Decoding pH‐Driven Phase Transition of Lipid Nanoparticles

Jan 17, 2026Small (Weinheim an der Bergstrasse, Germany)

Understanding How Changes in Acidity Cause Lipid Nanoparticles to Change State

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Abstract

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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The functionality of lipid nanoparticles (LNPs) as delivery systems in mRNA-based therapeutics is intricately linked to the protonation behavior of their aminolipid components. This study employs large-scale constant-pH molecular dynamics (CpHMD) simulations to decode the environment-dependentof aminolipids in the Comirnaty lipid formulation, providing a detailed view of their pH-dependent structural dynamics. Our results reveal a significant shift in the apparentof the aminolipid ALC-0315, from an intrinsic value of 9.3 in water to 4.9 within the LNP environment. This shift arises from the interplay between lipid reorganization and local electrostatic interactions, resulting in distinct protonation states across the LNP core and surface. At low pH, protonated aminolipids dominate the LNP surface, promoting efficient mRNA encapsulation, whereas at neutral pH, deprotonated aminolipids migrate to the hydrophobic core, driving structural stabilization. Notably, the localizedof aminolipids varies significantly with their position, decreasing from near-surface regions (7 to 8) to the hydrophobic core (4). These findings elucidate the molecular mechanisms underpinning LNP phase transitions and highlight the key role ofshifts for the design of aminolipids and for optimizing LNP compositions for enhanced therapeutic delivery. This study bridges experimental observations with molecular-level insights, advancing the rational development of next-generation lipid-based nanocarriers. pK a ${\rm pK}_{\text{a}}$ pK a ${\rm pK}_{\text{a}}$ pK a ${\rm pK}_{\text{a}}$ ≤ $\le$ pK a ${\rm pK}_{\text{a}}$

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Decoding pH‐Driven Phase Transition of Lipid Nanoparticles

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