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Chimeric antigen receptor macrophage (CAR\u2010M\u03a6) therapy shows great promise in cardiac fibrosis, however, the overwhelming apoptotic cells after MI results in an overburdened efferocytosis in CAR\u2010M\u03a6, 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\u2010M\u03a6s, restoring their antifibrotic capability. Specifically, with the in\u2010house customized macrophages\u2010targeting lipid nanoparticles, this work first creates an efferocytosis\u2010boosted fibrosis\u2010specific CAR\u2010M\u03a6s by introducing dual mRNAs that encode Lgmn, an endolysosomal cysteine protease, along with an anti\u2010fibroblast activation protein (FAP) CAR, respectively. This data demonstrate these CAR\u2010M\u03a6s displayed a significantly increased phagocytic capacity as well as improved efferocytosis and enhanced antifibrotic capability. Treatment with the in situ reprogrammed CAR\u2010M\u03a6s 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\u2010M\u03a6s, and enhanced their treatment efficacy of cardiac fibrosis with broad application in other fibrotic diseases.<\/jats:p>","DOI":"10.1002\/adma.202417831","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T03:35:36Z","timestamp":1744601736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Legumain In Situ Engineering Promotes Efferocytosis of CAR Macrophage to Treat Cardiac Fibrosis"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8267-7647","authenticated-orcid":false,"given":"Zejuan","family":"Liu","sequence":"first","affiliation":[{"name":"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\u2010Cerebral Resuscitation Research of Shandong Province Qilu..."},{"name":"Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics NMPA Key laboratory for technology Research and evaluation of drug Products and Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University  44 cultural West Road Jinan Shandong Province 250012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics NMPA Key laboratory for technology Research and 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