传出细胞增多
梅尔特克
巨噬细胞
药理学
再灌注损伤
CCR2型
炎症
缺血
癌症研究
医学
生物
细胞生物学
免疫学
受体
趋化因子
趋化因子受体
内科学
受体酪氨酸激酶
生物化学
体外
作者
Haipeng Tan,Weiyan Li,Zhiqing Pang,Xueyi Weng,Jiantou Gao,Jing Chen,Qiaozi Wang,Qiyu Li,Hongbo Yang,Dong Zheng,Zhengmin Wang,Guihua Zhu,Yiwen Tan,Yong Fu,Chengzhi Han,Sanjun Cai,Juying Qian,Zheyong Huang,Yanan Song,Junbo Ge
标识
DOI:10.1002/adhm.202303267
摘要
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. 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
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