Dynamic covalent/coordinated nanonetworks with DNase-mimetic and ROS scavenging properties for acute inflammation treatment.

Sterile inflammation driven by cell-free DNA (cfDNA) and reactive oxygen species (ROS) underlies acute inflammatory disorders, yet current therapies fail to specifically target these upstream mediators. We report a dynamic covalent/coordinated nanonetwork (DC2 NNW) that combines drug delivery, DNase-mimetic and ROS-scavenging functions through reaction-induced self-assembly and cerium coordination. DC2 NNWs efficiently degrade cfDNA, scavenge ROS, and release the loaded therapeutics, suppressing TLR9/NF-κB/NLRP3 and TLR4/MyD88/JAK signaling. In murine models of acute kidney injury (AKI) and endometritis, DC2 NNWs selectively accumulated in inflamed tissues, restored organ function, alleviated injury, and reduced oxidative stress. Transcriptomic analysis further showed downregulation of pro-inflammatory and neutrophil extracellular trap (NET)-associated genes, alongside activation of metabolic repair pathways including fatty acid oxidation and mitochondrial respiration. This multifunctional nanozyme platform, with its drug delivery properties, offers a targeted and upstream approach for modulating innate immune activation and metabolic dysfunction in AKI, endometritis, and other sterile inflammatory diseases.