Synthetic SIGLEC9-based chimeric switch receptor augments the efficacy of CAR macrophages against glioblastoma
Abstract
Chimeric antigen receptor macrophage (CAR-M) therapy represents a promising therapeutic approach for treating glioblastoma multiforme (GBM). However, durable antitumorigenic macrophage phenotype of CAR-Ms is limited by the highly immunosuppressive tumor microenvironment (TME), wherein Siglec–sialic acid signaling directly drives macrophage polarization toward a protumorigenic phenotype. We here report an in situ synthetic SIGLEC9-based chimeric switch receptor (CSR) for diverting the inhibitory signal into positive ones, augmenting the sustained proinflammatory phenotype and tumoricidal immunity of CAR-Ms in the GBM niche. Specifically, our results showed that macrophage-targeted ionizable lipid nanoparticles efficiently introduce dual circRNAs into macrophages to generate CSR functionalized CAR-Ms in vitro and in vivo. The modified macrophages maintained a proinflammatory state, exhibited superior phagocytic activity, resulting in rapid and efficient eradication of IL13Rα2-positive tumor cells. Moreover, an injectable nanoparticle–hydrogel system for reprogramming macrophages surrounding the glioma resection cavity initiated a locoregional antitumor immune response and elicited robust long-term immunological memory, inhibiting tumor relapse in the postoperative GBM model. In sum, our findings establish that the engineered SIGLEC9-based CSR significantly promotes the maintenance of an antitumoral phenotype of CAR-Ms in the hypersialylated acidic TME, contributing to the improvement of engineered macrophage-based immunotherapy against GBM.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Zhipeng Fu
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Xiaotian Zhao
Shenyang National Laboratory for Materials Science Institute of Metal Research Chinese Academy of Sciences
Qikang Zhang
Jinan Microecological Biomedicine Shandong Laboratory, Jinan Medical and Health Science and Technology Innovation Industrial Park
Maosen Han
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Jing Zhang
Zhenmei Yang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Yan Wang
Zichao Yao
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Ying Liu
Chunwei Tang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Kaiyan Xi
Jinan Microecological Biomedicine Shandong Laboratory, Jinan Medical and Health Science and Technology Innovation Industrial Park
Zhanyan Liu
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Yi Zhang
Kun Zhao
Na Li
Yulin Zhang
Yudong Song
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Xinyi Jiang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Chen Chen