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

Sepsis-associated secondary infection often leads to high mortality rate. Dysfunctional macrophages are the primary contributors to inadequate antimicrobial defense in patients with sepsis-associated immunosuppression, elevating the risk of opportunistic infections. Here, a bacteria-targeted transformable macrophage nanorejuvenator, designated as BATMAN, is developed to effectively tackle sepsis-associated secondary infection by coordinating the arrest of invasive bacteria and rejuvenation of dysfunctional macrophages based on the in situ responsive transformation. The results affirm the BATMAN’s effective binding and transformation on bacterial surface. The enzymatic removal of Chems by bacterial lipase disrupts the hydrophilic-hydrophobic balance of BATMAN, triggering the inside-out rearrangement that exposes the concealed tuftsin and facilitates its assembly into polyvalent peptide clusters on trapped bacteria driven by the assembly of FFVLK. This transformation not only reduces the invasiveness of bacteria, but enhances the interaction between tuftsin clusters and macrophage Fc gamma receptor, promoting bacterial phagocytosis and driving macrophage repolarization. As a result, BATMAN rejuvenates the compromised immune response to eliminate the polymicrobial- and even multidrug-resistant pathogen-induced pulmonary infection in septic mice. Consequently, we anticipate that our in situ transformable BATMAN holds promise as a therapeutic alternative for sepsis-associated secondary infection.