Background and Objectives:
Using lipid nanocarriers to deliver the mRNA of a specific antigen to immune cells is a powerful new approach to rapidly develop new safe and effective vaccines. Understanding and optimizing the mixing process necessary for mRNA lipid nanoparticles (LNP) is the focus of this review. The first objective is to review the fundamentals of fluid mixing process needed to understand the basic nanoparticle self-assembly process. Then some important experimental nanoparticle studies which are the basis for the current understanding of LNP mixing process will be reviewed. Finally, the current commercially available LNP mixing technology will be summarized.
Results:
LNP formulation by solvent-exchange mixing requires reducing the fluid homogenization time, t_mix , to significantly below the time required for the nanoparticle to self-assembly. Reducing t_mix is accomplished by reducing the striation length l_st of the mixing streams to allow for “rapid” molecular diffusion between the fluid streams. The two most popular passive fluid mixing conditions for reducing l_st are chaotic advection and turbulence.
Conclusions:
There appears to be no universally “best” mixing process for formulating nanoparticle or mRNA LNP. Both, chaotic advection and turbulent flow microfluidic mixing devices using the proper parameters for each device will formulate similar mRNA LNP vaccines during development. However, the low fluid output of microfluidic devices may not be practicable at higher fluid flow rates. Larger scale turbulent mixing devices are more suitable for clinical scale mRNA LNP production.