BPS2026 – Numerical modeling approach to capture nucleic acid-lipid nanoparticle size evolution in microfluidic channels

LNP-based delivery technology has demonstrated enormous potential in encapsulating nucleic acids for a wide range of therapeutic and biomedical applications. The production of LNPs within microchannels requires precise control over their size and uniformity to achieve optimal delivery performance. However, current methods for fine-tuning production and formulation parameters—such as flow rates and lipid composition—are largely empirical and experimental. Computational modeling attempts to capture nucleic acid-LNP self-assembly within the microchannel are still limited. In this study, we employed numerical simulation to simulate the LNP formation process within a microchannel. To model this process, we incorporated a population balance model (PBM) combined with reaction kinetics for individual lipid molecules. The model accounts for lipid adhesion-driven growth and nuclei aggregation, while considering solvent molar ratios and experimentally measurable lipid properties, such as the critical micelle concentration (CMC), as key indicators of lipid precipitation during self-assembly. The simulated size distributions closely matched those reported in previous experimental results, validating the robustness of our approach. Finally, we analyzed how different microfluidic operational and formulation parameters, including changing lipid type, flow rate, and flow rate ratio (FRR), impact the LNP size evolution and distribution. This method offers a predictive framework for optimizing LNP formulations, enhancing the precision and efficiency of LNP production.