Lipid nanoparticles can now target neurons
Novel peptide-modified lipid nanoparticles can cross the blood–brain barrier and target neurons, taking one step closer to next-generation treatments for neurological diseases.
Researchers at the University of Pennsylvania School of Engineering and Applied Science (PA, USA) have modified lipid nanoparticles (LNPs) to be able to cross the blood–brain barrier (BBB) and target specific cells within the brain. This development enables the delivery of mRNA to the brain, facilitating the potential for next-generation neurological treatments targeted at relevant cell types.
LNPs are vessels containing different therapeutic material, such as mRNA, that serve as delivery vehicles. Although they have had tremendous success forming the basis of the COVID-19 mRNA vaccines, trying to get these LNPs into the brain remains a challenge. That’s because the BBB, a tightly locked layer of cells protecting the brain, is designed to keep foreign – and potentially harmful – agents from infiltrating the brain. Unfortunately, this also includes therapeutic agents.
Fat-soluble molecules are allowed to cross the BBB, which is why substances like alcohol and THC affect the brain. Therefore, constructing LNPs that are partially made of fatty compounds present in everyday oils may be key to sneaking therapeutics through the BBB.
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Building on this idea, previous research by the same group demonstrated how to design LNPs to facilitate their movement across the BBB; however, these LNPs were not targetable to any specific cell types once in the brain. Now, the team has utilized peptides to ensure delivery of the LNPs to specific cellular destinations.
Although antibodies have been the predominant focus for targeting LNPs toward specific cells, the current research team decided that they would utilize peptides – being smaller and less likely to aggregate – to direct the LNPs. The inspiration behind the decision to pursue peptides instead of antibodies stemmed from an encounter first author Emily Han had with a bat flying into her room and the subsequent information she sought out regarding rabies vaccines. It was during this search that Han learned that the rabies virus can cross the BBB due to a glycoprotein on its surface.
Using click chemistry, the team attached peptides that specifically targeted overexpressed receptors on endothelial cells and neurons to their LNPs. They then had to confirm that the peptides were in fact binding properly before being able to assess their ability to target specific cells. They assessed the effect of LNP targeting on brain endothelial and neuronal cells in vitro, finding that peptide-modified LNPs enhance mRNA transfection in mouse brain cells. They further showed that one kind of peptide – called RVG29 – was particularly effective during in vivo experiments in mice.
The next step for the team is deciphering how many neurons need to be treated with peptide-modified LNPs to relieve neurological symptoms. The answer to this will inform how this therapeutic delivery method is developed further and eventually implemented in a clinical setting.
