Effects of different mixing techniques on mRNA lipid nanoparticle physicochemistry and biological performance

Apr 30, 2026Nature communications

How Mixing Methods Affect the Physical Properties and Biological Behavior of mRNA Lipid Nanoparticles

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Abstract

Lipid nanoparticles produced from different mixing techniques exhibit widely different physical properties and biological performance.

Manual pipetting, often used in academic settings, creates particles that differ significantly from those made by turbulent-flow mixers.
Lipid nanoparticles prepared using ten different mixers were compared while keeping all other formulation parameters constant.
Different mixing techniques may lead to variations in physicochemical characteristics due to distinct flow regimes.
Understanding how mixing affects lipid nanoparticle properties could help bridge the gap between bench-scale and commercial-scale production.

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Lipid nanoparticle (LNP) formulation requires a mixing step. Many studies, especially from academic groups, utilize microfluidic mixers or hand mixing to prepare LNPs, while commercial-scale processes use turbulent-flow mixers. This discrepancy in mixing techniques has been underexplored, as LNPs made by different techniques may exhibit different performance, meaning bench-scale results cannot be replicated using materials manufactured at scale. Here, we isolate and interrogate the effect of primary mixing on LNP formulation. LNPs are produced from ten mixers while holding all other formulation parameters constant, to directly compare across techniques. We show that LNPs produced from the different mixers exhibit widely different physical properties and biological performance. Notably, manual pipetting common in academic practice yields particles that do not resemble those produced by turbulent-flow mixers. Findings are connected mechanistically to physicochemical characteristics arising from different flow regimes. Further establishing the relationship between mixing and LNP properties is critical.

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Effects of different mixing techniques on mRNA lipid nanoparticle physicochemistry and biological performance

Abstract

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