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Background Periodontitis is caused by the imbalance of anti‐bacteria immune response and excessive inflammation whereas macrophages play an important role in inflammation. Thus, it is critical for finding efficient anti‐inflammatory strategies to alleviate periodontal inflammation and prevent bone destruction. Apoptosis of mesenchymal stem cells (MSCs) exerts immune silencing effects, however, using these effects to develop anti‐inflammatory strategies remains unknown. In our study, we extracted apoptotic extracellular vesicles (ApoEVs) from bone marrow MSCs (BMMSCs) and found ApoEVs inhibited macrophages polarizing into proinflammatory condition via AMPK/SIRT1/NF‐κB pathway. Besides that, we also found ApoEVs inhibited adjacent osteoclast formation by suppressing the secretion of TNF‐α of proinflammatory macrophages. Methods BMMSCs derived ApoEVs were extracted by gradient centrifugation. Protein expression level and secreted cytokines of ApoEVs treated macrophages were examined by western blot and ELISA, respectively. Besides, the change of NF‐κB pathway and related molecules were examined by immunofluorescence and western blot. The osteoclast formation under the different conditioned mediums from macrophages was measured by TRAP staining, MMP‐9 expression, and pit assay. Results ApoEVs were extracted from staurosporine‐induced apoptotic BMMSCs and were in sphere shapes whose diameters are between 100 and 1000 nm. ApoEVs could be phagocyted by macrophages and in turn reduce the expression of COX2 in proinflammatory macrophages. Besides that, ApoEVs suppressed the secretions of TNF‐α and IL‐6 while elevating the secretion of IL‐10 in a dose‐dependent manner. Further studies revealed that ApoEVs inhibited macrophages polarizing into proinflammatory phenotypes via AMPK/SIRT1/NF‐κB pathway. In addition, ApoEVs inhibited osteoclasts differentiation and bone resorption measured by TRAP staining, MMP‐9 expression, and pit resorption area by downregulating the secretion of TNF‐α of proinflammatory macrophages. Conclusions The results suggest that ApoEVs inhibited macrophages to skew into proinflammatory phenotypes via AMPK/SIRT1/NF‐κB pathway and suppress adjacent osteoclasts formation by reducing the secretion of TNF‐α. Our findings shed a light on the treatment for periodontitis based on EVs therapy.

Inflammation plays a crucial role in triggering regeneration, while inadequate or chronic inflammation hinders the regenerative process, resulting in refractory wounds. Inspired by the ideal regeneration mode in lower vertebrates and the human oral mucosa, realigning dysregulated inflammation to a heightened and acute response provides a promising option for refractory wound therapy. Neutrophils play important roles in inflammation initiation and resolution. Here, a hybrid biomaterial is used to stimulate transiently heightened inflammatory responses by precise tempospatial regulation of neutrophil recruitment and apoptosis. The hybrid biomaterial (Gel@fMLP/SiO 2 -FasL) is constructed by loading of formyl-met-leu-phe (fMLP) and FasL-conjugated silica nanoparticles (SiO 2 -FasL) into a pH-responsive hydrogel matrix. This composition enables burst release of fMLP to rapidly recruit neutrophils for heightened inflammation initiation. After neutrophils act to produce acids, the pH-responsive hydrogel degrades to expose SiO 2 -FasL, which induces activated neutrophils apoptosis via FasL-Fas signaling triggering timely inflammation resolution. Apoptotic neutrophils are subsequently cleared by macrophages, and this efferocytosis activates key signalings to promote macrophage anti-inflammatory phenotypic transformation to drive regeneration. Ultimately, Gel@fMLP/SiO 2 -FasL successfully promotes tissue regeneration by manipulating inflammation in critical-sized calvarial bone defects and diabetic cutaneous wound models. This work provides a new strategy for refractory wound therapy via inducing transiently heightened inflammatory responses.

Immediate iron restriction by the host is a critical process to protect against bacterial infections.Although the cell-dependent iron sequestration mechanism in liver or spleen has been identified, it is still unclear that whether the host launched humoral regulation mechanism to promptly acquire iron that widely distributes throughout body fluids. Here, we showed that after bacterial invasion, host immediately releases nanosized exosomes to capture circulating iron-containing proteins, which is required for prompt systemic iron sequestration and antibacterial defense. Mechanistically, in a sepsis model, we found that Salmonella Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol requiring enzyme 1α (IRE1α) signaling, triggering lysosomal dysfunction and promoting exosome release. These exosomes bearing transferrin receptors, CD163 and CD91 bind multiple iron-containing proteins, prevent bacteria from iron acquisition, and recycle them to tissue-resident macrophages, ultimately sequestering iron and protecting against infection. Our findings reveal a previously unknown humoral regulation mechanism of iron metabolism during bacterial infection, and suggest the release and circulation of extracellular vesicles could be an important way to promptly regulate systemic ion metabolism.

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