Ionizable Lipid Nanoparticles with Integrated Immune Checkpoint Inhibition for mRNA CAR T Cell Engineering.
Ionizable Lipid Nanoparticles with Integrated Immune Checkpoint Inhibition for mRNA CAR T Cell Engineering.
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用于 mRNA CAR T 细胞工程的具有集成免疫检查点抑制功能的可电离脂质纳米颗粒。
DOI：
10.1002/adhm.202301515
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发表时间：
2023
影响因子：
10
通讯作者：
Mitchell,MichaelJ
中科院分区：
文献类型：
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作者：
Hamilton,AlexG;Swingle,KelseyL;Joseph,RyannA;Mai,David;Gong,Ningqiang;Billingsley,MargaretM;Alameh,Mohamad-Gabriel;Weissman,Drew;Sheppard,NeilC;June,CarlH;Mitchell,MichaelJ
程序性细胞死亡蛋白1（PD-1）信号通路是肿瘤微环境中T细胞活性减弱的主要来源。虽然使用抗体阻断抑制PD-1通路的临床方法已经取得了广泛的成功，但这些方法导致广泛的PD-1抑制，增加了自身免疫反应的风险。这项研究报告了一种可电离脂质纳米颗粒（LNP）平台的开发，用于在T细胞中同时进行治疗性基因表达和RNA干扰（RNAi）介导的瞬时基因敲低。在开发这个平台时，当共封装时，在两种RNA货物之间观察到有趣的相互作用，与单独递送任何一种货物相比，导致表达和敲低特征的改善。采用该信使RNA（mRNA）/小干扰RNA（siRNA）共递送平台将靶向PD-1的嵌合抗原受体（CAR）mRNA和siRNA离体递送至原代人T细胞，并且观察到强CAR表达和PD-1敲低，而总体T细胞活化状态没有明显变化。该递送平台显示出用于许多免疫工程应用的瞬时免疫基因调节的巨大前景，包括改进的癌症免疫疗法的开发。
The programmed cell death protein 1 (PD‐1) signaling pathway is a major source of dampened T cell activity in the tumor microenvironment. While clinical approaches to inhibiting the PD‐1 pathway using antibody blockade have been broadly successful, these approaches lead to widespread PD‐1 suppression, increasing the risk of autoimmune reactions. This study reports the development of an ionizable lipid nanoparticle (LNP) platform for simultaneous therapeutic gene expression and RNA interference (RNAi)‐mediated transient gene knockdown in T cells. In developing this platform, interesting interactions are observed between the two RNA cargoes when co‐encapsulated, leading to improved expression and knockdown characteristics compared to delivering either cargo alone. This messenger RNA (mRNA)/small interfering RNA (siRNA) co‐delivery platform is adopted to deliver chimeric antigen receptor (CAR) mRNA and siRNA targeting PD‐1 to primary human T cells ex vivo and strong CAR expression and PD‐1 knockdown are observed without apparent changes to overall T cell activation state. This delivery platform shows great promise for transient immune gene modulation for a number of immunoengineering applications, including the development of improved cancer immunotherapies.