Dual mRNA co-delivery for in situ generation of phagocytosis-enhanced CAR macrophages augments hepatocellular carcinoma immunotherapy

• Published in: Journal of controlled release 2023-08, Vol.360, p.718-733
• Main Authors: Yang, Zhenmei, Liu, Ying, Zhao, Kun, Jing, Weiqiang, Gao, Lin, Dong, Xianghui, Wang, Yan, Han, Maosen, Shi, Chongdeng, Tang, Chunwei, Sun, Peng, Zhang, Rui, Fu, Zhipeng, Zhang, Jing, Zhu, Danqing, Chen, Chen, Jiang, Xinyi
• Format: Article
• Language: English
• Subjects: CD24; Chimeric antigen receptor macrophage; Hepatocellular carcinoma; Lipid nanoparticle; Protein corona
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.07.021

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. Lipid nanoparticle-mediated dual mRNA co-delivery for in situ generation of Siglec-GΔITIMs-expressing GPC3-specific CAR macrophages augments hepatocellular carcinoma immunotherapy. [Display omitted] •Dual mRNA co-laden lipid nanoparticle was developed for in situ macrophage reprogramming.•LNP-engineered CAR-macrophage exhibited GPC3-specific tumor phagocytosis.•Siglec-GΔITIMs mRNA co-engineering further enhanced the antitumor efficacy of CAR macrophage.