Neutrophil-Targeted Polyphenol-Based Nanoassembly Modulates Nets/Glycolysis For Periodontitis

Inhibition of neutrophil extracellular trap formation and HK-2-regulated macrophage gated glycolysis for periodontitis treatment Neutrophil-targeted nanoparticles were synthesized via polyphenol(EGCG)-amino acid(5-HT) self-assembly. Targeting specificity was confirmed by fluorescence labeling, competitive inhibition assays, and in vivo imaging. The nanoparticles suppressed neutrophil extracellular trap (NETs) formation, validated via TEM, RT-PCR, WB, and ELISA, while transcriptomics revealed NETs-mediated macrophage polarization via glycolytic modulation. In a murine periodontitis model (C57BL/6 mice, n=30, ethically approved), micro-CT and histopathology (HE/Masson/IHC) demonstrated therapeutic efficacy, including reduced bone resorption and inflammation. This dual-action strategy inhibits NETs-driven immunopathology and reprograms macrophage metabolism, offering a targeted approach for periodontitis treatment. Self-assembled nanoparticles (EHPs, ∼200 nm) were synthesized and shown to precisely target neutrophils at inflammatory sites via in vivo imaging and in vitro validation. Mechanistically, EHPs inhibited neutrophil-driven inflammation and NETs formation, reducing pro-inflammatory factor release (e.g., histones, MPO) and attenuating macrophage pro-inflammatory polarization. Transcriptomics further uncovered that EHPs remodeled the periodontal immune microenvironment by regulating neutrophil-macrophage crosstalk and macrophage glycolytic flux. Polyphenol-amino acid self-assembled nanoparticles mitigate periodontal inflammation by dual mechanisms: (1) reducing NETs formation through oxidative stress and mtDNA release inhibition, and (2) suppressing macrophage glycolytic flux to block inflammatory amplification