pH-driven dynamics and mechanisms of LNP-mediated siRNA delivery

A DLin-MC3-DMA (MC3)-based LNP carrying ~21 nt siRNA forms an inverted-hexagonal-type ~70 nm morphology, with hydrated channels that neutralize RNA via locally protonated MC3.

• Why it matters: Understanding pH-driven structure and endosomal escape is critical because siRNA delivery is often inefficient and slow, and global pKa measurements may miss key local effects near RNA.
• What they did: The study used coarse-grained and atomistic molecular dynamics to model unloaded and siRNA-loaded LNPs, including smaller LNP mimetics, to analyze encapsulation and simulate endosomal escape.
• The result: Endosomal escape is linked to spontaneous stalk formation and water-filled pore opening, but release is delayed by persistent electrostatic coupling between RNA and protonated MC3, matching time-dependent inhibitory activity.

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