Cationic lipidoids are promising vectors for intracellular protein delivery. Unfortunately, the fundamental mechanisms controlling packing efficiency are not well understood, preventing the rational design of improved lipidoid vectors. We employ molecular dynamics simulations to characterize protein-lipidoid assembly. We find that doubly charged cationic lipidoids with tail lengths ≥12 carbon atoms self-assemble in three dimensions into curved bicontinuous bilayers. In the presence of a cargo protein, local restructuring of these lipidoid bilayers is observed. As the lipidoid tail length increases, the bilayers become stiffer and less responsive to cargo proteins. This observation suggests that there exists an intermediate tail length for optimal packing efficiency. When lipidoid tail length is too short, packing efficiency is diminished owing to the incapability of the lipidoid to form bilayer structures. When lipidoid tail length is too long, packing efficiency decreases owing to the rigidity of the lipidoid bilayer and consequently reduced lipidoid-protein interactions.

Design rules for lipidoids as intracellular protein delivery vectors: Insights from computational studies of RNase A-lipidoid assembly

251st National Meeting (2016)

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