Hydrogen Bond-Assisted Two-Component Lipid Nanoparticles for Spleen-Specific mRNA Delivery

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery

Background:

• Conventional messenger RNA lipid nanoparticles (mRNA-LNPs) require acidic conditions and dialysis for preparation, limiting their practical applications.
• Existing methods often rely on electrostatic interactions, which can be less efficient for certain delivery goals.

Purpose of the Study:

• To synthesize peptide ionizable lipids (PILs) for hydrogen bond-assisted mRNA-LNP formation in RNase-free water.
• To develop an extrahepatic targeted mRNA delivery system simplifying LNP preparation.
• To establish a two-component (2C) LNP platform using PILs and cholesterol.

Main Methods:

• Solid-phase supported synthesis (SPSS) was used to create a series of PILs.
• Hydrogen bond interactions were utilized to assemble 2C-LNPs with cholesterol.
• In vivo studies evaluated mRNA expression in the spleen for 25 different 2C-PIL LNPs.

Main Results:

• Twenty out of 25 well-formulated 2C-PIL LNPs demonstrated significant mRNA expression in the spleen.
• a12K1 and a12Orn4 showed the best spleen-targeting performance.
• The 2C-LNP platform using hydrogen bonds outperformed conventional four-component (4C) LNPs in efficacy.

Conclusions:

• A hydrogen bond-assisted 2C-LNP platform offers a simplified and effective approach for spleen-targeted mRNA delivery.
• This platform shows potential for converting less effective LNPs into highly active ones.
• Tailored delivery vehicles can be designed for specific disease indications within the spleen.