Injectable cellular vesicle-based bone meal for inflammatory bone defect repair through restoring immune homeostasis

Rationale: Immune homeostasis microenvironment of bone regeneration is especially important for inflammatory-derived bone defect repair. The two key influencing factors for achieving ideal bone regeneration are the balance between inflammatory cells represented by T cells and anti-inflammatory cells represented by MDSCs, and the dynamic balance between osteoblasts and osteoclasts. Methods: Herein, an injectable thermosensitive bone meal was designed with Pluronic F127 hydrogel loading myeloid-derived suppressive cells (MDSCs) membrane vesicles coated nano-hydroxyapatite (F127/nHA/MDSCs-MV, abbreviated as F127/nHAM) for periodontitis-derived bone defect repair. Results: The proteomics revealed F127/nHAM were able to catalyze the production of adenosine from ATP depend on CD73 and CD39. In vitro and in vivo assays further showed that F127/nHAM inhibited the proliferation and function of T cells by component MDSCs-MV, exerting an anti-inflammatory role. Subsequently, the RNA-sequencing and confirmation experiments revealed that F127/nHAM inhibiting the differentiation of macrophages into osteoclasts through down-regulating the secretion of CCL2 and CCL5. In the periodontal bone defect rat model, the results of micro-CT and histological staining demonstrated that F127/nHAM had an outstanding anti-inflammatory and bone regeneration promoting properties, restoring immune homeostasis. Conclusion: This biomimetic and multifunctional bone meal opens new avenues for inflammatory-derived bone defect repair and future clinical application.