Microfluidic Synthesis of Highly Potent Limit-size Lipid Nanoparticles for In Vivo Delivery of siRNA

By Nathan M. Belliveau, J. Huft, Paulo J. C. Lin, Sam Chen, Alex K. K. Leung, T. Leaver, Andre W. Wild, Justin B. Lee, Robert J. Taylor, Ying K. Tam and 2 more. Molecular Therapy: Nucleic Acids, 2012

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Lipid nanoparticles (LNP) are the leading systems for in vivo delivery of small interfering RNA (siRNA) for therapeutic applications. Formulation of LNP siRNA systems requires rapid mixing of solutions containing cationic lipid with solutions containing siRNA. Current formulation procedures employ macroscopic mixing processes to produce systems 70-nm diameter or larger that have variable siRNA encapsulation efficiency, homogeneity, and reproducibility. Here, we show that microfluidic mixing techniques, which permit millisecond mixing at the nanoliter scale, can reproducibly generate limit size LNP siRNA systems 20 nm and larger with essentially complete encapsulation of siRNA over a wide range of conditions with polydispersity indexes as low as 0.02. Optimized LNP siRNA systems produced by microfluidic mixing achieved 50% target gene silencing in hepatocytes at a dose level of 10 µg/kg siRNA in mice. We anticipate that microfluidic mixing, a precisely controlled and readily scalable technique, will become the preferred method for formulation of LNP siRNA delivery systems.

Subfields: Biomedical Engineering, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9f53e633b664d2c272c675974f6de5f3c645030a

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Citations in the corpus

The role of lipid components in lipid nanoparticles for vaccines and gene therapy (2022, positive): “Multiple studies have shown that increasing the molar ratio of the PEG-lipid coheres with significantly smaller LNPs, independent of other lipid components [24,52,64].”
Microfluidic Devices for Drug Delivery Systems and Drug Screening (2018, background): “[36] designed a microfluidic device with a passive mixer that offers higher throughput than HFF (Figure 1C).”
Lipid Nanoparticle Systems for Enabling Gene Therapies. (2017, background): “For example, while relatively complete encapsulation of siRNA can be achieved at N/P values as low as 1, the resulting systems are not effective gene-silencing agents.(15) Optimized LNP systems exhibit N/P values in the range of 6 15, (16), indicating a need for non-siRNA-associated cationic lipids ”