FcγR-targeted tuftsin clusters rejuvenate macrophages in preclinical sepsis-associated secondary infection

Sepsis-associated secondary infection often leads to a high mortality rate. Dysfunctional macrophages are primary contributors to inadequate antimicrobial defense in patients with sepsis-associated immunosuppression. Rejuvenating macrophage antibacterial capacity is beneficial for host defense against secondary infection. Here, we developed "BATMAN" (bacteria-targeted transformable macrophage nanorejuvenator), a self-assembling peptide nanoparticle to tackle sepsis-associated secondary infection by coordinating the arrest of invasive bacteria and rejuvenation of dysfunctional macrophages. BATMAN comprises a bacteria-targeting ubiquicidin peptide domain, bacterial lipase-sensitive cholesteryl hemisuccinate, an assembly-driving FFVLK domain, and the immunoglobulin G-derived tuftsin peptide. Upon activation by bacterial lipase, the particles undergo an inside-out transformation and assembly to expose and cluster the concealed tuftsin peptides for interaction with macrophage Fcγ receptors. Interaction of tuftsin clusters with macrophage Fcγ receptors enhanced bacterial phagocytosis and drove macrophage repolarization. In a cecal slurry-induced septic mouse model with secondary pulmonary infection, BATMAN treatment improved survival rates and rejuvenated the sepsis-compromised immune response to address polymicrobial- and multidrug-resistant pathogen-induced pulmonary infections. These findings suggest that BATMAN holds promise for further development as a therapeutic alternative for sepsis-associated secondary infection.