Branched-tail lipid nanoparticles deliver mRNA effectively inside the body because they ionize better in acidic cell compartments

A single 0.75 mg/kg dose of the branched-tail lipidoid 306O induces substantial luciferase expression in mice.

• The study identifies lipid nanoparticle surface ionization as a key parameter influencing mRNA delivery efficacy.
• Two lipidoids, 306O and 306O, differ only in tail structure, with 306O having a branched tail.
• The branched-tail lipidoid 306O shows a tenfold improvement in efficacy compared to its straight-tailed counterpart.
• Strong surface ionization at a pH of 5.0 is associated with the enhanced potency of the branched-tail lipidoid.
• A secondary library of lipidoids confirms that branched-tail structures deliver mRNA more effectively than linear tails.

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