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

Abstract

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.

A whole-course-repair system based on ROS/glucose stimuli-responsive EGCG release and tunable mechanical property for efficient treatment of chronic periodontitis in diabetic rats

“…7(a)). 70,71 All the ligatures were removed after 3 weeks of placement, and different hydrogel treatments were injected locally around the maxillary second molar in the rats with CPDM. All the rats were grouped according to treatments assigned at randomization, which were finally separated into four groups, including the diabetes mellitus without chronic periodontitis (DM + NP) group, diabetes mellitus with chronic periodontitis without treatment (DM + P) group, DM + P treated with OPC hydrogel (DM + P-OPC) group and DM + P treated with OPCE hydrogel (DM + P-OPCE) group, respectively.…”

“…To induce experimental periodontitis, 70,71 SD rats were anesthetized by an intraperitoneal injection of 1% sodium pentobarbital. A 5-0 silk ligature and steel ligature were tied around the maxillary second molar on both sides.…”

Hydrogel-exosome system in tissue engineering: A promising therapeutic strategy

“…In another study focusing on endometrial injury, Lin et al designed a dynamic PEG hydrogel produced by Ag–S coordination, which dynamically coordinates and merges with ADSC-exos, simulating the endometrial microenvironment to promote neovascularization and tissue regeneration [ 313 ]. There have been few reports on the hydrogel-exosome system in the treatment of myocardial infarction, enteritis, and periodontitis [ [314] , [315] , [316] ]. Therefore, we encourage further exploration of tissues that are currently less researched to fill existing knowledge gaps.…”

Macrophage-Derived Exosomes as Advanced Therapeutics for Inflammation: Current Progress and Future Perspectives

“…Recent research has demonstrated the involvement of M-Exos in the pathological and physiological processes of inflammation and related diseases and have been studied as a potential diagnostic and prognostic markers of Notes: This schematic demonstrates that exosomes can serve as biomarkers (eg miR-155, 67 miR-17, 68 IL-1β, 69 TNF-α 70 ), nucleic acid and protein delivery vehicles (eg BDNF, 71 PPAR-γ, 72 miR-24-3p, 73 miR-370 74 ), drug delivery vehicles (eg berberine, 75 curcumin, 76 melatonin, 77 silibinin 78 ) and the combined strategy of exosome biomaterials (eg The M2 Exo/pDNA/BSP co-delivery system, 79 engineering of BP-loaded HNV 80 inflammation and associated diseases. 65 M-Exos cargoes from different pathological conditions (bacterial infection, viral infection and disease states) may show distinct genomic and proteomic profiles for distinguishing and identifying the diagnosis and development status assessment of different inflammatory stages and different inflammatory diseases, so as to serve as a reference for exploring the pathogenesis of inflammation and related diseases.…”