State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People's Republic of China.
Int J Nanomedicine. 2023 Dec 28;18:8059-8075. doi: 10.2147/IJN.S439381. eCollection 2023.
Messenger ribonucleic acid (mRNA)-based gene therapy has great potential in cancer treatment. However, the application of mRNA-based cancer treatment could be further developed. Elevated delivery ability and enhanced immune response are advantages for expanding the application of mRNA-based cancer therapy. It is crucial that the prepared carrier can cause an immune reaction based on the efficient delivery of mRNA.
We reported DMP nanoparticle previously, which was obtained by the self-assembly of 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and (ethylene glycol)--poly (ε-caprolactone) (mPEG-PCL). Research demonstrated that DMP can deliver mRNA, siRNA, and plasmid. And it is applied to various tumor types. In our work, the tumor cell lysate was introduced to the internal DMP chain, fusing cell-penetrating peptides (CPPs) modification on the surface forming the CLSV system. And then mixed encoded IL-22BP (interleukin-22 binding protein) mRNA and CLSV to form CLSV/IL-22BP complex.
The size of the CLSV system was 213.2 nm, and the potential was 45.7 mV. The transfection efficiency of the CLSV system is up to 76.45% in C26 cells via the micropinocytosis pathway. The CLSV system also could induce an immune response and significantly elevate the expression of CD80, CD86, and MHC-II in vivo. Then, by binding with IL-22BP (Interleukin-22 binding protein) mRNA, the CLSV/IL-22BP complex inhibited tumor cell growth, with an inhibition rate of up to 82.3% in vitro. The CLSV/IL-22BP complex also inhibited tumor growth in vivo, the tumor cell growth inhibition up to 75.0% in the subcutaneous tumor model, and 84.9% in the abdominal cavity metastasis tumor model.
Our work demonstrates that the CLSV system represents a potent potential for mRNA delivery.
信使核糖核酸 (mRNA) 为基础的基因治疗在癌症治疗中有很大的潜力。然而，mRNA 为基础的癌症治疗的应用可以进一步发展。提高递药能力和增强免疫反应是扩大 mRNA 为基础的癌症治疗应用的优势。至关重要的是，制备的载体可以在有效递 mRNA 的基础上引起免疫反应。
我们之前报道了 DMP 纳米粒子，它是由 1,2-二油酰基-3-三甲铵丙烷（DOTAP）和（乙二醇）-聚（ε-己内酯）（mPEG-PCL）自组装而成的。研究表明，DMP 可以递送 mRNA、siRNA 和质粒，并应用于各种肿瘤类型。在我们的工作中，将肿瘤细胞裂解物引入内部 DMP 链中，在表面融合穿膜肽（CPPs）修饰形成 CLSV 系统。然后将编码 IL-22BP（白细胞介素-22 结合蛋白）的 mRNA 与 CLSV 混合形成 CLSV/IL-22BP 复合物。
CLSV 系统的粒径为 213.2nm，电位为 45.7mV。CLSV 系统通过胞饮途径在 C26 细胞中的转染效率高达 76.45%。CLSV 系统还可以诱导免疫反应，并显著提高体内 CD80、CD86 和 MHC-II 的表达。然后，通过与 IL-22BP（白细胞介素-22 结合蛋白）mRNA 结合，CLSV/IL-22BP 复合物抑制肿瘤细胞生长，体外抑制率高达 82.3%。CLSV/IL-22BP 复合物也抑制体内肿瘤生长，皮下肿瘤模型中肿瘤细胞生长抑制率高达 75.0%，腹腔转移肿瘤模型中高达 84.9%。
我们的工作表明，CLSV 系统代表了一种有效的 mRNA 递送载体。
