Authors
Cheng, C., Ning, Q., Du, J., Dawulieti, J., Guo, C., Sun, M., Zhang, K., Li, H., Bi, Q., Li, J., Wu, Z., Huang, H., Ji, Z.-L., Du, J.-Z., Yang, C., Shao, D., Leong, K.
Abstract
Targeting the overwhelming inflammation driven by neutrophil extracellular traps (NETs) during infection provides an opportunity to manage severe sepsis. This potential needs to be realized by exploring selective NET-neutralization materials, which remains a challenge. Herein, we report a multivalent macromolecular strategy that targets NET-associated DNA-histone chromatin complexes while preserving antibacterial activity of aminoglycoside. We identify 8-arm PEG-conjugated netilmicin (8-arm Netil) as a lead NETs-neutralizer from a library of multivalent aminoglycoside-displayed materials. When compared with 2- and 4-arm counterparts, 8-arm Netil exhibits potent antibacterial activity and high-affinity binding to DNA-histone chromatin complexes through stable multivalent noncovalent interactions, thereby suppressing NET-induced TLR4/TLR9 activation and macrophage inflammatory responses. In severe septic mice, intravenously administered 8-arm Netil preferentially accumulates in inflamed tissues, leading to improved survival protection, owing to the reduction of bacterial dissemination, NET accumulation, systemic cytokine production, and multiple-organ injury. These findings establish NET-associated DNA-histone chromatin complexes as actionable extracellular targets and demonstrate multivalent chromatin targeting as a rational material design strategy for selective NET neutralization and inflammation control in severe sepsis.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 01 Jul 2026.
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