Coacervation drives morphological diversity of mRNA encapsulating nanoparticles

TL;DR

This paper models how coacervation influences the structural diversity of mRNA-encapsulating nanoparticles, predicting various morphologies based on salt and hydrophobicity, with validation from cryo-EM images.

Contribution

Develops a field theoretic simulation model to predict nanoparticle morphologies driven by coacervation and hydrophobicity, and provides an open-source simulation codebase.

Findings

Predicted multiple nanoparticle morphologies depending on salt and hydrophobicity.

Validated model predictions with cryo-EM imaging.

Provided a GPU-accelerated simulation tool for the community.

Abstract

The spatial arrangement of components within an mRNA encapsulating nanoparticle has consequences for its thermal stability, which is a key parameter for therapeutic utility. The mesostructure of mRNA nanoparticles formed with cationic polymers have several distinct putative structures: here, we develop a field theoretic simulation model to compute the phase diagram for amphiphilic block copolymers that balance coacervation and hydrophobicity as driving forces for assembly. We predict several distinct morphologies for the mesostructure of these nanoparticles, depending on salt conditions and hydrophobicity. We compare our predictions with cryogenic-electron microscopy images of mRNA encapsulated by charge altering releasable transporters. In addition, we provide a GPU-accelerated, open-source codebase for general purpose field theoretic simulations, which we anticipate will be a useful tool for the community.