Sequential clearance of neutrophil extracellular traps for precision therapy of sepsis

Sepsis, a life-threatening syndrome driven by dysregulated host response to infection, is critically exacerbated by the uncontrolled formation of neutrophil extracellular traps (NETs), which amplify inflammation, promote microthrombosis, and precipitate multiple organ dysfunction. However, current therapeutic approaches remain inadequate in effectively targeting and modulating NETs, leaving a significant clinical gap in managing sepsis progression. Herein, we propose a "sequential NETs-clearance" strategy to precisely mitigate NET-associated pathologies by simultaneously inhibiting NET overproduction and facilitating their targeted capture and degradation. We engineered a multifunctional metal-organic framework (MOF818) with intrinsic antioxidant activity, functionalized with a NETs-capturing poly(amidoamine) dendrimer and loaded with a NETs-degrading enzyme, micrococcal nuclease (MNase). This integrated platform efficiently scavenges excessive reactive oxygen species (ROS) to inhibit NETosis, while simultaneously capturing existing NETs via electrostatic interactions and enzymatically cleaving their DNA scaffold, thereby disrupting the self-sustaining inflammatory cascade. In vitro, this combinatorial treatment markedly reduced NET-mediated inflammatory responses, while treatment in murine models of sepsis significantly mitigated systemic cytokine storms, alleviated organ damage, and improved survival in septic mice. Importantly, this therapeutic efficacy was corroborated in ex vivo human specimens, where the nanocomposite significantly suppressed NETosis and reduced inflammatory cytokines in neutrophils and plasma derived from sepsis patients. This work establishes a versatile nanotherapeutic paradigm for multi-target modulation of NETs and oxidative stress, offering a promising translational avenue for the precise treatment of sepsis.