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Research Article

Engineering SIRPα cellular membrane-based nanovesicles for combination immunotherapy

Mingyue Wang1,2,§, Yanfang Wang3,4,§, Yeteng Mu1,2,§, Fuxu Yang1,2, Zebin Yang2, Yuxuan Liu2, Lili Huang2, Shi Liu5, Xingang Guan1,2(), Zhigang Xie5(), Zhen Gu3,4,6,7,8()
School of Medicine, Taizhou University, Taizhou 318000, China
College of Medical Technology, Beihua University, Jilin 132013, China
Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Jinhua Institute of Zhejiang University, Jinhua 321299, China
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
Zhejiang Laboratory of Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou 311121, China
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China

§ Mingyue Wang, Yanfang Wang, and Yeteng Mu contributed equally to this work.

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Graphical Abstract

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Zebularine (Zeb)-loaded signal regulatory protein α nanovesicles (SIRPα NVs) promote the M1 polarization of macrophages, the phagocytosis of tumor cells, and the immunogenicity of melanoma, augmenting anti-tumor immune response for combination cancer immunotherapy.

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment for their unprecedented clinical efficacy. Signal regulatory protein α (SIRPα) is a phagocytic checkpoint expressed on macrophages, dendritic cells, and other myeloid cells. Cancer cells inhibit macrophage phagocytosis through the interaction of the CD47–SIRPα axis. Disrupting the CD47–SIRPα axis has therefore been a promising strategy in restoring the immune attack against cancer. Herein, we engineered cellular membrane nanovesicles (NVs) presenting SIRPα receptors for phagocytosis checkpoint blockade to augment the antitumor immune response. Furthermore, zebularine (Zeb), an inhibitor of DNA methyltransferase, was encapsulated into SIRPα NVs to reprogram the immunosuppressive tumor microenvironment together with blockade of phagocytosis checkpoint. It is demonstrated that SIRPα@Zeb can improve tumor immunogenicity, the polarization of tumor-associated macrophages to the M1 phenotype, and increase the infiltration of CD8+ T lymphocytes in tumors. The robust antitumor immune response induced by SIRPα@Zeb significantly suppressed tumor growth and extended mice-bearing melanoma xenograft survival.

Keywords

drug deliverysignal regulatory protein αnanovesicletumor-associated macrophagescancer immunotherapy

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Nano Research
Volume 16 Issue 5,
May 2023
Pages 7355-7363
DOI: 10.1007/s12274-023-5397-4
Cite this article:
Wang M, Wang Y, Mu Y, et al. Engineering SIRPα cellular membrane-based nanovesicles for combination immunotherapy. Nano Research, 2023, 16(5): 7355-7363. https://doi.org/10.1007/s12274-023-5397-4
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