Neutrophil-Mimetic Nanoscavengers Target the Inflammatory Microenvironment to Eliminate NETs/ROS and Immunomodulate cGAS-STING Signaling in Septic AKI.

Abstract

Sepsis-associated acute kidney injury (SAKI) remains a life-threatening condition with limited therapeutic options, primarily driven by rampant oxidative stress, inflammatory dysregulation. Importantly, aberrant formation of neutrophil extracellular traps (NETs) and sustained innate immune activation further exacerbate renal injury, highlighting the need for strategies that precisely modulate these intertwined pathological mechanisms. Here, we present neutrophil-mimetic nanoscavengers (MD@NM) that comprise a catalytic core of DNase-1-loaded MnOnanozymes enveloped by a neutrophil membrane engineered to actively target and simultaneously disrupt multiple pathological circuits in SAKI. The neutrophil membrane confers chemokine-receptor (e.g., CXCR2) mediated homing to injured kidneys, while the MnOnanozymes catalytically scavenge ROS and the loaded DNase-1 enzymatically degrades NETs-derived extracellular DNA, thereby suppressing the cGAS-STING pathway and skewing macrophage polarization toward an M2 reparative phenotype. In a murine model of LPS-induced SAKI, MD@NM treatment facilitated robust renal targeting, attenuated neutrophilic infiltration, resolved cytokine storm, and ameliorated structural kidney damage. Collectively, this biomimetic platform represents a novel strategy for precision immunomodulation and multi-mechanistic therapy against SAKI by integrating antioxidative, NETs-scavenging, and anti-inflammatory functions into a single nanotherapeutic agent.