Engineering lipid nanoparticle surface hydrophobicity to modulate nano-bio interface and enable tissue-selective mRNA...

Area of Science:

• Biotechnology
• Nanomedicine
• Gene Therapy

Background:

• Lipid nanoparticle (LNP) accumulation in the liver hinders gene therapy applications.
• Surface properties of LNPs, like pKa, influence tissue-specific delivery.
• Alternative mechanisms for LNP delivery beyond liver targeting are being explored.

Purpose of the Study:

• To investigate the role of LNP surface hydrophobicity in extrahepatic delivery.
• To establish modulation of surface hydrophobicity as a strategy for targeted gene delivery.

Main Methods:

• Utilized dendrimers as modular components to create tunable dendrimer-based LNPs (dLNPs).
• Developed and employed an in-house surface hydrophobicity assay.
• Analyzed plasma protein adsorption and cellular targeting of dLNPs with varying hydrophobicity and surface charge.

Main Results:

• Reduced lipid grafting decreased dLNP surface hydrophobicity, plasma stability, and protein adsorption, diminishing liver targeting.
• Lower hydrophobicity enhanced granulocyte targeting, potentially via complement interactions.
• Quaternary amine modification increased surface charge, improving lung epithelial cell targeting and lung delivery, linked to distinct protein coronas.

Conclusions:

• LNP surface hydrophobicity is a critical factor influencing extrahepatic delivery mechanisms.
• Modulating hydrophobicity and surface charge offers a novel strategy to control LNP biodistribution for targeted gene therapies.
• This work opens new avenues for optimizing LNP delivery beyond the liver.