Coacervation drives morphological diversity of mRNA encapsulating nanoparticles

Area of Science:

• Biophysics
• Materials Science
• Computational Chemistry

Background:

• The spatial arrangement of components within messenger RNA (mRNA) nanoparticles influences their thermal stability, a critical factor for therapeutic efficacy.
• Understanding the mesostructure of mRNA nanoparticles, particularly those formed with cationic polymers, is essential for optimizing their design.
• Existing knowledge lacks detailed predictive models for nanoparticle mesostructure formation based on polymer properties and environmental conditions.

Purpose of the Study:

• To develop a field theoretic simulation model for predicting the phase diagram of mRNA nanoparticles.
• To investigate how amphiphilic block copolymer properties (coacervation and hydrophobicity) drive nanoparticle assembly.
• To elucidate the relationship between nanoparticle mesostructure, salt conditions, hydrophobicity, and thermal stability.

Main Methods:

• Development of a field theoretic simulation model for nanoparticle assembly.
• Computation of the phase diagram for amphiphilic block copolymers.
• Comparison of simulation predictions with experimental data from cryogenic-electron microscopy (cryo-EM).
• Creation of a GPU-accelerated, open-source codebase for field theoretic simulations.

Main Results:

• Prediction of distinct nanoparticle mesostructures based on salt conditions and polymer hydrophobicity.
• Validation of simulation predictions against cryo-EM images of mRNA nanoparticles.
• Identification of key parameters governing nanoparticle morphology and stability.
• Development of a versatile simulation tool for the scientific community.

Conclusions:

• The spatial arrangement within mRNA nanoparticles significantly affects their thermal stability and therapeutic potential.
• The developed simulation model accurately predicts nanoparticle mesostructures and their dependence on environmental factors.
• The open-source codebase provides a valuable resource for researchers studying nanoparticle self-assembly and design.