Actuation-dependent plume geometry in nasal spray delivery of lipid nanoparticles influences nasal deposition site and particle integrity
This study demonstrates that optimizing both the mechanical actuation parameters of nasal spray devices and the formulation of lipid nanoparticle suspensions is essential to simultaneously achieve targeted superior nasal deposition for nose-to-brain mRNA delivery and maintain particle integrity.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer
Getting medicine into the brain is one of the hardest challenges in modern medicine. The brain is protected by a formidable wall known as the blood-brain barrier, a security system that blocks nearly all large molecules and most drugs from entering. This defense keeps the brain safe from toxins but also prevents life-saving treatments for conditions like Alzheimer's or Parkinson's disease from reaching their target. Scientists have long looked to the nose as a potential backdoor. Because the nasal cavity has direct nerve pathways leading straight to the brain, spraying a drug inside the nose could allow it to bypass the blood-brain barrier entirely. However, the nose is a complex, winding tunnel. If a spray is too coarse or hits the wrong spot, the medicine gets stuck in the front of the nose and is swept away by the body's natural cleaning mechanisms before it can travel to the brain.
To make this nose-to-brain delivery work, researchers are turning to messenger RNA, or mRNA, the same technology used in vaccines, but packaged inside tiny, protective bubbles called lipid nanoparticles. These bubbles are fragile. They must remain intact and keep their cargo sealed until they reach the brain. The problem is that the very act of spraying them—forcing the liquid through a tiny nozzle at high speed—can rip these bubbles apart or leak their contents. A new study from researchers at Chungbuk National University in South Korea investigates how to balance these competing needs. They wanted to know if they could tune the spray mechanism to hit the right spot in the nose without destroying the medicine in the process, and whether adding specific ingredients to the liquid could help protect the fragile particles during the journey.
The team used a mechanical nasal spray pump, the kind that relies on a spring to push liquid out, and tested it under a variety of conditions. They varied how hard they pressed the spring, using forces of 4.8, 8.0, and 11.2 newtons, and how fast they pressed it, ranging from 80 to 180 millimeters per second. They filmed the spray in slow motion to see the shape of the mist, measured the size of the droplets, and then sprayed the liquid into a transparent, three-dimensional model of a human nose to see exactly where the drops landed. They also checked the health of the mRNA nanoparticles before and after the spray to see if the process had damaged them.
The results revealed a delicate trade-off. When the researchers pressed the spring harder, the spray produced smaller, finer droplets that traveled with more force. These powerful, fine droplets were much better at reaching the upper regions of the nasal cavity, specifically the superior turbinate, which is the area closest to the brain. However, this same forceful spray damaged the nanoparticles. Even though the particles looked roughly the same size after being sprayed, the amount of mRNA trapped inside them dropped significantly. In the most forceful tests, the efficiency of the particles holding their cargo fell from over 86 percent to below 55 percent. This means that simply turning up the power to get the medicine deeper into the nose actually destroyed a large portion of the dose.
Conversely, when the researchers pressed the button faster but with less force, the spray spread out wider. This wider mist tended to hit the middle part of the nose rather than the top, missing the target area for brain delivery. The study showed that the speed of the press and the force of the spring controlled different parts of the spray: the speed determined how wide the mist spread, while the force determined how small the droplets were. Neither setting alone could solve the problem; increasing the force helped with targeting but hurt the medicine, while changing the speed only shifted where the spray landed without fixing the damage.
To solve the damage problem, the researchers tested adding different stabilizing ingredients to the liquid, similar to how a chef might add an egg to a sauce to keep it from separating. They tried three different substances: hyaluronic acid, a cellulose derivative, and polyvinyl alcohol. All three helped prevent the nanoparticles from clumping together into large, useless masses. One ingredient, polyvinyl alcohol, stood out. When added at a concentration of 0.5 percent, it kept the nanoparticles safe from the stress of the spray, preserving their ability to hold the mRNA. Interestingly, adding this ingredient did not change the shape of the spray mist, but it did make the droplets larger. These slightly larger droplets landed more heavily in the middle of the nose, showing that the liquid itself could influence where the medicine went, independent of the spray device.
The study concludes that you cannot design the spray device and the medicine separately. The way the pump works and the ingredients in the liquid are locked in a relationship where one affects the other. To successfully deliver mRNA to the brain, engineers must tune the spray mechanism to aim for the upper nose while simultaneously designing the liquid to survive the violent process of being sprayed. The researchers found that while the device can be adjusted to hit the right target, it is the formulation—the specific mix of ingredients—that ultimately protects the fragile cargo. This integrated approach, where the machine and the medicine are developed together, offers a realistic path forward for turning nasal sprays into a viable way to treat diseases of the brain.
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