Chimeric IL‐6/4R‐LL37 Engineered Macrophages Achieve Synchronized Inflammation Control and Antimicrobial Defence in Sepsis

ABSTRACT

Treatment of septic patients is confronted with complex immune dysregulation: excessive pro‐inflammatory responses trigger cytokine storm leading to organ damage and high mortality, while concurrent and persistent immune dysfunction manifesting as T cell exhaustion, monocyte and macrophage functional suppression, and impaired antigen presentation significantly increases the risk of secondary infections. 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‐term survival in sepsis patients. This study reported a multifunctional engineered macrophage therapeutic strategy based on in situ LNP delivery of IL‐6/4 fusion protein and LL37 antimicrobial peptide mRNA. The IL‐6/4 fusion blocks IL‐6 mediated pro‐inflammatory signaling and activates IL‐4 mediated anti‐inflammatory 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.