Overcoming the Blood-Brain Barrier with Peptide-Functionalized Lipid Panoparticles

Peptide-functionalized lipid nanoparticles (pLNPs) for targeted messenger RNA (mRNA) delivery to the brain.
Problem:
Ionizable lipid nanoparticles (LNPs) have emerged as clinically advanced delivery vehicles for nucleic acids. However, as LNPs typically accumulate to the liver, tissue-specific delivery remains challenging, and systemic LNP delivery to the brain is particularly challenging due to the highly selective blood-brain barrier (BBB). Current targeting approaches mainly use antibodies or proteins that bind to receptors overexpressed on the BBB. Although these ligands have high affinity to the BBB, they often have high immunogenicity, are large, expensive, and susceptible to degradation. Thus, alternative strategies are needed for LNPs to successfully cross the BBB and deliver nucleic acid therapeutics to the brain.
Solution:
LNPs are functionalized with brain-targeting peptides, which are much smaller alternatives to traditional targeting antibodies and proteins. These peptide-functionalized lipid nanoparticles (pLNPs) enhance mRNA delivery to the brain, and specifically neurons, and are a promising non-viral delivery platform for mRNA therapies for neurological disorders.
Technology:
A suite of pLNPs were designed with peptides targeting receptors overexpressed on brain endothelial cells and neurons, which were conjugated to LNPs using click chemistry. The pLNPs demonstrated high transfection efficiency in brain endothelial and neuronal cells in two-dimensional culture and co-culture transwell models in vitro. Following systemic injection, pLNPs enhanced mRNA transfection in the mouse brain and more specifically, in neurons, and had lower relative transfection in the liver compared to untargeted LNPs. These pLNPs demonstrate the potential of using targeting peptides and LNPs to deliver mRNA therapeutics across the BBB.
Advantages:

Lower immunogenicity, production costs, and size compared to targeting antibodies or proteins, which enable higher functionalization density for improved binding affinity and improved LNP stability and size profiles.
pLNPs improved transfection efficiency at least 5-fold in cultured brain endothelial and neuronal cells compared to untargeted LNPs.
pLNPs successfully enabled nucleic acid delivery across the BBB and to neurons in the brain parenchyma in vivo, improving transfection as high as ~70-fold compared to untargeted LNPs.
pLNPs preferentially targeted the brain instead of the liver in vivo, with a brain to liver ratio ~8-fold greater than mice treated with untargeted LNPs.

Stage of Development:

Proof of Concept

Schematic depicting peptide-functionalized LNP (pLNP) formulation, in vitro screening and validation, and in vivo systemic administration (top). Luciferase images demonstrate that pLNPs using various peptides enhanced nucleic acid delivery to the brain in mice compared to untargeted LNP (control, left) (bottom).
Intellectual Property: