RNA can change the expression of any gene, making these molecules promising drugs. However, whether the drug is comprised of siRNA, mRNA, lncRNA, or another nucleic acid, it is limited by one problem: drug delivery. Chemists design thousands of distinct nanoparticles to deliver DNA or RNA to the desired cell type. However, after nanoparticles are synthesized, their ability to deliver drugs is evaluated using in vitro systems devoid of a liver, kidney, spleen, immune system, pulsatile blood flow, and other selection pressures known to affect nanoparticle delivery in vivo. Here we describe DNA barcoding platforms to quantify how thousands of nanoparticles deliver nucleic acids in vivo. These systems enable us to quantify how hundreds of chemically distinct nanoparticles deliver mRNA or siRNA into up to 30 cell types, all in a single animal. To analyze these large in vivo drug delivery datasets, we have also developed an open source bioinformatics pipeline to iteratively ‘evolve’ nanoparticles that target cells in vivo. Using this high throughput, iterative, in vivo approach, we have identified nanoparticles with tropism to many novel cell types without the use of active targeting ligands.

Delivering RNA to non-liver tissues by testing thousands of nanoparticles in vivo

ACS Spring 2022

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