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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

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. Therefore, we aim to develop a strategy that challenges all three barriers in an integrated manner. Methods : We design a collaborative drug delivery strategy based on genetically modified macrophage therapy. The genetic engineering of exogenous macrophages involves overexpression of C-C chemokine receptor type 2 (CCR2) and cleavage-resistant MerTK (MerTK CR ) by adenovirus. Liposomes loaded with PEP-20 (a CD47 antagonist) are then anchored to the engineered macrophage surface by click chemistry. Results : CCR2 targets exogenous macrophages to the injured heart as a direct supplement to efferocytosis effector cells, while MerTK CR preserves functional intact locally. PEP-20 is responsively released to block the braking effect of CD47 on cardiac efferocytosis. 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. Conclusion : Genetically engineered macrophages co-loaded with CD47 inhibitors synergistically reconstruct efferocytosis and improve cardiac remodeling post MI/R injury. This article is protected by copyright. All rights reserved