Summary: Researchers have developed lipid nanoparticles ( LNPs ) that cross the blood-brain barrier ( BBB ) and precisely target brain cells, a major step toward treating neurological diseases like Alzheimer’s. Researchers were able to deliver targeted mRNA to neurons and epithelial cells by attaching little peptides to LNPs, avoiding invasive procedures.
Proteins are smaller, more secure, and easier to use than antigens, making them ideal for LNP-based treatment. The findings offer a method for delivering therapies instantly to damaged cells, potentially changing the treatment for mental diseases.
Researchers are now trying to determine the amount of neurons needed to achieve therapeutic results by improving distribution effectiveness. This development significantly brings mRNA-based remedies for mental disorders to therapeutic use.
Essential Information
- Precise Targeting: Acids on fat particles allow mRNA to pin brain cells.
- Crossing the BBB: LNPs effectively bypass the blood-brain challenge to provide care.
- Therapy Potential: Could lead to mRNA-based procedures for Alzheimer’s and Parkinson’s.
Origin: University of Pennsylvania
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 discovery represents a major advance in the development of novel procedures for Alzheimer’s and Parkinson’s neurological conditions.
The researchers demonstrate how little strings of amino acids, known as peptides, may be specific targeting molecules, enabling LNPs to provide mRNA especially to the epithelial cells that line the brain’s blood vessels and neurons in a , a new document in Nano Letters.  ,
Any treatments that target neurological conditions will need to guarantee that mRNA arrives at the appropriate place given this significant progress in delivering rna to the cell types.  ,
Researchers at the same  previously demonstrated that LNPs you cross the BBB and provide mRNA to the mind, but they did not attempt to determine which tissues the LNPs targeted.
” Our first paper was a proof-of-concept lipid nanoparticle design”, says , Michael J. Mitchell, Associate Professor in Bioengineering ( BE ) and the paper’s senior author.
” It was like demonstrating that we could deliver a package from Pennsylvania to California, but we had no idea where it would land. Then, with peptides, we can handle the bundle to specific places with shared functions, like every house with a dark mailbox”.
Accessing the Mind: A Challenge to the Journey
Crossing the BBB is tough because the construction has evolved to maintain out almost any harmful or unusual substances, including most medicines, mRNA molecules are too big to reach the challenge, as are most pharmaceuticals. Additionally, the BBB constantly recycles any waste it considers harmful.  ,
” You can add a remedy directly into the head or spine, but these are very aggressive procedures”, says , Emily Han, a graduate student in the Mitchell Lab and the paper’s second author.  ,
Certain formulations of LNPs, which are partially made of the same family of fatty compounds found in regular oils, can sneak through the brain because the BBB allows fat-soluble molecules through ( like alcohol and THC), which is why those substances affect the brain.  ,
Peptides vs. Antibodies
Bis now, the majority of research on using LNPs to target specific organs has focused on combining them with large proteins that act like biological nametags.
” When you put antibodies on LNPs, they could become unstable and larger, which makes it really difficult to squeeze through the barrier,” Han claims.  ,
In contrast to antibodies, which can be hundreds of amino acids in length, peptides are just dozens of amino acids long. Because of their smaller size, they are also less expensive to manufacture and are also less expensive to place in large numbers on LNPs. Peptides are also much less likely than antibodies to aggregate while being formulated into LNPs or to trigger unintended immune responses.
Han and a bat that had an unanticipated encounter with her made the decision to use peptides, which might have given her the opportunity to contract rabies. Han became aware of the fact that one of the ways the rabies virus crosses the BBB is through the rabies virus glycoprotein while researching the vaccines she received against the disease.
” I then stumbled across one of our most promising targeting peptides”, Han says, a molecule known as RVG29, a 29-amino-acid segment of that protein.  ,
Testing the Concept
The researchers first needed to check whether the peptides adhered to the LNPs in order to confirm that they were working as intended.
” Our LNPs are a complex mixture of nucleic acids, lipids and peptides”, says Han.
We had to “optimize quantification techniques to pick out the peptides against all those other signals.”
The researchers then had to check whether or not the peptide-functionalized LNPs (pLNPs ) actually reached the intended targets in animal models once they had learned the peptides had adhered to the LNPs.
” It’s really difficult to set up”, says Han, “because in the brain, you have so many different cell types and a lot of fat that can interfere with measurements”.
Han spent more than six months developing a procedure that was meticulously disassembled brain tissue, almost like a mechanic disassembles an engine.  ,
Future Directions
Next, the team wants to determine how many neurons must be treated with pLNPs to effectively treat symptoms or possibly treat neurological conditions. ” Returning to the same analogy, do we need to send these to every house with a red mailbox, or just 10 % of them? Would 10 % of neurons be enough”? asks Mitchell.  ,
Answering this question will guide the development of even more efficient delivery strategies, bringing the promise of mRNA-based treatments for Alzheimer’s, Parkinson’s and other brain diseases closer to reality.  ,
Funding: This study was conducted at the University of Pennsylvania School of Engineering and Applied Science and supported by the U. S. National Institutes of Health ( DP2 TR002776 ), the Burroughs Wellcome Fund, the US National Science Foundation ( CBET-2145491 ), and the American Cancer Society ( RSG-22-122-01-ET ).
Additional co-authors include Sophia Tang, Dongyoon Kim, Amanda M. Murray, Kelsey L. Swingle, Alex G. Hamilton, Kaitlin Mrksich, Marshall S. Padilla and Jacqueline Li of Penn Engineering, and Rohan Palanki of Penn Engineering and the Children’s Hospital of Philadelphia.  ,
The authors claim that Emily Han and Michael J. Mitchell are the inventors of a patent relating to this work, which was submitted by the University of Pennsylvania’s Trustees ( U.S. Provisional Patent Application No. 2 ). 63/710, 179, filed October 22, 2024 ). All other authors make the declaration that they have no competing interests.
About this news about genetics and neurotechnology research
Author: Ian Scheffler
Source: University of Pennsylvania
Contact: Ian Scheffler – Univesity of Pennsylvania
Image: The image is credited to Neuroscience News
Original Research: Closed access.
Michael Mitchell and colleagues ‘” For brain-targeted systemic mRNA delivery, lipid nanoparticles with Peptide-functionalized lipid nanoparticles” Nano Letters
Abstract
For brain-targeted systemic mRNA delivery, lipid nanoparticles with Peptide-functionalized lipid nanoparticles
The blood-brain barrier ( BBB ) and the tendency for delivery vehicles to accumulate in the liver are some of the obstacles to systemic delivery of large nucleic acids, such as mRNA, to the brain.
Here, we design a peptide-functionalized lipid nanoparticle ( LNP ) platform for targeted mRNA delivery to the brain.
We use click chemistry to functionalize LNPs by using peptides that target receptors that have been overexpressed on brain endothelial cells and neurons, such as the RVG29, T7, AP2, and mApoE peptides.
We evaluate the effect of LNP targeting on brain endothelial and neuronal cell transfection , in vitro, investigating factors such as serum protein adsorption, intracellular trafficking, endothelial transcytosis, and exosome secretion.
Finally, we demonstrate that LNP peptide functionalization reduces hepatic delivery following systemic administration and enhances mRNA transfection in the mouse brain.
Specifically, RVG29 LNPs improved neuronal transfection , in vivo, establishing its potential as a nonviral platform for delivering mRNA to the brain.
