Mechanically reprogrammed PDLSC-derived small extracellular vesicles accelerate bone remodeling via a neutrophil-NETs-osteoclast axis

Osteoclast-mediated bone resorption constitutes the rate-limiting initiation step of physiological bone remodeling and governs the efficiency and timeline of broadly clinical therapies, while the safe, endogenous, and precisely targeted regulators of the process remain lacking. Orthodontic tooth movement (OTM) serves as a unique physiological model, in which periodontal ligament stem cells (PDLSCs) act as the central mechanosensory hub linking mechanical cues to innate immune responses and osteoclastogenesis. We report that mechanically reprogrammed small extracellular vesicles derived from compressive force-loaded PDLSCs (For-sEVs) accelerate bone remodeling by orchestrating a previously unrecognized neutrophil-NETs-osteoclast axis. Transcriptomic analysis showed that compressive force induced PDLSC transcriptional reprogramming toward neutrophil activation and enriched interleukin-6 (IL-6) in For-sEVs. Functionally, For-sEVs were efficiently taken up by neutrophils and significantly lowered the threshold for neutrophil extracellular trap (NET) formation, and NETs enhanced RANKL-induced osteoclast differentiation in a dose-dependent manner. In a mouse OTM model, local injection of For-sEVs increased osteoclast numbers on the compression side and accelerated tooth movement, effects that were reversed by DNase I-mediated NET degradation. This work delineates a mechanical force-PDLSC-sEV-neutrophil/NETs-osteoclast regulatory axis and presents a genetically and chemically unmodified mechanical programming strategy for endogenous sEV nanobiomaterials. Our findings not only deepen the mechanistic understanding of mechano-immune regulation in bone remodeling but also provide a safe, biocompatible, and translationally promising nanoplatform for accelerating orthodontic treatment and diverse skeletal regenerative therapies.