Controlling mRNA delivery by changing charged nitrogen groups in fat-based carriers

Double pH-responsive lipo-xenopeptides are identified as highly effective carriers for mRNA delivery.

• The effectiveness of carriers is influenced by the lipid tail length and the position of the ionizable nitrogen within the lipo amino fatty acid domain.
• Bundles with short lipid tails and U-shapes with medium-length lipid tails exhibit stronger mRNA delivery activity than other configurations.
• Distinct biological mechanisms are triggered by variations in carrier topology and lipid structure, affecting endosomal acidification and escape.
• Molecular dynamics simulations indicate that protonation alters carrier polarity and hydration, with bundles showing more pronounced changes.
• The placement of nitrogen affects interfacial enrichment and hydrogen bonding, which correlates with the observed activity profiles of the carriers.

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