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An experimental nasal spray improved memory and reduced brain inflammation in aged mice by delivering microscopic packets released by human neural stem cells.

The finding is still an early trial, and it’s only been shown in mice, but it points to a promising idea: maybe some of the brain-supporting effects of stem cells can be delivered without surgery, cell implants, or invasive procedures.

The treatment used tiny biological parcels called extracellular vesicles. These vesicles were released by human neural stem cells and appeared to reach the brain through the nose. Once there, they seemed to calm microglia, the immune cells that can help drive chronic inflammation in the aging brain.

If scientists can make the approach safe, reliable, and effective in humans, it could open a new route for treating age-related cognitive decline.

The Fire Alarm in the Brain

Aging can creep in quietly, both in your muscles and in your brain. A little oxidative stress here, some irritable cells there, and suddenly a slow fog starts to settle over your memory circuits.

You can slow down that process by having a healthy lifestyle, especially by reducing chronic inflammation. In the hippocampus, one of the brain’s key memory hubs, this type of inflammation is exactly what usually causes aging-related problems. But it’s not the raging inflammation you have during an infection. It’s more like a chirping smoke alarm that just doesn’t stop.

Now, researchers report that a treatment delivered through the nose helped hush that alarm in aged mice.

Scientists have pursued several broad strategies to protect or repair the brain. Some aim to replace or regenerate neurons, while others try to change the brain environment — for example, by reducing inflammation, oxidative stress or toxic protein buildup. In this study scientists tested the second approach. Instead of trying to replace old neurons or grow new ones, they delivered tiny biological parcels (called extracellular vesicles) from human neural stem cells into the noses of aging mice.

These extracellular vesicles are small, membrane-bound packets stuffed with proteins, RNA molecules and other cargo. In this study, the vesicles came from neural stem cells made from human induced pluripotent stem cells (adult cells that have been reprogrammed into a stem-like state and then pushed to become neurons).

The Brain-Nose Shortcut

The study was led by Ashok Shetty from Texas A&M University, along with senior research scientists Madhu Leelavathi Narayana and Maheedhar Kodali.

“Brain age-related diseases like dementia are a major health concern worldwide,” Shetty said. “What we’re showing is brain aging can be reversed, to help people stay mentally sharp, socially engaged and free from age-related decline.”

The researchers used 18-month-old mice, which the authors describe as roughly equivalent to late middle age in humans. The mice received two intranasal doses of extracellular vesicles, spaced two weeks apart.

“The mode of delivery is one of the most exciting aspects of our approach,” Kodali said. “Intranasal delivery allows us to reach, and treat, the brain directly without invasive procedures.”

The vesicles carried microRNAs, small molecules that help regulate gene activity and biological signaling pathways.

“MicroRNAs act like master regulators,” Narayana said. “They help modulate and regulate many gene and signaling pathways in the brain.”

Calming the Brain

The vesicle-treated mice showed less inflammation in the hippocampus, a memory-related region of the brain. The vesicles appeared to work by changing the state of immune cells in the aging brain. In treated mice, microglia showed less inflammatory activity, while the hippocampus showed lower oxidative stress and stronger signs of mitochondrial energy function.

The treated mice also performed better on memory tests.

The researchers used two tests. In one, mice were expected to recognize a new object. In the other, they were expected to notice when an object had been moved to a new location. The treated mice spent more time exploring the new or moved object, which the researchers interpreted as better recognition and spatial memory.

The likely reason is a healthier brain environment. The vesicles appeared to calm overactive microglia, the “janitor” cleaners of the brain. The treatment also appeared to reduce inflammatory pathways, lower oxidative stress and improve signs of mitochondrial energy function in the hippocampus, a brain region important for memory.

Basically, the treatment is enabling the brain to keep itself healthier.

“We are seeing the brain’s own repair systems switch on, healing inflammation and restoring itself,” Shetty said.

Does It Work on Humans? How the approach would work in humans.

The study doesn’t show that such a nasal spray would work in people. Mouse brains age differently from human brains, and the route from a mouse test to a human one is long. The authors also flagged unanswered questions about when treatment should begin, which dose is best, how durable the effects are, and whether males and females may respond differently in subtle ways.

Still, the work points to an appealing possibility.

Cell transplantation has long been an attractive idea, because the brain loses or damages cells in many disorders, and replacing them sounds like a direct fix. This study suggests that rather than transplanting cells into the brain, it may one day be possible to deliver some of their useful messages through the nose — nudging aging immune cells away from chronic inflammation and toward a calmer state.

“As we develop and scale this therapy, a simple, two-dose nasal spray could one day replace invasive, risky procedures or maybe even months of medication,” Shetty said.

The findings are all the more important as dementia is set to rise sharply around the world. The World Health Organization estimates that 57 million people were living with dementia in 2021, with nearly 10 million new cases each year. Alzheimer’s Disease International projects that the number will reach 78 million by 2030 and 139 million by 2050.