Division of Cancer and Stem Cells, School of Medicine , University of Nottingham , Nottingham NG7 2RD , United Kingdom.
Translate Bio , Lexington , Massachusetts 02421 , United States.
Nano Lett. 2018 Oct 10;18(10):6449-6454. doi: 10.1021/acs.nanolett.8b02917. Epub 2018 Sep 20.
mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority of progress in mRNA delivery has been confined to the liver. Previously, we demonstrated that poly(β-amino esters), a class of degradable polymers, are capable of systemic mRNA delivery to the lungs in mice when formulated into nanoparticles with poly(ethylene glycol)-lipid conjugates. Using experimental design, a statistical approach to optimization that reduces experimental burden, we demonstrate herein that these degradable polymer-lipid nanoparticles can be optimized in terms of polymer synthesis and nanoparticle formulation to achieve a multiple order-of-magnitude increase in potency. Furthermore, using genetically engineered Cre reporter mice, we demonstrate that mRNA is functionally delivered to both the lung endothelium and pulmonary immune cells, expanding the potential utility of these nanoparticles.
mRNA 疗法通过蛋白质替代、免疫调节和基因编辑，在治疗多种疾病方面具有巨大潜力。然而，与 siRNA 疗法一样，大多数在 mRNA 传递方面的进展都局限于肝脏。此前，我们证明了聚（β-氨基酯），一类可降解聚合物，当与聚乙二醇-脂质缀合物制成纳米颗粒时，能够在小鼠体内将全身 mRNA 递送到肺部。本文通过实验设计，即一种优化方法，可减少实验负担，证明了这些可降解聚合物-脂质纳米颗粒可以在聚合物合成和纳米颗粒配方方面进行优化，从而使效力提高几个数量级。此外，我们利用基因工程 Cre 报告小鼠证明，mRNA 被递送到肺内皮细胞和肺部免疫细胞，从而扩大了这些纳米颗粒的潜在用途。
