Structural evolution of ionizable lipids for nucleic acid delivery

Ionizable lipid nanoparticles have emerged as a potent non-viral delivery platform for nucleic acid therapeutics, achieving clinical breakthroughs ranging from the FDA-approved small interfering RNA therapeutic to mRNA vaccines against coronavirus disease 2019 and respiratory syncytial virus. Their success stems from the ability of ionizable lipids to remain neutral in physiological environments, yet protonate in acidic endosomes, enabling the efficient release of genetic cargo. Over the last several decades, their structures have evolved extensively through the application of combinatorial chemistry, rational design, incorporation of functional elements and, most recently, machine learning and artificial intelligence-guided strategies. These innovations have expanded ionizable lipids from passive carriers into multifunctional materials capable of organ-specific targeting, responsiveness, immunomodulation and theranostics. In this Review, we highlight the development, synthesis and structural evolution of ionizable lipids as well as their emerging on-demand design functionalities and next-generation biomedical applications. We provide insights into the challenges and gaps for translation, manufacturing and expansion of lipid nanoparticle-mediated nucleic acid therapeutics for precision RNA medicine.