Synthetic molecule libraries for nucleic acid delivery: Design parameters in cationic/ionizable lipids and polymers

Recent progress in the design of cationic lipids and polymers has successfully translated nucleic acid drugs into clinical applications, such as the treatment of liver diseases and the prevention of virus infection. Small or large libraries of delivery molecules have been used to find the key chemical structures to protect nucleic acids from nucleases in the extracellular milieu and to facilitate the endosomal escape after endocytosis. This review introduces three essential design parameters (i.e., acid dissociation constant, hydrophobicity, and biodegradability) to develop synthetic molecules for nucleic acid delivery. The significance and mechanism of each parameter are described based on the results obtained from in vitro and in vivo evaluations. Other design parameters were then discussed to create the next generation of delivery molecules for future nucleic acid therapeutics.