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

Delai Chen, Kevin T. Love, Yi Chen, Ahmed A. Eltoukhy, Christian Kastrup, Gaurav Sahay, Alvin Jeon, Yizhou Dong, Kathryn A. Whitehead, Daniel G. Anderson

Research output: Contribution to journalArticlepeer-review

281 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)6948-6951
Number of pages4
JournalJournal of the American Chemical Society
Volume134
Issue number16
DOIs
StatePublished - Apr 25 2012

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