Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics

Significance The effectiveness of nucleic acid drugs is limited by inefficient delivery to target tissues and cells and by unwanted accumulation in off-target organs. Although thousands of chemically distinct nanoparticles can be synthesized, nanoparticles designed to deliver nucleic acids in vivo were first tested in cell culture, yielding poor predictions for delivery in vivo. To facilitate testing of many nanoparticles in vivo, we designed and optimized a high-throughput DNA barcoding system to simultaneously measure nucleic acid delivery mediated by dozens of distinct nanoparticles in a single mouse. This nano-barcoding system can be used to study hundreds, or even thousands, of nanoparticles directly in vivo and could dramatically accelerate the discovery and understanding of nanoparticle drug delivery systems.