Evaluating the breadth of nucleic acid-based payloads delivered in lipid nanoparticles to establish fundamental differences in development.

Introduction: Nucleic acid (NA)-based therapeutics have shown great potential for downregulating or augmenting gene expression, and for promising applications, e.g., protein-replacement therapy and vaccination, a comprehensive understanding of the requirements for their targeted delivery to specific tissues or cells is needed.

Areas covered: In this review, we discuss clinical applications of four representative types of NA-based therapeutics, i.e. antisense oligonucleotides, small interfering RNA, messenger RNA, and circular RNA, with a focus on the lipid nanoparticle (LNP) technology used for intracellular delivery. The in vivo fate of LNPs is discussed to improve the understanding of trafficking of nanomedicines at the systemic and cellular levels. In addition, NA-based vaccines are discussed, focusing on targeting antigen-presenting cells and immune activation.

Expert opinion: Optimization of delivery systems for NA-based therapeutics is mainly focused on the standard requirements of prolonged systemic circulation and enhancing endosomal escape. Depending on the final destination in specific target tissues or cells, strategies should be adjusted to achieve the desired biodistribution of NA-based payloads. More studies relating to the pharmacokinetics of both cargo and carrier are encouraged, because their in vivo fates may differ, considering the possibility of premature cargo release before reaching the target.