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Advancing lipid nanoparticle development with structure-based modeling platform and services

Overview

Lipid nanoparticle (LNP) technology has become the basis for many types of therapeutics. A detailed understanding of LNP structures and their behaviors will aid in implementing and optimizing many therapeutics. Schrödinger offers a computational modeling platform that enables structure-based modeling of LNPs to address challenges in composition-driven LNP structural and behavioral variations.

Bleb formation is an active area of LNP research that is believed to affect mRNA expression levels. Schrödinger can simulate the transition from mRNA dispersed within the LNP at low pH (left) to its localization in a bleb at high pH (right). Light blue: Water; Dark blue: Positively charged ionizable lipid; Green: Neutral ionizable lipid; Orange: Pegylated lipid; Red: mRNA.

Key Capabilities

Characterize LNPs as a function of composition1

  • Internal and surface structures
  • pH dependence
  • Water content
  • mRNA-lipid interactions

Predict apparent pKa values of ionizable lipids2

  • Key property for LNP performance
  • Structure based
  • Formulation dependent

Simulate features relevant for passive LNP targeting

  • Nature of LNP surface as a function of LNP composition
  • Association with endogenous proteins as a function of LNP composition

Elucidate active LNP targeting

  • Characterize key ligand-LNP behaviors, including: ligand attachment during production; effectiveness of tethering to LNP surface; and exposure targeting entities beyond the PEG layer
  • Quantify ligand-target engagement

Model endosomal escape to support the improvement of translation efficiency

  • Simulate the escape process
  • Identify trends in mRNA release as a function of LNP composition

References

  1. Coarse-grained simulation of mRNA-loaded lipid nanoparticle self-assembly.

    Grzetic DJ, Hamilton NB, and Shelley JC. Molecular Pharmaceutics. 2024, 21, 4747-4753.

  2. Calculating apparent pKa values of ionizable lipids in lipid nanoparticles.

    Hamilton NB, Arns S, Shelley M, Bechis I, and Shelley JC. Molecular Pharmaceutics. 2025, 22, 588-593.

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