Antisense microRNA185 loaded liposome for efficient inhibition of the hepatic endogenous microRNA185 level

MicroRNA185 (miR185), an endogenous noncoding RNA with 23 nucleotides, is one of key posttranscriptional modulators of cholesterol metabolism in hepatic cells. The antisense inhibitor of miR185 (miR185i) could decrease cholesterol level in vivo, providing a promising agent for anti-atherosclerosis strategy. In this work, a novel LipomiR185i was constructed by thin film hydration method and post-PEGylation as DOPE: DOTAP: Chol: DSPE-PEG2000 at the molar ratio of 1:1:1:0.1 with a nitrogen-to-phosphate ratio of 3, through the optimization of three cationic lipids (DOTAP, DODMA and DLin-MC3-DMA), six helper lipids (PC-98T, HSPC, DOPE, DMPC, DPPC and DSPC), different amounts and incorporation approaches of DSPE-PEG2000 and nitrogen-to-phosphate ratio. LipomiR185i was characterized with a particle size of 174 ? 11 nm, a zeta potential of 7.0 ? 3.3 mV, high encapsulation efficiency and transfection activity. It could protect miR185i from the rapid degradation by nucleases in serum, enhance cellular uptake and promote lysosomal escape in HepG2 cells. LipomiR185i could accumulate in the liver and remain for at least two weeks. More importantly, LipomiR185i significantly downregulated the hepatic endogenous miR185 level in vitro and in vivo without significant tissue damage at 14 mg?kg? 1. The construction of LipomiR185i provides a potential anti-atherosclerotic nanodrug as well as a platform for delivering small RNAs to the liver efficiently and safely.

Automated summary

miR185 inhibitor miR185i is a promising drug for reducing cholesterol levels; LipomiR185i is a nanoparticle drug carrier with high encapsulation efficiency and transfection activity; LipomiR185i can safely and effectively deliver miR185i to the liver, downregulate miR185 levels without significant tissue damage.