Abstract
Lipid nanoparticles (LNPs) represent the most widely employed and clinically validated platform for in vivo RNA delivery. However, currently used LNP formulations, which consist of lipids and cholesterol, exhibit limited transfection efficiency and off-target hepatic transfection. These limitations necessitate higher dosage and pose potential safety concerns. In this study, three derivatives of corosolic acid (CA) were synthesized to create a library of cholesterol-free lipid nanoparticles, CAxLNPs. From this library, CAβLNP was identified as the most effective, exhibiting enhanced tumor cell uptake and superior endosomal membrane fusion capabilities compared to cholesterol-containing LNP formulations, leading to optimal endosomal escape and efficient cytoplasmic delivery of mRNA/siRNA. Following intratumoral injection, CAβLNP demonstrated significantly improved retention and penetration within tumor tissues while minimizing undesired hepatic transfection. This LNP formulation offers a safer, more effective carrier for RNA delivery, providing promising potential to expand the applications of RNA therapeutics.
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