Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, Oregon 97239, United States.
Mol Pharm. 2022 Dec 5;19(12):4696-4704. doi: 10.1021/acs.molpharmaceut.2c00738. Epub 2022 Nov 21.
Recently, therapeutics based on mRNA (mRNA) have attracted significant interest for vaccines, cancer immunotherapy, and gene editing. However, the lack of biocompatible vehicles capable of delivering mRNA to the target tissue and efficiently expressing the encoded proteins impedes the development of mRNA-based therapies for a variety of diseases. Herein, we report mRNA-loaded polymeric nanoparticles based on diethylenetriamine-substituted poly(aspartic acid) that induce protein expression in the lungs and muscles following intravenous and intramuscular injections, respectively. Animal studies revealed that the amount of polyethylene glycol (PEG) on the nanoparticle surface affects the translation of the delivered mRNA into the encoded protein in the target tissue. After systemic administration, only mRNA-loaded nanoparticles modified with PEG at a molar ratio of 1:1 (PEG/polymer) induce protein expression in the lungs. In contrast, protein expression was detected only following intramuscular injection of mRNA-loaded nanoparticles with a PEG/polymer ratio of 10:1. These findings suggest that the PEG density on the surface of poly(aspartic acid)-based nanoparticles should be optimized for different delivery routes depending on the purpose of the mRNA treatment.
最近，基于信使 RNA（mRNA）的治疗方法在疫苗、癌症免疫疗法和基因编辑方面引起了极大的关注。然而，缺乏能够将 mRNA 递送到靶组织并有效表达编码蛋白的生物相容性载体，阻碍了基于 mRNA 的治疗方法在各种疾病中的发展。在此，我们报告了基于二亚乙基三胺取代聚（天冬氨酸）的负载 mRNA 的聚合物纳米粒子，它们分别通过静脉内和肌肉内注射在肺部和肌肉中诱导蛋白表达。动物研究表明，纳米粒子表面上的聚乙二醇（PEG）的量会影响递送到靶组织中的编码蛋白的 mRNA 的翻译。在系统给药后，只有用摩尔比为 1:1（PEG/聚合物）修饰的负载 mRNA 的纳米粒子在肺部诱导蛋白表达。相比之下，仅在肌肉内注射 PEG/聚合物比为 10:1 的负载 mRNA 的纳米粒子后才检测到蛋白表达。这些发现表明，基于聚（天冬氨酸）的纳米粒子表面上的 PEG 密度应根据 mRNA 治疗的目的针对不同的给药途径进行优化。
