Legumain In Situ Engineering Promotes Efferocytosis of CAR Macrophage to Treat Cardiac Fibrosis
Abstract
Abstract Uncontrolled and excessive cardiac fibrosis after myocardial infarction (MI) is a primary contributor to mortality by heart failure. Chimeric antigen receptor macrophage (CAR‐MΦ) therapy shows great promise in cardiac fibrosis, however, the overwhelming apoptotic cells after MI results in an overburdened efferocytosis in CAR‐MΦ, which compromises their antifibrotic potency. This work here reports an in situ engineered legumain (Lgmn) to elevate the cargo degradation of phagolysosome for promoting the efferocytosis of CAR‐MΦs, restoring their antifibrotic capability. Specifically, with the in‐house customized macrophages‐targeting lipid nanoparticles, this work first creates an efferocytosis‐boosted fibrosis‐specific CAR‐MΦs by introducing dual mRNAs that encode Lgmn, an endolysosomal cysteine protease, along with an anti‐fibroblast activation protein (FAP) CAR, respectively. This data demonstrate these CAR‐MΦs displayed a significantly increased phagocytic capacity as well as improved efferocytosis and enhanced antifibrotic capability. Treatment with the in situ reprogrammed CAR‐MΦs in MI mice obviously reduced the infarct size and mitigated cardiac fibrosis, leading to significant restoration of cardiac function. In sum, these findings establish that promoting efferocytosis through Lgmn engineering effectively relieved the overburdened efferocytosis of CAR‐MΦs, and enhanced their treatment efficacy of cardiac fibrosis with broad application in other fibrotic diseases.
Article Details
Authors (17)
Zejuan Liu
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics School of Pharmaceutical Sciences Department of Neurosurgery Jinan Microecological Biomedicine Shandong Laboratory NMPA Key Laboratory For Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education) Qilu Hospital Cheeloo College of Medicine Shandong University ...
Chen Chen
Yulin Zhang
Fengping Ji
Department of Emergency Medicine Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine China's Ministry of Education Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine Key Laboratory of Cardiopulmonary‐Cerebral Resuscitation Research of Shandong Province Qilu...
Hehui Liu
Department of Emergency Medicine Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug Medical and Pharmaceutical Basic Research Innovation Center of Emergency and Critical Care Medicine China's Ministry of Education Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine Key Laboratory of Cardiopulmonary‐Cerebral Resuscitation Research of Shandong Province Qilu...
Han Du
Yunyun Guo
Xianghui Dong
Zhenmei Yang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Maosen Han
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Chunwei Tang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Kehui Yang
Departments of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (S.S., X. Zhang, H.Y., C.F., Y.G., X.L., S.C., K.Y., X. Zhao, C.P., F.X., Y.C.).
Jian Zhang
Kun Zhao
Yuguo Chen
Xinyi Jiang
State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, National Medical Products Administration Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University
Feng Xu
Faculty of Pharmaceutical Sciences