Yang Wenqian, Chen Pengwen, Boonstra Eger, Hong Taehun, Cabral Horacio
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Pharmaceutics. 2022 Jun 6;14(6):1205. doi: 10.3390/pharmaceutics14061205.
Messenger RNA (mRNA) is emerging as a promising therapeutic modality for a variety of diseases. Because of the fragility and limited intracellular access of mRNA, the development of delivery technologies is essential for promoting the applicability of mRNA-based treatments. Among effective nanocarriers, polymeric micelles loading mRNA by polyion complex (PIC) formation with block catiomers have the potential to meet the delivery needs. Since PICs are relatively unstable in in vivo settings, herein, we constructed mRNA-loaded micelles having pH-responsive cross-linked cores by complexing mRNA with -aconitic anhydride-modified poly(ethylene glycol)-poly(l-lysine) (PEG-pLL(CAA)) block copolymers. The micelles were stable at physiological pH (pH 7.4) but achieved the complete release of the mRNA at endosomal pH (pH 5.5-4.5). The cross-linking also enhanced the stability of the micelles against disassembly from polyanions and protected the loaded mRNA from degradation by nucleases. Thus, the cross-linked micelles increased the delivery of mRNA to cancer cells, promoting protein expression both in vitro and in vivo. Our results highlight the potential of PEG-pLL(CAA)-based micelles for mRNA delivery.
信使核糖核酸（mRNA）正成为治疗多种疾病的一种有前景的治疗方式。由于mRNA的脆弱性和有限的细胞内摄取能力，开发递送技术对于促进基于mRNA的治疗方法的适用性至关重要。在有效的纳米载体中，通过与嵌段阳离子聚合物形成聚离子复合物（PIC）来负载mRNA的聚合物胶束有潜力满足递送需求。由于PIC在体内环境中相对不稳定，在此，我们通过使mRNA与衣康酸酐修饰的聚（乙二醇）-聚（L-赖氨酸）（PEG-pLL（CAA））嵌段共聚物复合，构建了具有pH响应交联核心的负载mRNA的胶束。这些胶束在生理pH（pH 7.4）下稳定，但在内体pH（pH 5.5 - 4.5）下实现mRNA的完全释放。交联还增强了胶束对聚阴离子解聚的稳定性，并保护负载的mRNA不被核酸酶降解。因此，交联胶束增加了mRNA向癌细胞的递送，在体外和体内均促进了蛋白质表达。我们的结果突出了基于PEG-pLL（CAA）的胶束用于mRNA递送的潜力。
