Intracellular delivery of messenger RNA for the therapeutic production on proteins can transform modern medicine. While lipid-based nanoparticles (LNPs) remain in the forefront of delivery of nucleic acids, there endosomal sequestration remains a formidable barrier for cytosolic delivery. In studies with siRNA, even the most potent cationic lipids (the active ingredients within LNPs) enable a mere &lt;2% release of nucleic acid to its cytosolic target. We have identified novel naturally occurring lipid that can enhance cytosolic delivery of nucleic acids and decoded structural activity relationships using analogues of these lipids to reveal the nature of endosomal escape processes. We found that these inclusions of these endosomal escape agents can lead to LNP mediated mRNA delivery (eLNPs) to about ~200-fold. 3D-Dynamic Photon Localization Tracking showed that eLNPs had improved diffusivity inside cells as compared to LNPs which remain in a mostly immobile state suggesting endosomal entrapment. eLNP-delivered mRNA also exhibited substantial cytosolic localization as visualized through single-molecule RNA-FISH. These novel lipids are a new class of endosomal agents that can boost gene delivery by overcoming endosomal barriers.<br/><br/>

Novel formulation strategies to overcome endosomal barriers for enhanced nucleic acid delivery

2019 Fall National Meeting

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