Design of cationic ionizable lipids for the delivery of therapeutic nucleic acids

Ionizable cationic lipids are a critical component of lipid nanoparticles (LNPs), enabling the clinical success of nucleic acid therapeutics through effective encapsulation, delivery, and release. As the field accelerates beyond first-generation RNA medicines, the rational design of next-generation ionizable lipids has become a key area of research. In this review, we outline key design principles that guide the development of efficacious and safe ionizable lipids for nucleic acid delivery. We highlight emerging structural motifs and discuss how these features contribute to improved potency, tolerability, and endosomal escape. Representative lipid structures are used to illustrate these trends. In addition, we describe promising lipids that deviate from heuristic design principles, offering insights into alternative strategies to expand the chemical space. Together, this review provides a framework for the rational development of next-generation ionizable lipids for genetic medicines.