Table 1 Challenges erected by evolutionary barriers to RNA therapeutic delivery

Oligonucleotide size and charge

Too large or too charged to passively diffuse across the lipid bilayer

RNase susceptibility

Rapid degradation by blood and tissue RNases.

Reticuloendothelial system

Rapid clearance from the blood by the kidneys and liver scavenger receptors

Immunogenicity

Oligonucleotides activate extracellular and intracellular innate immune responses

Endocytosis

Oligonucleotides are taken up, but trapped inside endosomes