Lung-Specific mRNA Delivery by Ionizable Lipids with Defined Structure-Function Relationship and Unique Protein...

Area of Science:

• Biomedical Engineering
• Drug Delivery
• Nanotechnology

Background:

• Targeted delivery of messenger RNA (mRNA) using lipid nanoparticles (LNPs) shows promise for treating lung diseases.
• Current limitations include a lack of design principles for effective lung-homing lipids, hindering mRNA therapeutic applications in the pulmonary system.

Purpose of the Study:

• To establish rational design principles for nonpermanently charged, lung-targeted ionizable lipids for mRNA delivery.
• To investigate the role of protein corona composition in the lung tropism of LNPs.

Main Methods:

• Combinatorial screening and structure-function analysis of ionizable lipids.
• Systematic variation of lipid chemical structures to assess pulmonary selectivity and efficiency.
• Identification and correlation of protein corona components with lung tropism.

Main Results:

• Ionizable lipids with N-methyl and secondary amine head groups and three epoxyalkane-derived tails demonstrated superior pulmonary selectivity and efficiency.
• Proteins rich in arginine-glycine-aspartic acid (RGD) motifs, including vitronectin, fibrinogen, and fibronectin, were identified in the LNP protein corona.
• A strong correlation was found between these RGD-rich proteins and lung tropism of the LNPs.

Conclusions:

• This study provides a rational design strategy for developing effective lung-targeting ionizable lipids for mRNA therapeutics.
• The findings reveal a novel association between RGD-rich proteins in the LNP protein corona and enhanced lung tropism, offering new insights for optimizing pulmonary drug delivery.