Multifunctional pH-sensitive ionizable lipids for efficient nucleic acid delivery

Efficient nucleic acid delivery remains a critical challenge in gene therapy. This expert insight review discusses the design rationale of multifunctional pH-sensitive ionizable lipids, their structure-function relationships, and pH-sensitive amphiphilic endosomal escape and cytosolic cargo release, and examines a lead lipid ECO for nucleic acid therapeutics. ECO features an ethylenediamine headgroup (E), cysteine-based disulfide linkers (C), and distal oleoyl tails (O) that enable nucleic acid condensation through electrostatic and hydrophobic interactions. ECO spontaneously self-assemble with nucleic acids to form stable lipid nanoparticles (ELNP) without helper lipids or large volumes of organic solvent. Its pH-sensitive ionization facilitates site-specific endosomal escape, while redox-cleavable disulfide bonds in ELNP ensure cytosolic cargo release. We present case studies demonstrating ELNP’s efficacy across diverse nucleic acid cargoes and provide comparative analysis against existing delivery systems. This work highlights the potential of multifunctional pH-sensitive ionizable lipids to overcome key barriers in nucleic acid delivery and outlines directions for clinical translation.