Melatonin Engineering M2 Macrophage‐Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy

Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play a crucial role in inflammatory response. An appropriate and timely transition from proinflammatory (M1) to anti‐inflammatory (M2) macrophages is indispensable for treating periodontitis. As M2 macrophage‐derived exosomes (M2‐exos) can actively target inflammatory sites and modulate immune microenvironments, M2‐exos can effectively treat periodontitis. Excessive endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) are highly destructive pathological characteristics during inflammatory periodontal bone loss. Although melatonin has antioxidant and anti‐inflammatory effects, studies focusing on melatonin ER stress modulation remain limited. This study fabricates engineered M2‐exos loading with melatonin (Mel@M2‐exos) for treating periodontitis. As a result, M2‐exos drive an appropriate and timely macrophage reprogramming from M1 to M2 type, which resolves chronic inflammation and accelerated periodontal healing. Melatonin released from Mel@M2‐exos rescues the osteogenic and cementogenic differentiation capacity in inflammatory human periodontal ligament cells (hPDLCs) by reducing excessive ER stress and UPR. Injectable gelatin methacryloyl (GelMA) hydrogels with sustained‐release Mel@M2‐exos accelerate periodontal bone regeneration in rats with ligation‐induced periodontitis. Taken together, melatonin engineering M2 macrophage‐derived exosomes are promising candidates for inflammatory periodontal tissue regeneration.