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Engineered Microparticles for Treatment of Murine Brain Metastasis by Reprograming Tumor Microenvironment and Inhibiting MAPK Pathway

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单位： [1]College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, P. R. China. [2]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P. R. China. [3]Beijing Institute of Clinical Research, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, P. R. China. [4]Department of Biomedical Sciences, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, HKG, P. R. China. [5]Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA.

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关键词： blood-brain barrier cancer immunotherapy extracellular vesicles macrophages polarization USP7

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Brain metastases (BRM) are common in advanced lung cancer. However, their treatment is challenging due to the blood-brain barrier (BBB) and the immunosuppressive tumor microenvironment (ITME). Microparticles (MPs), a type of extracellular vesicle, can serve as biocompatible drug delivery vehicles that can be further modulated with genetic engineering techniques. MPs prepared from cells induced with different insults are compared and it is found that radiation-treated cell-released microparticles (RMPs) achieve optimal targeting and macrophage activation. The enzyme ubiquitin-specific protease 7 (USP7), which simultaneously regulates tumor growth and reprograms M2 macrophages (M2Φ), is found to be expressed in BRM. Engineered RMPs are then constructed that comprise: 1) the RMP carrier that targets and reprograms M2Φ; 2) a genetically expressed SR-B1-targeting peptide for improved BBB permeability; and 3) a USP7 inhibitor to kill tumor cells and reprogram M2Φ. These RMPs successfully cross the BBB and target M2Φ in vitro and in vivo in mice, effectively reprogramming M2Φ and improving survival in a murine BRM model. Therapeutic effects are further augmented when combined with immune checkpoint blockade. This study provides proof-of-concept for the use of genetically engineered MPs for the treatment of BRM.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

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第一作者单位： [1]College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, P. R. China. [2]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, P. R. China.

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