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Current clinical therapeutic strategies can effectively control infection and cytokine storm, but fail to resolve persistent T cell exhaustion, which is a critical determinant of poor long\u2010term survival in sepsis patients. This study reported a multifunctional engineered macrophage therapeutic strategy based on in situ LNP delivery of IL\u20106\/4 fusion protein and LL37 antimicrobial peptide mRNA. The IL\u20106\/4 fusion blocks IL\u20106 mediated pro\u2010inflammatory signaling and activates IL\u20104 mediated anti\u2010inflammatory pathways, reducing inflammatory injury and promoting tissue repair. LL37 antimicrobial peptide disrupts bacterial membranes to reduce bacterial burden while modulating immune responses. In sepsis mouse models, engineered macrophages significantly improved survival rates, reduced histopathological damage and organ bacterial burden, and effectively restored T cell and macrophage functions, achieving infection control, inflammation modulation, and immune reconstitution. These findings demonstrate the substantial clinical translational potential of this engineered macrophage approach for precision sepsis treatment.<\/jats:p>","DOI":"10.1002\/advs.77016","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:34:26Z","timestamp":1786102466000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chimeric IL\u20106\/4R\u2010LL37 Engineered Macrophages Achieve Synchronized Inflammation Control and Antimicrobial Defence in Sepsis"],"prefix":"10.1002","volume":"13","author":[{"given":"Tianyang","family":"Jie","sequence":"first","affiliation":[{"name":"Department of Bone and Joint Surgery Department of Orthopedics Renji Hospital Shanghai Jiaotong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bone and Joint 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