Lipid nanoparticle (LNP) has emerged as a promising platform for drug delivery. The
properties of LNP can be finely tuned to enable specifically target organ or diseases. Among
various properties, particle size distribution (PSD) plays a critical role in determining the
biodistribution of drug molecules in the body, as particle size influences tissue permeability
and cellular internalization. Although experimental studies have suggested strategies and
mechanisms to control PSD, these have rarely been confirmed in the mathematical
modeling study, limiting application of PSE strategies. To address this gap, we present a
population balance equation (PBE)-based model to predict the dynamic evolution of PSD
during LNP fabrication based on nucleation, growth, and coalescence kinetics. The model
satisfactorily predicted experimental trends and identified dominant kinetic mechanisms in
the shape of PSD. we evaluated three key parameters—lipid concentration, flow rate ratio
(FRR), and mixing rate—revealing the role of dilution and supersaturation in minimizing
particle size. We suggest that achieving high supersaturation without introducing an
additional liquid phase is key to producing small particle sizes. These findings provide
valuable insights into the rational design of LNP manufacturing systems
