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Peptide-Functionalized Lipid Nanoparticles for Targeted Systemic mRNA Delivery to the Brain
Emily L Han1, Sophia Tang1, Dongyoon Kim1
1Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Nano Letters
|December 17, 2024
Summary
Targeted lipid nanoparticles (LNPs) carrying messenger RNA (mRNA) can now be delivered to the brain. Peptide-functionalized LNPs improve brain transfection and reduce liver accumulation for effective mRNA delivery.
Area of Science:
- Biotechnology
- Neuroscience
- Drug Delivery
Background:
- Systemic delivery of mRNA to the brain faces challenges due to the blood-brain barrier (BBB) and liver accumulation of delivery vehicles.
- Targeted delivery systems are crucial for overcoming these obstacles and enabling brain therapies.
Purpose of the Study:
- To design and evaluate a peptide-functionalized lipid nanoparticle (LNP) platform for targeted mRNA delivery to the brain.
- To investigate the efficacy of various targeting peptides (RVG29, T7, AP2, mApoE) in enhancing brain cell transfection and reducing off-target effects.
Main Methods:
- Utilized click chemistry to functionalize LNPs with brain-targeting peptides.
- Evaluated LNP transfection efficiency in brain endothelial and neuronal cells *in vitro*, assessing factors like protein adsorption and transcytosis.
- Assessed *in vivo* mRNA delivery, brain transfection, and biodistribution in mice after systemic administration.
Main Results:
- Peptide functionalization of LNPs enhanced mRNA transfection in brain endothelial and neuronal cells *in vitro*.
- RVG29-functionalized LNPs demonstrated improved neuronal transfection *in vivo* compared to non-functionalized LNPs.
- Systemic administration of peptide-functionalized LNPs reduced accumulation in the liver.
Conclusions:
- Peptide-functionalized LNPs represent a promising nonviral platform for targeted mRNA delivery to the brain.
- The RVG29 peptide shows particular potential for enhancing neuronal mRNA transfection *in vivo*.
- This approach offers a strategy to overcome BBB limitations for brain-targeted nucleic acid therapies.
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