Ongoing efforts to enhance stability

Over the last few decades, a large variety of nucleic acid‑based therapeutic approaches and drug formulations have been developed in the lab, tested in the clinic, and brought to market, ranging from antisense oligonucleotides (ASOs) and siRNAs to aptamer inhibitors and mRNA vaccines, with DNA and RNA nanostructure therapeutics already looming on the horizon. However, being susceptible toward hydrolysis, oxidation, non‑specific binding, and nuclease digestion, unmodified nucleic acids are rapidly degraded in vivo, resulting in poor therapeutic performance. Therefore, several stabilization strategies have been developed in order to protect those fragile molecules against adverse conditions during storage and in the body, while simultaneously accommodating their various mechanisms of action such as cellular uptake, target binding, or translation. These strategies include chemical modifications at the nucleoside level, complexation with proteins and polymers, and encapsulation in lipid nanoparticles (LNPs). Despite this variety of available methods, the field still faces many challenges, and this issue aims to provide an overview of the ongoing efforts to enhance the stability of therapeutic nucleic acids.