Bioengineers on the verge of crossing the blood-brain barrier

Think of the brain as an air traffic control tower, overseeing the crucial and complex “airport” operations of the body. This tower, essential for coordinating the incessant flow of neurological signals, is guarded by a formidable layer that functions like the airport security team, diligently controlling everything and everyone, ensuring that no unwanted intruders disrupt the vital functioning inside.

However, this safety, while vital, has a major drawback: Sometimes a “mechanic” – in the form of essential medications needed to treat neurological disorders – is sometimes needed inside the control tower to troubleshoot problems. which occur. But if security is too tight, denying even these essential agents entry, the very operations they are meant to protect could be compromised.

Now, researchers led by Michael Mitchell of the University of Pennsylvania are addressing this long-standing frontier in biology, known as the blood-brain barrier, by developing a method akin to providing that mechanic with a key card special to bypass security. Their conclusions, published in the journal Nano letterspresent a model that uses lipid nanoparticles (LNPs) to deliver mRNA, offering new hope for treating diseases such as Alzheimer’s and seizures, much like solving control tower problems without compromise its security.

“Our model was more successful in crossing the blood-brain barrier than others and helped us identify organ-specific particles that we then validated in future models,” says Mitchell, associate professor of bioengineering at Penn’s School of Engineering and Applied Science, and lead author. on the study. “This is an exciting proof of concept that will undoubtedly inform new approaches to treating diseases such as traumatic brain injury, stroke and Alzheimer’s disease.”

Find the key

To develop the model, Emily Han, a Ph.D. candidate and NSF graduate researcher at the Mitchell Lab and first author of the paper, explains that it started with a search for the right in vitro screening platform, saying, “I combed through the literature, the Most of the platforms I found were limited. to an ordinary 96-well plate, a two-dimensional array that cannot represent both the upper and lower parts of the blood-brain barrier, which correspond to the blood and the brain, respectively.

Han then explored high-throughput Transwell systems with both compartments, but found that they did not account for the cells’ mRNA transfection, revealing a gap in the developmental process. This led her to create a platform that could measure the transport of mRNA from the blood compartment to the brain, as well as the transfection of various types of brain cells, including endothelial cells and neurons.

“I spent months determining the optimal conditions for this new in vitro system, including cell growth conditions and fluorescent reporters to use,” says Han. “Once robust, we looked at our library of LNPs and tested them in animal models. Seeing the brains express proteins through the mRNA we delivered was exciting and confirmed that we were on the right track.”

The team’s platform is poised to significantly advance treatments for neurological disorders. It is currently designed to test a range of LNPs containing peptides, antibodies and various lipid compositions targeting the brain. However, it could also deliver other therapeutic agents like siRNA, DNA, proteins or small molecule drugs directly into the brain after intravenous administration.

Furthermore, this approach is not limited to the blood-brain barrier, as it shows promise for exploring treatments for pregnancy-related diseases by targeting the blood-placental barrier, and for retinal diseases by focusing on the blood-brain barrier. focusing on the blood-retinal barrier.

The team looks forward to using this platform to examine new designs and test their effectiveness in different animal models. They are particularly interested in working with collaborators on advanced animal models of neurological disorders.

“We are collaborating with researchers at Penn to establish models of brain diseases,” says Han. “We are examining the impact of these LNPs in mice with a variety of brain conditions, ranging from glioblastoma to traumatic brain injury. We hope to make progress in repairing the blood-brain barrier or targeting damaged neurons after injury.”

Other authors include Marshall Padilla, Rohan Palanki, Dongyoon Kim, Kaitlin Mrksich, Jacqueline Li, Sophia Tang and Il-Chul Yoon of Penn Engineering.