Predictive Lung- and Spleen-Targeted mRNA Delivery with Biodegradable Ionizable Lipids in Four-Component LNPs.

Area of Science:

• Biotechnology and Nanomedicine
• Drug Delivery Systems
• Molecular Biology

Background:

• Lipid nanoparticles (LNPs) are crucial for mRNA delivery, with ionizable lipids (ILs) being key components.
• Understanding the relationship between IL structure and LNP organ targeting is essential for optimizing delivery.
• Biodegradable ILs with beta-propionate linkers were developed to improve LNP extrahepatic selectivity and protein expression.

Purpose of the Study:

• To investigate the impact of structural modifications in ILs on LNP organ targeting and biodistribution.
• To establish structure-function relationships for ILs in LNP formulations for precise mRNA delivery.
• To identify novel ILs for targeted delivery to specific organs, such as the spleen and lungs.

Main Methods:

• Synthesized and formulated a library of biodegradable ILs with varying hydrophobic chains and polar-head groups.
• Evaluated LNP biodistribution, organ-specific targeting, and protein expression levels in vivo.
• Analyzed protein corona formation for mechanistic insights into LNP targeting.

Main Results:

• Structural modifications of ILs precisely controlled LNP biodistribution between spleen and lungs.
• Branched hydrophobic chains enhanced spleen targeting; polar-head group modifications shifted lung to spleen targeting.
• Identified zeta potential as a key determinant for extrahepatic targeting; A3T2C7 showed 97% lung selectivity.

Conclusions:

• Elucidated structure-function relationships of ILs for passive, organ-specific mRNA delivery.
• Demonstrated that fine-tuning IL structure (hydrophobic chains, polar-head groups, zeta potential) controls LNP biodistribution.
• Findings enable rational design of targeted LNP systems for spleen and lung therapeutic applications.