Artificial exosomes synergistically reshape sepsis immune homeostasis by modulating neutrophil fate and blocking PD-1/PD-L1.

A critical challenge in sepsis treatment lies in its complex immune microenvironment, characterized by concurrent hyperinflammation and immunosuppression. This imbalance is jointly driven by dysregulated neutrophil programmed death and abnormal activation of the PD-1/PD-L1 immune checkpoint. Therefore, precisely modulating neutrophil fate and blocking this immune checkpoint are highly promising therapeutic strategies. We engineered an artificial exosome nano-decoy (AT@NV-PD1) that homes to senescent-like neutrophils. It comprises a pH-responsive bovine serum albumin core carrying AT7519, a cyclin-dependent kinase inhibitor, cloaked with macrophage membrane presenting PD-1. After intravenous delivery, PD-1 selectively binds PD-L1 on target neutrophils. In the mildly acidic microenvironment, AT7519 release triggers timely neutrophil apoptosis, curbing excessive inflammation. Concurrently, the nano-decoy neutralizes bacterial toxins and inflammatory cytokines. By engaging PD-L1, AT@NV-PD1 also alleviates T cell exhaustion, reduces immunosuppression, and promotes immune homeostasis. In conclusion, AT@NV-PD1 represents a sepsis therapy by precisely regulating neutrophil fate and rebuilding immune balance.