Effect of Downstream Buffer Type on LNP Size

Introduction

After self-assembly of lipid nanoparticles (LNPs) through mixing of lipid and cargo solutions, further dilution or buffer exchange is required to reduce/remove ethanol and stabilize the particles. During this process, the pH is raised resulting in de-protonation of the ionizable lipids which subsequently fuse to form the hydrophobic, amorphous core of the LNPs. Small LNPs may also gradually fuse to form larger particles that are more energetically favorable through a process known as Ostwald ripening.

Particle size is one of the most significant parameters that affects LNP biodistribution . In many cases, LNPs with a certain size range are required to achieve better tissue, organ, or intracellular targeting. The LNP size can be tuned via adjusting the PEG-lipid content, microfluidic mixing conditions, and formulation buffer composition. However, the fusion and ripening phenomenon of LNPs during downstream processing often results in a particle size increase which increases the risk of LNP size exceeding the target range. In this study, we aim to compare the effect of different downstream buffer types on the LNP particle fusion, morphology and final size.

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