Nature communicationsApr 30, 2026

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

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Primary mixing technique can strongly reshape mRNA LNP properties and performance, making hand mixing a poor proxy for turbulent-flow manufacturing.

Evidence

Formulation platform experiments made LNPs with ten mixers while holding other formulation parameters constant, then compared physicochemical characteristics and biological performance.

Caveat

The abstract does not specify payloads, assay systems, or effect sizes, so generality across LNP chemistries and scales remains unresolved.

Simplified

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

Abstract

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