体内
信使核糖核酸
肝细胞
生物
材料科学
细胞生物学
生物化学
体外
基因
生物技术
作者
Qian Zheng,Fengming Qin,Rui-Jie Luo,Chaohui Jin,Hai Huang,Xi He,Wen Xiao,Mengran Guo,Shuping Yang,Siyan He,Cheng Li-zhi,Na Fan,Shaohua Yao,Xiangrong Song
标识
DOI:10.1002/adfm.202011068
摘要
Abstract Messenger RNA (mRNA) has come into the spotlight due to its potential for addressing a staggering number of diseases, while the lack of effective and safe carriers for in vivo delivery significantly limits its clinical application. Herein, the potential of lipid‐like nanoparticles (LLNs) containing three new cholesterol derivatives to achieve the liver targeting delivery of mRNA is investigated. The central composite design (CCD) is used to tailor the formulation of LLNs through in vivo optimization of the molar ratios of these cholesterol derivatives required for liver targeting. The optimized LLNs (O‐LLNs) are able to systemically deliver mRNA to the liver of mice with a synergistic action of prolonged systemic circulation, increased liver targeting, and enhanced hepatocyte uptake. The O‐LLNs outperformed DLin‐MC3‐DMA (MC3) in functional delivery of Cre‐recombinase (Cre) and human erythropoietin (hEPO) mRNA. Successful delivery of cytidine base editor mRNA (CBE mRNA) and sgRNA by O‐LLNs achieved more than 8% correction rates in a liver‐related metabolism disorder, phenylketonuria (PKU). In conclusion, the general method above can accelerate in vivo screening and optimization of multicomponent nanoparticle formulations, and the optimized ones demonstrate great potential as delivery vehicles for targeted gene therapy in specific tissues.
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