MRNA‐Loaded Lipid‐Like Nanoparticles for Liver Base Editing Via the Optimization of Central Composite Design. (4th June 2021) - Zheng, Qian
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. Abstract : This study reports the development of non‐viral gene carriers with efficient and specific targeting delivery, especially based on simple biomaterials conducive to facile production and clinical translation. It is the first time to optimize delivery carriers in vivo with a central composite design as well as to investigate non‐viral carrier for base editing in phenylketonuria mice.