Scientific reportsJul 3, 2026

Improving mRNA lipid nanoparticle preparation by testing different mixing methods and important factors

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 4, 2026

Abstract

Streamlined S-channel designs and non-microfluidic methods can yield LNPs functionally equivalent in quality to complex staggered herringbone mixers.

Microfluidic architectures, such as staggered herringbone and serpentine-only channels, influence lipid nanoparticle (LNP) size, stability, and transfection efficiency.
Critical parameters, including total flow rate, flow rate ratio, and lipid-to-mRNA ratio, govern the characteristics of LNP formulations.
In vivo assessments indicate that optimized formulations demonstrate systemic biocompatibility, maintaining stable physiological growth and organ function.
No adverse histological changes or tissue damage were observed over an 8-week period.

Simplified

Although mRNA LNPs are a leading delivery platform, achieving reproducible, high-quality formulations across diverse fabrication techniques remains a challenge. This study systematically investigates the impact of microfluidic architectures - staggered herringbone (SS) and serpentine-only (S) channels - alongside T-junction and rapid pipetting methods. We evaluate how critical parameters, including total flow rate (TFR), flow rate ratio (FRR), and lipid-to-mRNA ratio (N/P ratio), govern LNP size, stability, and transfection efficiency. Our findings demonstrate that streamlined S-channel designs and non-microfluidic methods can yield LNPs functionally equivalent in quality and performance to complex staggered herringbone mixers through precise parameter tuning. Furthermore, in vivo assessment confirms the systemic biocompatibility of the optimized formulations, characterized by stable physiological growth, preserved hepatic and renal function, and an absence of adverse histological changes or tissue damage over 8 weeks. By bridging the gap between fluidic process optimization and long-term systemic tolerability, this work provides a foundational framework for the accessible and reproducible production of mRNA LNPs across varying laboratory environments and production scales.

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Funding

Competing interests

Declarations. Competing interests: The authors declare no competing interests. Hyung-Jun Im is a co-founder and Chief Scientific Officer of Portrai. Ethics : All procedures and ethics in animal research was approved by Seoul National University Institutional Animal Care and Use Committee (IACUC) and were conducted in complied with the ARRIVE guidelines 2.0.

PubMed

Improving mRNA lipid nanoparticle preparation by testing different mixing methods and important factors

Abstract

Full Text

Funding

Competing interests

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