Reconstitution of lipid nanoparticle-mediated siRNA transfer across endosomal membrane mimics

Acidification drives LNP-mediated siRNA translocation across an early endosome-like membrane in GUVs while preserving transmembrane pH gradient, with no detectable membrane rupture.

• Why it matters: Endosomal escape constrains RNA delivery, and if it required rupture, delivery would be tightly linked to membrane damage and toxicity.
• What they did: Using a cell-free GUV system with an early endosome-like lipid composition, they measured siRNA transfer after acidification, including transmembrane pH gradient dissipation, cryo-electron tomography, and fluorescence correlation spectroscopy.
• The result: They observed lipid redistribution and local interfacial lipid reorganization without rupture, heterogeneous diffusion of translocated siRNA, and reduced translocation after serum or apolipoprotein-E preincubation, supporting barrier-preserving crossing via siRNA-lipid association.

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