肝细胞癌
吞噬作用
免疫疗法
巨噬细胞
癌症研究
免疫学
免疫系统
西格莱克
生物
CD24型
免疫
嵌合抗原受体
医学
细胞
CD44细胞
体外
生物化学
遗传学
作者
Zhenmei Yang,Ying Li,Kun Zhao,Weiqiang Jing,Lin Gao,Xiaowei Dong,Yan Wei,Maosen Han,Chongdeng Shi,Chunwei Tang,Ping Sun,Rui Zhang,Zhipeng Fu,Jing Zhang,Danqing Zhu,Chen Chen,Xinyi Jiang
标识
DOI:10.1016/j.jconrel.2023.07.021
摘要
Hepatocellular carcinoma (HCC) is a prevalent and lethal disease, and tumor regression rarely occurs in advanced HCC patients due to limited effective therapies. Given the enrichment of macrophages in HCC and their role in tumor immunity, transforming them into chimeric antigen receptor macrophages (CAR-Ms) is thought to increase HCC cell-directed phagocytosis and tumoricidal immunity. To test this hypothesis, mRNA encoding CAR is encapsulated in a lipid nanoparticle (LNP) that targets liver macrophages. Notably, the LNPs adsorb specific plasma proteins that enable them to target HCC-associated macrophages. Moreover, mRNA encoding Siglec-G lacking ITIMs (Siglec-GΔITIMs) is codelivered to liver macrophages by LNP to relieve CD24-mediated CAR-Ms immune suppression. Mice treated with LNPs generating CAR-Ms as well as CD24-Siglec-G blockade significantly elevate the phagocytic function of liver macrophages, reduce tumor burden and increase survival time in an HCC mouse model. Arguably, our work suggests an efficacious and flexible strategy for the treatment of HCC and warrants further rigorous evaluation in clinical trials.
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