Extracellular Vesicles from Compression‐Loaded Cementoblasts Promote the Tissue Repair Function of Macrophages

Abstract Treatment strategies for hard tissue defects aim to establish a mineralized microenvironment that facilitates tissue remodeling. As a mineralized tissue, cementum shares a similar structure with bone and exhibits an excellent capacity to resist resorption under compression. Macrophages are crucial for mineralized remodeling; however, their functional alterations in the microenvironment of cementum remain poorly understood. Therefore, this study explores the mechanisms by which cementum resists resorption under compression and the regulatory roles of cementoblasts in macrophage functions. As a result, extracellular vesicles from compression‐loaded cementoblasts (Comp‐EVs) promote macrophage M2 polarization and enhance the clearance of apoptotic cells (efferocytosis) by 2‐ to 3‐fold. Local injection of Comp‐EVs relieves cementum destruction in mouse root resorption model by activating the tissue repair function of macrophages. Moreover, Comp‐EV‐loaded hydrogels achieve significant bone healing in calvarial bone defect. Unexpectedly, under compression, EV secretion in cementoblasts is reduced by half. RNA‐Seq analysis and verification reveal that Rab35 expression decreases by 60% under compression, thereby hampering the release of EVs. Rab35 overexpression is proposed as a modification of cementoblasts to boost the yield of Comp‐EVs. Collectively, Comp‐EVs activate the repair function of macrophages, which will be a potential therapeutic strategy for hard tissue repair and regeneration.