Nanoengineering multifunctional extracellular vesicles availably mitigate bone loss in osteoporosis through binding to RANKL and rebalancing the Treg/Th17 cells

The balance between regulatory T cells (Treg) and T helper 17 cells (Th17) plays an important role in bone loss in osteoporosis. Hyperactivation of Th17 cells, where a large amount of cytokine RANKL is secreted, promotes the osteoclast phenotype. The restoration of immune homeostasis of Treg/Th17 cells could inhibit bone loss. However, the engineered strategy is still absent. Herein, we report an immunomodulatory bioactive glass nanoparticle-engineered bone marrow-derived macrophages (BMDMs) to generate extracellular vesicles (SrBGN + Mφ-EVs), which could regulate the Treg/Th17 balance and inhibit the bone loss in osteoporosis. SrBGN + Mφ-EVs contain both SrBGNs immunomodulatory active ions and anti-inflammatory factors of M2-type BMDMs and have good biocompatibility in vitro. SrBGN + Mφ-EVs regulated the Treg/Th17 balance by promoting Treg cell differentiation and inhibiting Th17 cell differentiation in vitro. More importantly, more RANK was enriched on the surface of SrBGN + Mφ-EVs with strong affinity to RANKL, which acted as a competitive inhibitor of RANKL-RANK interaction and inhibited the activation of osteoclasts. In vivo experiments, SrBGN + Mφ-EVs showed excellent biocompatibility and improved the immune environment of osteoporotic mice to inhibit bone loss. This study may provide new ideas for the regulatory strategy of bioactive glass and its engineered extracellular vesicles in re-establishing immune homeostasis in osteoporosis, as well as a solution for treating bone resorption disorders.