Toward Rational Design of Lipid Nanoparticles: A Multiscale Framework for Nucleic Acid Delivery

Lipid nanoparticles (LNPs) are central to nucleic acid delivery, yet their morphological evolution during formation—especially under manufacturing-relevant conditions—remains poorly understood. This work introduces a multiscale modeling approach that bridges quantum-scale lipid interactions, molecular dynamics simulations, and data-driven analysis, integrated with experimental observations from impinging jet mixers and microfluidic platforms. We focus on how formulation parameters and flow conditions influence the fusion-driven self-assembly of mRNA-loaded LNPs, affecting particle size and morphology. Simulations capture the emergence of non-spherical, bleb-like structures under specific regimes, consistent with experimental findings. These results highlight the sensitivity of LNP morphology to subtle variations in lipid composition and mixing dynamics. By connecting molecular interactions to mesoscale organization and macroscopic outcomes, this framework provides a physics-based perspective on LNP formation across scales. Ultimately, this work supports the rational design and scalable optimization of LNPs for therapeutic applications by linking formulation strategies to emergent structure and function.