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J Am Chem Soc. 2012 Apr 25;134(16):6948-51. doi: 10.1021/ja301621z. Epub 2012 Apr 10.

Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation.

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David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, and Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.


The discovery of potent new materials for in vivo delivery of nucleic acids depends upon successful formulation of the active molecules into a dosage form suitable for the physiological environment. Because of the inefficiencies of current formulation methods, materials are usually first evaluated for in vitro delivery efficacy as simple ionic complexes with the nucleic acids (lipoplexes). The predictive value of such assays, however, has never been systematically studied. Here, for the first time, by developing a microfluidic method that allowed the rapid preparation of high-quality siRNA-containing lipid nanoparticles (LNPs) for a large number of materials, we have shown that gene silencing assays employing lipoplexes result in a high rate of false negatives (~90%) that can largely be avoided through formulation. Seven novel materials with in vivo gene silencing potencies of >90% at a dose of 1.0 mg/kg in mice were discovered. This method will facilitate the discovery of next-generation reagents for LNP-mediated nucleic acid delivery.

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