Lipid nanoparticles (LNPs) are widely used for the delivery of nucleic acids, yet the physical mechanisms governing their structural evolution during assembly remain poorly understood. Among the notable features observed experimentally are bleb-like morphologies¹, whose formation has not been systematically linked to molecular-level interactions or mesoscale organization. This work introduces a multiscale modeling framework to investigate the self-assembly of mRNA-loaded LNPs, focusing on how lipid and solvent composition affect particle shape and internal structure—features that reflect and influence the stability and efficiency of mRNA encapsulation. Under specific formulation regimes, the simulations reveal non-spherical surface features, highlighting how small variations in conditions during assembly can result in pronounced morphological differences. These findings are consistent with experimental observations of structural diversity in LNPs and offer insights into how conditions characteristic of high-shear or rapid mixing environments may influence LNP morphology. By connecting formulation parameters to emergent structural features, the study provides a physics-based foundation for understanding and guiding the design of next-generation delivery platforms.
1 Udepurkar, A., Devos C., Sagmeister P., Destro F., Inguva, P., Ahmadi, S., Boulais E., Quan Y., Braatz R.D., Myerson, A.S. Structure and Morphology of Lipid Nanoparticles for Nucleic Acid Drug Delivery: A Review. Under Review
Acknowledgement: This research is based on work funded by the Gates Foundation. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Gates Foundation.
