Quantitative measurements and rational materials design for intracellular delivery of oligonucleotides

Antisense oligonucleotides and short interfering RNAs are widely used for sequence-specific silencing of gene expression. More widespread acceptance and adoption of these agents in vitro and in vivo is limited by the efficiency and cell-type variability of oligonucleotide delivery. An impressive variety of polymeric and lipid-based reagents have been developed to improve oligonucleotide delivery, but their development, testing, and interpretation have relied primarily on empirical design and measurement methodologies. Recently, mathematical models and quantitative measurements of biophysical events experienced by delivery vectors have emerged, paving the way for rational design of materials that can overcome intracellular delivery barriers. Recent progress toward the iterative design and quantitative measurement of intracellular events in oligonucleotide delivery is reviewed.