Turmeric-derived nanovesicles reprogram pathological NETosis to mitigate inflammatory bone loss

Inflammatory bone destruction is a progressive pathological process driven by persistent immune-mediated inflammation and osteoclast-dependent bone resorption, exemplified by periodontitis. Increasing evidence indicates that dysregulated inflammatory microenvironments and aberrant osteoclast activation form a self-amplifying loop that accelerates bone loss. Neutrophils are central to this process through the formation of neutrophil extracellular traps (NETs), while excessive NETosis further amplifies inflammation and promotes bone resorption. Although NETosis has emerged as a promising therapeutic target, current strategies largely rely on single-molecule inhibitors, which often suffer from limited targeting efficiency, poor bioavailability, and uncertain long-term safety. Therefore, developing biomimetic delivery-based, multi-component and multi-target therapeutic strategies to precisely regulate NET-associated signalling pathways remains a major challenge.

Single-cell transcriptomic analysis of Gene Expression Omnibus (GEO) datasets identified aberrant NET formation as a key pathogenic feature and a potential therapeutic target in periodontitis. To address this challenge, we developed a natural biomimetic nanodelivery system based on turmeric-derived nanovesicles (TNVs). This platform may attenuate inflammatory responses and NET formation through vesicle-mediated delivery of intrinsic bioactive cargo. TNVs possess a plant-derived lipid bilayer structure enriched with bioactive compounds, exhibiting excellent biocompatibility and efficient uptake by neutrophils. Functional studies demonstrated that TNVs markedly suppressed NET formation, accompanied by reduced intracellular reactive oxygen species (ROS) levels, decreased expression of citrullinated histone H3 (CitH3), myeloperoxidase (MPO), neutrophil elastase (ELANE), and reduced extracellular DNA release. Transcriptomic profiling further confirmed that TNVs downregulated NET-associated pathways while enhancing antioxidant and anti-inflammatory responses. In a murine periodontitis model, TNVs preferentially accumulated at inflamed sites, inhibited NET formation and osteoclastogenesis, alleviated inflammation, reduced bone loss, and preserved bone microarchitecture.

TNVs represent a promising plant-derived biomimetic nanoplatform that preferentially accumulates in inflamed tissues and exerts immunomodulatory effects. By integrating intrinsic bioactive cargo with efficient delivery capacity, TNVs offer a compelling therapeutic strategy for inflammation-induced bone loss, including periodontitis.