Inflammatory bone loss represents a major clinical challenge, leading to irreversible tissue damage and impaired function. Probiotic-derived nanovesicles show immense potential as novel cell-free nanomedicines; however, the lack of clarity regarding their precise mechanism of action in bone tissue regeneration restricts their clinical application. This study utilized a ligature-induced periodontitis mouse model (in vivo) and in vitro models, including macrophage functional assays and macrophage-osteoblast co-culture systems, to investigate the therapeutic effects and mechanism of Lactobacillus rhamnosus GG-derived extracellular vesicles (LEVs). In the periodontitis mouse model, LEVs effectively mitigated inflammatory infiltration and promoted alveolar bone regeneration. In vitro studies demonstrated that LEVs enhance macrophage polarization toward a reparative (M2) phenotype. Mechanistically, we identify LEVs as bioactive nanocarriers that deliver tryptophan metabolites. Upon internalization by macrophages, these metabolites trigger a critical metabolic and phenotypic shift by activating the aryl hydrocarbon receptor (AhR). Further research revealed that this effect is mediated by the AhR/NAD(P)H:quinone oxidoreductase 1 (NQO1)/carnitine palmitoyltransferase 1A (CPT1A) signaling axis: AhR transcriptionally up-regulates NQO1, which critically inhibits the 26S proteasome-mediated degradation of CPT1A. The resulting sustained CPT1A expression dramatically boosts fatty acid oxidation, which is essential for driving the reparative macrophage phenotype. These findings highlight the critical role and molecular delivery mechanisms of probiotic-derived nanovesicles in ameliorating inflammatory bone loss via immunometabolic reprogramming, thereby providing new targets and a theoretical basis for their application as nanocarriers in regenerative biomaterials.
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