Structure–Activity Relationship of Ionizable Lipids for siRNA and mRNA Lipid Nanoparticle Design

A total of 465 lipids were evaluated to identify those with high mRNA delivery efficacy.

• Chemical alterations in the carbon chain of ionizable amino lipids were synthesized and tested for their impact on lipid nanoparticle potency.
• Physicochemical properties such as size, polydispersity index, pH, and buffering capacity were measured to understand their relationship with mRNA delivery effectiveness.
• The findings suggest that both pH and buffering capacity may be important indicators for predicting hepatic delivery of mRNA-loaded lipid nanoparticles.
• The acceptable pH range for lipid nanoparticles was expanded to 6.2-7.4 based on structural evaluations.
• The study emphasizes the significance of the chemical structure of ionizable amino lipids in optimizing lipid nanoparticle design for RNA delivery.

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