mRNA-LNP vaccines are manufactured by nanoprecipitation: an ethanol stream carrying the four lipids (ionizable lipid, helper phospholipid, cholesterol, PEG-lipid) is merged with an acidic aqueous stream carrying mRNA inside a microfluidic chip. As the streams mix, ethanol dilutes below the lipids' solubility limit and they self-assemble around the anionic mRNA in milliseconds.
Re = ρ·v·D_h / μ (Reynolds number, channel flow)
v = Q_total / A (mean velocity from total flow rate)
d(nm) ≈ d_min + (d_max − d_min)·exp(−k·Mix) (empirical size trend)
Straight microchannels stay laminar (low Re) and mix only by slow molecular diffusion across the stream interface — far too slow relative to the chip length, so lipids nucleate unevenly into large, polydisperse particles. Real production chips (e.g. NanoAssemblr-type cartridges) cut grooved staggered-herringbone ridges into the channel floor; even though the flow stays laminar, the grooves repeatedly split, stretch and fold the two streams (chaotic advection), collapsing the diffusion distance and mixing the streams in milliseconds.
- Total flow rate — raises mean velocity and Reynolds number, strengthening the chaotic-advection folding and shortening supersaturation time → smaller, more uniform particles.
- Flow-rate ratio (aqueous:organic) — more aqueous buffer dilutes the ethanol faster, dropping lipid solubility sooner and trapping mRNA more efficiently (higher encapsulation efficiency).
- Ionizable-lipid concentration — sets how many nucleation sites are available; higher concentration means more, slightly larger particles for the same mixing quality.
- Herringbone grooves toggle — switches the chip between chaotic-advection mixing and diffusion-only laminar co-flow at the same Reynolds number, showing why the grooves exist.
The diameter/PDI curves shown here are a simplified, representative model calibrated to realistic clinical LNP sizes (~40–150 nm) and trends reported for microfluidic mRNA-LNP production (Belliveau et al. 2012; Stroock et al. 2002 for staggered-herringbone chaotic advection) — not a substitute for a validated process model.