Researchers have developed a novel nanomedical technology that uses a nasal spray to deliver gold nanoparticles loaded with lithium directly to the brain. This method targets neuropsychiatric and neurodegenerative diseases at their source, potentially revolutionizing treatment for conditions like bipolar disorder and Alzheimer’s disease while minimizing the significant side effects associated with current therapies.
The new device, created by scientists at Università Cattolica in Rome in collaboration with the University of Salerno, overcomes the longstanding challenge of bypassing the blood-brain barrier. By using an intranasal delivery system, the therapeutic agent can reach the central nervous system without entering the systemic bloodstream, offering a safer, more targeted approach. Preclinical studies in animal models of Alzheimer’s disease have already shown that this method can restore memory function and inhibit a key enzyme implicated in the disease’s progression, paving the way for future clinical applications.
Overcoming the Brain’s Defenses
Delivering drugs to the brain is notoriously difficult due to the blood-brain barrier, a highly selective membrane that protects the brain from toxins and pathogens in the bloodstream. While essential for survival, this barrier also blocks the vast majority of therapeutic molecules, making treatment of neurological disorders a significant medical challenge. Traditional methods, such as oral medications, require high doses to ensure a sufficient amount reaches the brain, leading to widespread effects on other organs and often severe side effects. Direct injections are invasive and carry substantial risks.
The intranasal route offers a non-invasive shortcut. The nasal cavity contains pathways—specifically, the olfactory and trigeminal nerves—that lead directly to the brain. Administering therapies through a nasal spray allows drugs to travel along these neural pathways, bypassing the blood-brain barrier entirely. This technique not only increases the concentration of the drug delivered to the brain but also reduces its exposure to the rest of the body, thereby enhancing safety and efficacy.
A Novel Nanoparticle Carrier System
The core of the new technology is a specially designed gold nanoparticle. This carrier system is engineered to be loaded with a therapeutic payload—in this case, lithium—and transported efficiently into brain cells.
The Gold Vehicle
Gold was chosen as the carrier material due to its unique properties. It is an inert metal, meaning it is biologically harmless and does not react undesirably within the body. The nanoparticles are functionalized with glutathione, a compound that encourages the particles to form aggregates that can easily enter cells. Once inside, these aggregates break down, releasing their payload. The gold itself is eventually eliminated from the body through the kidneys, which limits its accumulation in the brain over time, even with repeated administrations. According to the researchers, the synthesis process for these nanoparticles is straightforward, which could help keep manufacturing costs low for a future pharmaceutical product.
Lithium as a Therapeutic Payload
The drug chosen for this delivery system is lithium, a potent inhibitor of an enzyme called glycogen synthase kinase-3 beta (GSK-3β). This enzyme is vital for many cellular functions, but its abnormal hyperactivity is a known factor in the pathology of several major diseases. In neuropsychiatric conditions like bipolar disorder and neurodegenerative diseases such as Alzheimer’s, GSK-3β is overactive, leading to the malfunction of key proteins like tau. Lithium is already a standard treatment for bipolar disorder, but the high oral doses required to impact the brain can be toxic to the kidneys and thyroid. This new method allows for much lower doses to be used, concentrating the drug where it is needed most.
Preclinical Success in Alzheimer’s Model
The research team demonstrated the effectiveness of their nanodevice in a mouse model of Alzheimer’s disease. The study, published in the journal Advanced Materials, showed significant results over a relatively short period. After just five days of administering the lithium-coated gold nanoparticles (referred to as LiG-AuNPs), there was a measurable inhibition of GSK-3β activity in the hippocampus, a brain region critical for memory.
When the treatment was extended to two months, the effects were even more pronounced. The mice showed a significant regression of memory deficits, with their performance in behavioral and molecular analyses improving notably. These results were achieved without any observable adverse events in the test animals, highlighting the safety of the targeted, low-dose approach. These findings provide strong evidence that the nasal spray can effectively deliver a therapeutic dose of lithium to halt and even reverse key pathological indicators of the disease in a preclinical setting.
Reducing Side Effects and Systemic Load
A primary motivation for developing this technology was to mitigate the well-documented side effects of oral lithium therapy. When taken as a pill, lithium circulates throughout the body via the bloodstream before a small fraction of it crosses the blood-brain barrier. This systemic exposure exerts toxic effects on other organs, particularly the thyroid and kidneys, requiring patients to undergo regular monitoring.
The intranasal gold nanoparticle system avoids this issue almost entirely. By delivering lithium directly to the brain, it achieves effective concentrations in nerve cells with a much lower overall dose. This site-specific action is a major innovation that could make lithium a safer and more viable long-term treatment option not only for bipolar disorder but also for neurodegenerative conditions where its therapeutic potential has been limited by the risk-benefit ratio of high-dose administration.
Future Therapeutic Potential
The research team, which has secured a patent for the technology, is confident that its applications extend far beyond Alzheimer’s disease. The versatility of the gold nanoparticle platform is a key advantage; the carriers can be loaded with different pharmacologically active ingredients to target a wide range of conditions. The hyperactivation of the GSK-3β enzyme is implicated in other neurodegenerative and psychiatric disorders, suggesting this specific formulation could have broader use.
Furthermore, researchers note that the GSK-3β enzyme plays a role in the entry of certain viruses into the central nervous system, including Herpes Simplex Virus type 1, which some studies have linked to neurological damage. This suggests the nanodevice could be adapted to develop new therapeutic approaches for viral brain infections. Studies are ongoing to explore these other applications and to complete the safety assessments necessary to advance toward clinical trials in humans.