Targeting Neutrophil/Eosinophil Extracellular Traps by Aptamer‐Functionalized Nanosheets to Overcome Recalcitrant Inflammatory Disorders

Abstract Excessive generation of neutrophil extracellular traps (NETs) and eosinophil extracellular traps (EETs) can drive various inflammatory disorders by stimulating intracellular nucleic acid receptors. Although extracellular traps (ETs) are promising therapeutic targets for recalcitrant chronic inflammation, for example, otitis media with effusion (OME), practical and specific targeting of NETs/EETs in pathological tissues remains challenging. In this study, an ultrathin, 2D sheet‐like nanoscavenger C‐TA _H is developed by modifying copper indium thiophosphate (CIPS) nanosheets with tannic acid (TA) and histone aptamers. The findings reveal that C‐TA _H effectively binds the dsDNA of NETs/EETs, inhibits bacterial growth, and reduces reactive oxygen species (ROS) levels, leading to a depressed local inflammation in ovalbumin (OVA)‐induced OME rats. In addition, the therapeutic results also include reductions in inflammatory cytokines release, suppression of ETs‐activated danger signaling pathways, including toll‐like receptor 9 (TLR9) and nuclear factor‐kappa B (NF‐κB), as well as decreased mucous exudation and improved hearing functions. Comprehensively, transcriptomic analysis with RNA‐sequencing confirms that C‐TA _H treatment significantly reverses the pathological gene expression changes after OVA sensitization. This work introduces an aptamer modification strategy for the target and capture of NETs/EETs, providing a potential therapeutic approach for modulating inflammatory signaling in OME as well as other recalcitrant inflammatory disorders.