间充质干细胞膜修饰载药脂质体影响骨髓归巢逐级靶向递送CRISPR/Cas9抗急性髓系白血病效应与机制

急性髓系白血病靶向治疗有着传统的化疗放疗所没有的优势，研发新的治疗方式在清除急性髓系白血病的同时不影响正常细胞的功能，对患者的治疗和预后有着重要的意义。基于CRISPR/Cas9的基因编辑技术在靶向基因治疗方面有着远大的前景，如何将CRISPR/Cas9精准递送到肿瘤细胞内，保证其在肿瘤微环境中的有效浓度，抑制致癌基因的表达，是该治疗手段亟须解决的问题之一。本课题拟利用间充质干细胞的归巢能力，将包裹有RNP的脂质体纳米粒递送到骨髓壁龛中，再用CD64抗体修饰脂质体达到对固定细胞群体的靶向，最终实现对骨髓壁龛微环境以及AML细胞的逐级靶向。本课题拟阐述MSCM@GM1CD64/RNP在体内体外模型中逐级靶向骨髓壁龛微环境和AML细胞群的具体机制。为靶向递送CRISPR/Cas9治疗急性髓系白血病提供新的策略与理论基础。

Targeted therapy of acute myeloid leukemia has advantages which is not existed in traditional chemotherapy and radiotherapy. The development of new treatment methods can eliminate acute myeloid leukemia without affecting the function of normal cells, which is of great significance to the treatment and prognosis of patients. Gene editing technology based on CRISPR/Cas9 has great view in targeted gene therapy. It is a barrier that to accurately deliver CRISPR/Cas9 into tumor cells, ensure its effective concentration in the tumor microenvironment, and inhibit the expression of oncogenes. This project intends to use the homing ability of mesenchymal stem cells to deliver RNP-encapsulated liposome nanoparticles to the bone marrow niche, and then use CD64 antibody to modify the liposomes to target the AML cell population, and finally achieve the target to the bone marrow niche microenvironment and the gradual targeting of AML cells. This topic intends to explain the dual-target mechanism of MSCM@GM1CD64/RNP in the in vitro and in vitro models that target the microenvironment of the bone marrow niche and the AML cell population step by step. It provides a new strategy and theoretical basis for targeted delivery of CRISPR/Cas9 to treat acute myeloid leukemia.