It presents the most common ON classifications and chemical modifications from a fundamental scientific perspective and provides a roadmap of the cellular uptake pathways by which ONs are trafficked. This review provides a background to the design and mode of action of existing FDA-approved ONs. There are a range of approaches to overcome this, and in this review, we focus on three: altering the chemical structure of the ONs, formulating synthetic, lipid-based nanoparticles to encapsulate the ONs, or biologically loading the ONs into extracellular vesicles. While cell uptake has been improved, “endosomal escape” remains a significant problem. Historically, the largest hindrance to the widespread usage of ON therapeutics has been their inability to effectively internalize into cells and escape from endosomes to reach their molecular targets in the cytosol or nucleus. ONs can be subdivided into several classes based on their chemical modifications and on the mechanisms of their target interactions. ONs are small (15–30 bp) nucleotide-based therapeutics which are capable of targeting DNA and RNA as well as other biomolecules. In recent years, the list of FDA-approved ON therapies has rapidly expanded. Oligonucleotides (ONs) comprise a rapidly growing class of therapeutics.
