(165) Lung editing via inhalation of base editors delivered by amino acid-derived lipid nanoparticles

Introduction: LNPs represent a promising non-viral alternative to adeno-associated viruses in gene editing delivery, offering transient expression, flexible cargo capacity, and compatibility with repeat dosing. Pulmonary delivery of mRNA via inhalable LNPs is hindered by barriers (mucus penetration and endosomal escape). In this study, we synthesized and screened 960 amino-acid-derived ionizable lipids, identifying CHCha-10 as the top candidate. CHCha-10 LNPs achieved high RNA-based ABE system delivery efficiency in vivo, correcting the CFTR G542X mutation, restoring CFTR function in vitro and in vivo.