Affiliation:
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& Shanghai Clinical Research Center for Interventional Medicine Shanghai 200032 China
3. Key Laboratory of Viral Heart Diseases National Health Commission Shanghai 20032 P. R. China
4. School of Pharmacy Fudan University Key Laboratory of Smart Drug Delivery Ministry of Education. 826 Zhangheng Road, Pudong New Area Shanghai 201210 P. R. China
Abstract
AbstractEfferocytosis, 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 (MerTKCR) 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 MerTKCR 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
Subject
Pharmaceutical Science,Biomedical Engineering,Biomaterials