脂质纳米粒-mRNA递送系统及其在嵌合抗原受体T细胞治疗中的应用

Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy

尽管嵌合抗原受体(CAR)T细胞治疗在血液系统恶性肿瘤患者中取得了显著的临床疗效,但需要进一步优化。脂质纳米粒(LNP)-信使核糖核酸(mRNA)递送系统作为一种非病毒性基因载体运用于CAR-T细胞治疗研究中,一方面通过LNP将密封蛋白-6 mRNA靶向递送至抗原提呈细胞,从而实现抗原提呈细胞辅助性增强密封蛋白-6靶向的CAR-T细胞的功能,以进一步诱导对实体瘤的清除;另一方面,通过LNP将成纤维细胞激活蛋白(FAP)CAR mRNA靶向递送至T细胞,实现体内FAP靶向的CAR-T细胞的制备,以通过阻断心脏纤维化过程达到治疗急性心肌损伤的目的。在CAR-T细胞研究和治疗中,LNP-mRNA递送系统具有不与细胞基因组整合、价格便宜、毒副作用小及可修饰等优点,亦存在蛋白瞬时表达导致调控细胞功能的持久性不足及制备等方面的技术局限性。本文综述了LNP-mRNA递送系统及其在CAR-T细胞治疗中的应用研究。

Chimeric antigen receptor(CAR)T cell therapy has shown significant efficacy for hematological malignancies,however,it needs to be further optimized.Recently,the lipid nanoparticle(LNP)-mRNA delivery system as a nonviral gene transfer vector has gained rapid progress in CAR-T cell therapy.The claudin-6(CLDN6)mRNA is delivered to antigen presenting cells(APCs)through LNP system,thereby enhancing the function of CLDN6 CAR-T cells for the clearance of solid tumor cells.For treatment of acute cardiac injury,the fibroblast activation protein(FAP)CAR mRNA can be delivered to T cells through LNP system for the in vivo production of FAP CAR-T cells,thereby blocking the process of myocardial fibrosis.The LNP-mRNA delivery system has advantages including having no integration in host genome,inexpensiveness,low toxicity and modifiability;on the other hand,it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.This article reviews the research advance in LNP-mRNA in vivo delivery system and its application in CAR-T cell therapy.