Understanding How Changes in Acidity Cause Lipid Nanoparticles to Change State

A significant shift in the apparent pK_a of the aminolipid ALC-0315 from 9.3 in water to 4.9 within the lipid nanoparticle environment was observed.

• The protonation behavior of aminolipids in lipid nanoparticles (LNPs) is influenced by their structural dynamics and the surrounding pH.
• At low pH, protonated aminolipids are predominant at the LNP surface, facilitating the encapsulation of mRNA.
• At neutral pH, deprotonated aminolipids relocate to the hydrophobic core, contributing to the structural stability of the LNPs.
• The localized pK_a values of aminolipids vary depending on their position within the LNP, decreasing from 7 to 8 near the surface to 4 in the hydrophobic core.
• These findings provide insights into the molecular mechanisms of LNP phase transitions and the importance of pK_a shifts in optimizing lipid compositions for therapeutic applications.

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