Unlocking the brain: Peptide-guided nanoparticles deliver mRNA to neurons
Researchers in the lab of Michael Mitchell in Penn Engineering have developed a method for delivering lipid nanoparticles across the blood-brain barrier specifically to targeted neurons.
Penn Engineers have modified lipid nanoparticles (LNPs)—the revolutionary technology behind the COVID-19 mRNA vaccines—to not only cross the blood-brain barrier (BBB) but also to target specific types of cells, including neurons. This breakthrough marks a significant step toward potential next-generation treatments for neurological diseases like Alzheimer’s and Parkinson’s.
Emily Han is a doctoral student in the Mitchell Lab in Penn’s School of Engineering and Applied Science.
(Image: Bella Ciervo)
In a new paper in Nano Letters, the researchers demonstrate how peptides—short strings of amino acids—can serve as precise targeting molecules, enabling LNPs to deliver mRNA specifically to the endothelial cells that line the blood vessels of the brain, as well as neurons.
This represents an important advance in delivering mRNA to the cell types that would be key in treating neurodegenerative diseases; any such treatments will need to ensure that mRNA arrives at the correct location. Previous work by the same researchers proved that LNPs can cross the BBB and deliver mRNA to the brain, but did not attempt to control which cells the LNPs targeted.
The lab’s initial research “was like showing we could send a package from Pennsylvania to California, but we had no idea where in California it would end up,” says Michael J. Mitchell, associate professor in bioengineering and the paper’s senior author. “Now, with peptides, we can address the package to specific destinations with shared features, like every house with a red mailbox.”
Crossing the BBB is difficult because the structure has evolved to keep out virtually any dangerous or foreign molecules, including most medicines; mRNA molecules are too large to penetrate the barrier, as are most pharmaceuticals. The BBB also actively expels materials it deems hazardous.
Until now, most research on targeting specific organs with LNPs has focused on combining them with antibodies, large proteins that function like biological nametags. “When you put antibodies onto LNPs, they could become unstable and larger in size, which makes it really hard to squeeze through the barrier,” says Emily Han, a doctoral student in the Mitchell Lab and the paper’s first author.
In contrast to antibodies, which can be hundreds of amino acids in length, peptides are just dozens of amino acids long. Their smaller size means they’re not only easier to place in large numbers onto LNPs but cheaper to manufacture. Peptides are also much less likely than antibodies to aggregate during LNP formulation or to provoke unintended immune responses.
In Senegal, the ambitious Dakar Greenbelt project seeks to create an extensive network of ecological infrastructure in and around the city to sustainably address environmental concerns and enhance urban life. With support from David Gouverneur and Ellen Neises, Ph.D. candidate Rob Levinthal in the Weitzman School of Design led two courses that included a field trip to Dakar, that culminated in students presenting their visions for parts of the Greenbelt.
From a desert to an oasis: Penn engages in ambitious greening effort in the Sahel
Students from the Weitzman School of Design journeyed to Senegal to help with a massive ecological and infrastructural greening effort as part of their coursework. The Dakar Greenbelt aims to combat desertification and promote sustainable urban growth.
As part of an undergraduate course, Penn faculty and students curated an Arthur Ross Gallery exhibition of works from the Neumann family’s extensive collection of modern and contemporary art.
The University’s nexus for technology transfer supports researchers in their innovative efforts, from CAR T to mRNA advancements that have dramatically reshaped the world.
