Table 1.

General characteristics of RNA therapeutics as compared with small-molecule and protein drugs. ADME, absorption, metabolism, distribution, and excretion; pharmacokinetics; PD, pharmacodynamics.

Properties	Small-molecule drugs	Protein therapeutics	RNA therapeutics
Chemistry	Molecular weight < 1 kDa; Hydrophobic	Molecular weight >100 kDa; Positive/negative/neutral	Molecularweight 7–20 kDa; Negative charge
Dosing	Oral primarily, intravenous, etc.; Often daily	Mainly intravenous and subcutaneous; Weekly to monthly	Intravenous, subcutaneous, or specific local injections; Weekly to once every 3–6 months
ADME or PK	Orally bioavailable; Distributed to all organs and tissues; Cell permeable; Metabolized by Phase I and II drug-metabolizing enzymes; Excreted mainly in bile and urine	Not orally bioavailable; Distributed mainly in plasma or extracellular fluids; Cell impermeable; Catabolized extensively to peptides or amino acids by peptidases; Mainly urine	Not orally bioavailable; Distributed extensively to liver, kidney and lung; Intracellular delivery using various strategies; Catabolized extensively to shorter oligos or mononucleotides by nucleases or hydrolases; Mainly urine
PD	Target extra—/intra-cellular or cell-surface proteins mainly, and RNAs & DNAs; Direct or indirect link to blood PK	Target predominantly the cell-surface or extracellular proteins; Direct or indirect models linked to blood PK	Target intracellular RNAs primarily, as well as extra—/intra-cellular proteins, and nuclear DNAs; More relevant to tissue PK, but can linked to blood PK
Safety	Risk of various off-target effects	Risk of immunogenicity or immune reactions	Risk of immunogenicity or immune responses