Periodontal disease is an inflammatory disease with periodontal tissue destruction and loss (Niemiec, 2008). Conventional therapies are useful in controlling active inflammation but not in regenerating damaged periodontal tissue (Kwon et al., 2021). Recent advances in the treatment of periodontal disease have focused on regenerative therapy, which aims to restore the physiological function of teeth by rebuilding periodontal tissue (Liu et al., 2019). In the treatment of periodontitis, periodontal ligament (PDL) tissue is regarded as an appropriate cell source for periodontal regeneration (Rios et al., 2011). Among them, periodontal ligament cells (PDLCs) from the fibroblastic and osteoblastic mesenchymal lineages are a diverse population of cells that can exist in various stages of development and lineage commitment (Gay et al., 2007). When compared to healthy PDLCs, periodontal ligament cells from periodontitis affected teeth (p-PDLCs) demonstrated impaired immunomodulatory activity, apoptosis, and lower regeneration potential (Tang et al., 2016, Liu et al., 2012, Lin et al., 2023). Inflammation-induced suppression of osteogenesis, proliferation, and immune regulation in PDLCs is a major cause of defective periodontium regeneration, which remains an ongoing challenge in the management of periodontitis (Liu et al., 2021, Yuan et al., 2023).

Small extracellular vesicles (sEV) are enriched exosomes that can exert biological effects on cells via transferring biological molecules such as proteins, DNA, and miRNAs, thus, repairing damaged tissues and cells (Kalluri &LeBleu, 2020). Studies have indicated that exosomes can promote periodontal tissue regeneration by facilitating the conversion of macrophages from a pro-inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2) and recovering the osteogenic differentiation capacity of p-PDLCs (Shen et al., 2020, Lei et al., 2022, Lin et al., 2022). The immunomodulatory effects on tissue repair of exosomes were improved by inflammatory cytokines, such as interleukin and lipopolysaccharide (LPS) (Song et al., 2017, Kurte et al., 2020).

Furthermore, the paracrine activity and immunomodulatory impact of dental follicle cells (DFCs) were boosted by LPS, one of the most frequent virulence factors of the essential periodontal pathogen Porphyromonas gingivalis (P. gingivalis) (Shi et al., 2020). Recent studies showed that compared to DFCs-derived small extracellular vesicles, small extracellular vesicles derived from lipopolysaccharide-preconditioned dental follicle cells (L-D-sEV) have promoted stronger osteogenic differentiation of p-PDLCs and periodontal tissue regeneration in rats and dog periodontitis models (Shi et al., 2020, Huang et al., 2022). However, the effects and mechanism of L-D-sEV on inflammatory periodontal ligament and p-PDLCs biology remain unclear. In this study, we established an experiment periodontitis model in mice and obtained inflamed PDLCs from periodontitis patients to evaluate the effects of L-D-sEV on alveolar bone loss and the biology of p-PDLCs and its underlying mechanism in vivo and in vitro.