Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury

Haipeng Tan; Weiyan Li; Zhiqing Pang; Xueyi Weng; Jinfeng Gao; Jing Chen; Qiaozi Wang; Qiyu Li; Hongbo Yang; Zheng Dong; Zhengmin Wang; Guangrui Zhu; Yiwen Tan; Yuyuan Fu; Chengzhi Han; Shiteng Cai; Juying Qian; Zheyong Huang; Yanan Song; Junbo Ge

doi:10.1002/adhm.202303267

Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury

Adv Healthc Mater. 2024 Jan 10:e2303267. doi: 10.1002/adhm.202303267. Online ahead of print.

Authors

Haipeng Tan^{1

2

3}, Weiyan Li^{1

2

3}, Zhiqing Pang⁴, Xueyi Weng^{1

2

3}, Jinfeng Gao^{1

2

3}, Jing Chen^{1

2

3}, Qiaozi Wang^{1

2

3}, Qiyu Li^{1

2

3}, Hongbo Yang^{1

2

3}, Zheng Dong^{1

2

3}, Zhengmin Wang^{1

2

3}, Guangrui Zhu^{1

2

3}, Yiwen Tan^{1

2

3}, Yuyuan Fu^{1

2

3}, Chengzhi Han^{1

2

3}, Shiteng Cai^{1

2

3}, Juying Qian^{1

2

3}, Zheyong Huang^{1

2

3}, Yanan Song^{1

2

3}, Junbo Ge^{1

2

3}

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 20032, P. R. China.
² National Clinical Research Center for Interventional Medicine and Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, P. R. China.
³ Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 20032, P. R. China.
⁴ Key Laboratory of Smart Drug Delivery, School of Pharmacy, Fudan University, Ministry of Education, 826 Zhangheng Road, Pudong New Area, Shanghai, 201210, P. R. China.

PMID: 38198534
DOI: 10.1002/adhm.202303267

Abstract

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

Keywords: cell therapies; click chemistry; efferocytosis; immune checkpoints; macrophages; myocardial ischemia-reperfusion injury; reactive oxygen species responsive.

Abstract

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