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Decoding pH-Driven Phase Transition of Lipid Nanoparticles.

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Lipid nanoparticle (LNP) aminolipid protonation is key for mRNA therapeutics. Simulations reveal how ALC-0315

Keywords:
aminolipidconstant‐pH molecular dynamics simulationlipid nanoparticlepKaprotonation

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Area of Science:

  • Biochemistry and Molecular Biology
  • Materials Science
  • Pharmaceutical Sciences

Background:

  • Lipid nanoparticles (LNPs) are crucial delivery systems for mRNA therapeutics.
  • The protonation state of aminolipids within LNPs dictates their functionality.
  • Understanding pH-dependent behavior is essential for LNP design and efficacy.

Purpose of the Study:

  • To investigate the environment-dependent pKa of aminolipids in the Comirnaty LNP formulation.
  • To elucidate the structural dynamics and protonation states of aminolipids within LNPs.
  • To correlate aminolipid behavior with LNP stability and mRNA encapsulation.

Main Methods:

  • Large-scale constant-pH molecular dynamics (CpHMD) simulations.
  • Analysis of pKa shifts for ALC-0315 in aqueous and LNP environments.
  • Examination of lipid reorganization and electrostatic interactions.

Main Results:

  • The apparent pKa of ALC-0315 shifts significantly from 9.3 in water to 4.9 within the LNP.
  • Protonation states vary across the LNP, with protonated lipids at the surface (low pH) and deprotonated lipids in the core (neutral pH).
  • Localized pKa values decrease from 7-8 near the surface to <=4 in the hydrophobic core.

Conclusions:

  • Aminolipid pKa shifts are critical for LNP phase transitions and structural stability.
  • Protonation state modulation influences mRNA encapsulation and release.
  • These findings advance the rational design of advanced lipid-based nanocarriers for improved therapeutic delivery.