Ligand-free hepatocyte-targeting of nanomedicines by selective stealth coating of liver reticuloendothelial system scavenger cells

通过将不同量的mRNA包被到由DOTMA和DOPE组成的脂质体上来制备包封的编码腺苷酸酶的mRNA的阳离子（脂质与mRNA的比例为5：1，电荷+52 mV，尺寸155 nm）和阴离子（脂质与mRNA的比例为1：2，电荷-30 mV，尺寸221 nm）mRNA-脂质复合物。与没有肝脏涂层相比，用双臂-PEG-寡聚物（L-赖氨酸）对肝脏正弦RES壁进行先前的隐形涂层显著增强了肝脏中阴离子脂质体的荧光素酶表达（增加14.1倍）。同样，与没有涂层相比，肝脏清道夫细胞壁的PEG涂层使肝脏中的荧光素酶表达增加了3.6倍。基于这些结果，申请人将选择阴离子mRNA-lipoplex用于未来的肝脏定向治疗应用。

The luciferase-encoding mRNA encapsulated cationic (lipid to mRNA ratio 5:1, charge +52 mV, size 155 nm) and anionic (lipid to mRNA ratio 1:2, charge -30 mV, size 221 nm) mRNA-lipoplexes were prepared by different coating amounts of the mRNA onto liposomes composed of DOTMA and DOPE. Prior stealth coating of the liver sinusoidal RES wall with two-arm-PEG-Oligo(L-Lysine) substantially enhanced the luciferase expression (14.1-fold increase) of anionic liposome in the liver compared to without liver coating. Similarly, PEG coating to the liver scavenger cell wall augmented the luciferase expression in the liver up to 3.6-fold compared to without coating. Based on these results, the applicant will choose anionic mRNA-lipoplex for future liver-directed therapeutic applications.