological active ingredients and are able to evade biological cellular defenses, allowing their targeted transport to specific physiological active sites."

“Furthermore, the intranasal route is an elective route for directly targeting the brain and bypassing the systemic circulation, thus optimizing the safety of our nanodevice. Gold, an inert metal that has already been proven to be harmless in biological systems, is eliminated through renal excretion, limiting its accumulation in the brain following repeated administrations over time,” said Piacentini.

“To date, lithium-based drugs are widely used for the treatment of neuropsychiatric diseases, but unfortunately, they are not without significant side effects. Taken orally in tablet form, lithium reaches the brain through the bloodstream and therefore ends up exerting toxic effects on other organs such as the kidneys and thyroid. Achieving effective concentrations of lithium in nerve cells through ‘brain-targeted’ administration of low doses of the ion with the aid of gold nanoparticles is therefore an important innovation for the development of new and safer ways of treating patients. 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,” said Claudio Grassi.

“Finally, our nanoparticles can be synthesized very easily and that simplifies the production process, keeping low the costs of manufacturing a product that may be launched on the pharmaceutical market in the near future,” concluded Alfonso Grassi.

References

1. In a nasal spray, gold “nanoparticles” deliver a targeted treatment to the brain. a potentially revolutionary approach to mental disorders and neurodegenerative diseases already has a patent. New release. October 7, 2025. Accessed October 8, 2025. https://www.newswise.com/articles/in-a-nasal-spray-gold-nanoparticles-deliver-a-targeted-treatment-to-the-brain-a-potentially-revolutionary-approach-to-mental-disorders-and-neurodegenerative-diseases-already-has-a-patent/?sc=mwhr&xy=5013482

2. Buonerba A, Puliatti G, Puma DDL, et al. Lithium-charged gold nanoparticles: a new powerful tool for lithium delivery and modulation of glycogen synthase kinase 3 activity. Adv Mater. 2025:e13858. Online ahead of print.