Berberine-inspired ionizable lipid for self-structure stabilization and potent brain targeting delivery of nucleic acid therapeutics

Abstract

Despite advancements in targeting organs such as the liver, spleen, and lungs with lipid nanoparticles (LNPs), the challenge of traversing the blood-brain barrier (BBB) significantly impedes the progress of gene therapies for neurological disorders. Motivated by the structural and functional characteristics of alkaloids, we developed a novel library of ionizable lipid molecules based on the tetrahydroisoquinoline structure characteristic of the protoberberine family. Our findings reveal that: (i) LNPs incorporating berberine-derived ionizable lipids notably enhance the ability to cross the BBB, increasing in vitro endocytosis efficiency by up to 65-fold and achieving an in vivo brain-to-liver distribution ratio of approaching 20%; (ii) these lipids form stable self-assemblies with polyA, enhancing nucleic acid stability through mechanisms beyond conventional electrostatic interactions, thus providing effective RNA protection without the need for additional modifications; (iii) the lipids inherit the diverse brain-protective properties of protoberberine-type alkaloids, including anti-inflammatory and antioxidant effects, thereby synergistically enhancing the therapeutic management of brain diseases while exhibiting minimal immunogenicity.