Erythropoietin‐Stimulated Macrophage‐Derived Extracellular Vesicles in Chitosan Hydrogel Rescue BMSCs Fate by Targeting EGFR to Alleviate Inflammatory Bone Loss in Periodontitis

Abstract Loss of periodontal tissue due to persistent inflammation in periodontitis is a major cause of tooth loss in adults. Overcoming osteogenic inhibition in the inflammatory periodontal environment and restoring the regenerative capacity of endogenous bone marrow mesenchymal stem cells (BMSCs) remain critical challenges in current treatment approaches. Macrophage‐derived extracellular vesicles (EVs) are key regulators of osteogenesis in recipient cells, yet the role of erythropoietin (EPO) in modifying macrophages and the function of their EVs in bone regeneration remain unclear. In this study, EVs from EPO‐stimulated macrophages (EPO‐EVs) are isolated, and they are encapsulated in a chitosan/β‐sodium glycerophosphate/gelatin (CS/β‐GP/gelatin) hydrogel to create a controlled‐release EVs delivery system for localized periodontal environment. EPO‐EVs restore the osteogenic function of mouse BMSCs (mBMSCs) and mitigate inflammatory bone loss in a periodontitis mouse model. Mechanistically, miR‐5107‐5p, significantly enriched in EPO‐EVs, is delivered to mBMSCs, where it suppresses epidermal growth factor receptor (EGFR) expression and alleviates EGFR's inhibitory effect on RhoA. This process counteracts osteogenic inhibition in inflammatory settings through the EGFR/RhoA axis. Overall, EVs from EPO pretreated macrophages restore the osteogenic capacity of mBMSCs under inflammation by inhibiting EGFR expression, providing new insight into therapeutic mechanisms and offering a promising approach for future periodontitis treatment.