Splice quantitative trait loci (sQTL) serve as another critical link between genetic variations and human diseases, besides expression quantitative trait loci (eQTL). Their role in oral squamous cell carcinoma (OSCC) development remains unexplored. We collected surgically resected cancer and adjacent normal epithelial tissue samples from 67 OSCC cases, and extracted RNA for sequencing after quality control. A genome-wide sQTL analysis was performed using the RNA sequencing data from 67 normal oral epithelial tissue samples. We included peripheral blood DNA samples from 1044 patients with OSCC and 3199 healthy controls to conduct a genome-wide association study. Systematic screening of sQTLs associated with OSCC risk identified a sQTL variant—the rs737540-T allele—independent of eQTLs, significantly associated with an increased risk of OSCC (OR = 1.2, P = 6.84 × 10−4). The rs737540-T allele reduced skipping of EGFR alternative exon 4 by enhancing TAR DNA binding protein (TARDBP) binding to the RNA sequence, leading to increased expression of the longer isoform (EGFR-001) and reduced expression of the truncated isoform (EGFR-004). Compared with EGFR-004, EGFR-001 promoted OSCC cell proliferation by reducing ATP-binding cassette subfamily A member 1 (ABCA1) ubiquitination through lower EGFR phosphorylation. ABCA1 was demonstrated to increase the cholesterol content of the plasma membrane via cholesterol efflux, thus affecting membrane fluidity and vimentin-mediated epithelial–mesenchymal transition. An antisense oligonucleotide targeting rs737540 significantly inhibited OSCC proliferation and reversed membrane cholesterol-induced resistance. This study provides novel insights into how genetic variants regulating alternative splicing contribute to OSCC risk and identifies potential therapeutic targets.

The regeneration of aged bone is severely compromised by a deteriorating microenvironment characterized by excessive reactive oxygen species (ROS) and consequential endoplasmic reticulum stress (ERS). Herein, we report a biomimetic nanozyme engineered through synergistic p-d orbital hybridization and youthful membrane camouflage to precisely reverse this degenerative cascade. The designed Cu-Sn dual-atom core exhibits exceptional multi-enzymatic activity, scavenging superoxide anions with a 2.5-fold higher efficiency than Cu single-atom control. Mechanistic studies confirm that p-d hybridization redistributes electron density at the Sn site, lowering the energy barrier for ROS adsorption and conversion. This catalytic core is cloaked with a hybrid membrane derived from young mesenchymal stem and endothelial cells, which facilitates targeted delivery to senescent bone niches and provides intrinsic pro-regenerative signals. The composite nanozyme effectively mitigates intracellular oxidative stress and ERS in aged cells, rescuing their osteogenic and angiogenic potential. In an aged mouse model of jawbone defect, a single treatment regimen promoted robust bone regeneration, increasing the bone volume fraction (BV/TV) by 1.7-fold and significantly enhancing new bone mineralization. This work establishes a dual-principle design-orbital hybridization for catalytic amplification and youthful membrane for targeted rejuvenation-offering a versatile platform for treating a spectrum of senescence-associated diseases.

CD73, encoded by NT5E, is an ecto-5'-nucleotidase implicated in tumour progression, but its association with glycolysis-related metabolic features in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, we combined public transcriptomic analyses with in vitro and in vivo experiments to investigate the relationship between NT5E/CD73 and these features in HNSCC. NT5E expression was positively associated with glycolysis-related signatures, and a high glycolysis score was associated with poorer overall survival in an exploratory analysis. In CAL27 cells, NT5E knockdown reduced extracellular acidification rate and oxygen consumption rate and decreased the expression of glucose transporter 3 (GLUT3), lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2), indicating a broader reduction in metabolic activity. In a xenograft model, NT5E depletion suppressed tumour growth and reduced GLUT3, LDHA and PKM2 expression. ADORA2B was upregulated in HNSCC, and its silencing decreased glycolysis-related gene expression, whereas pharmacological activation of A2B partially restored glycolysis-related protein expression and migratory capacity after NT5E knockdown. These findings support an association between NT5E/CD73 and glycolysis-related metabolic features in HNSCC and suggest that A2B signalling may contribute, at least in part, to the associated metabolic and migratory changes.

Radiotherapy-induced osteoradionecrosis of the jaw (ORNJ) affects quality of life by causing severe pain, persistent infections, and stomatognathic dysfunction. Current ORNJ treatments are limited by several factors, including surgical trauma and notable individual differences. Oxidative stress, which is a critical driver of radiation-induced injury, promotes inflammation and disrupts the balance between bone formation and resorption. Here, we developed ceria-doped silicate nanozymes (CeSNs) to eliminate reactive oxygen species (ROS) by inducing a superoxide dismutase-like (SOD-like) and catalase-like (CAT-like) cascade. ROS-eliminating mitophagy contributed to the restoration of jawbone radiation injury. Dl-3-n-butylphthalide (NBP) encapsulated in CeSNs (NBP@CeSNs) demonstrated improved pH-responsive release for enhanced angiogenesis, while the silicon ions of silicate enhanced jawbone osteogenesis, thus providing the nanozymes with angiogenesis and osteogenesis capabilities. Our NBP@CeSNs nanozymes provided a promising pathway for ORNJ treatment.

INTRODUCTION:Restoration of dental rehabilitation is the ultimate goal of functional jaw reconstruction, which is called "occlusion-driven jaw reconstruction", whereas fibular mandibular reconstruction (FMR) in the Asian population fails to adequately provide adequate bone volume for subsequent dental implantation. This study proposed a preoperative occlusion-driven design of FMR and compared the peri-implant bone thickness in fibular-reconstructed mandibles with or without preoperative occlusion-driven design. METHODS:The patients underwent FMR and following dental implantation were reviewed, consisting of 10 cases with preoperative occlusion-driven design of free fibular flap (FFF) as the experimental group and the other 12 cases as the control group. A total of 82 endosseous implants were radiographically evaluated and the cross-sectional buccal, lingual, and bottom distances between implant and fibula were calculated. RESULTS:The lingual bone thickness at the crown third of the peri-implant in the premolar region and at the middle third of the peri-implant in the molar region was 2.36±0.36 and 4.90±0.43 mm in the experimental group, significantly greater than 1.57±0.15 and 3.73±0.32 mm in the control group, respectively (P=0.04, P=0.032). The bone thickness at the root of the peri-implant in the experimental group was significantly greater than that in the control group (P=0.007). Specifically, the anterior and premolar regions in the experimental group were 4.31±0.24 and 4.29±0.30 mm, significantly greater than 3.21±0.40 and 4.16±0.30 mm in the control group, respectively (P=0.019 and P=0.009). No significant difference was found in the buccal bone thickness at the crown, middle, and root third of the peri-implant between the experimental and control groups. CONCLUSIONS:On the basis of the results of limited cases, this study demonstrated preoperative occlusion-driven design of the intended fibula segment for implant placement could provide adequate bone volume for endosseous implants, contributing to maximize successful osseointegration and minimize complications for FMR patients.

BACKGROUND Mesenchymal stem cells (MSCs) and their secretome offer a promising approach for treating osteoradionecrosis of the jaw (ORNJ); however, their efficacy remains controversial and the underlying molecular mechanisms require elucidation. AIM To investigate the role of small extracellular vesicles derived from human amniotic MSCs (hAMSCs-sEVs) in ORNJ. METHODS A Sprague-Dawley rat model of ORNJ received local hAMSCs-sEVs after mandibular molar extraction and the socket healing was assessed via micro computed tomography, hematoxylin and eosin, Masson trichrome, and immunohistochemical staining. In vitro, bone marrow MSCs (BMSCs) and human umbilical vein endothelial cells (HUVECs) were irradiated (12 Gy). The effects of hAMSCs-sEVs on osteogenic differentiation and angiogenesis were evaluated using alkaline phosphatase (ALP), Alizarin Red S, tube formation, and migration assays. Gene and protein expression were analysed by quantitative real time polymerase chain reaction and western blot. RNA sequencing identified the involved signaling pathways, which were validated with specific inhibitors. RESULTS In vivo, hAMSCs-sEVs enhanced socket healing in ORNJ rats, with micro computed tomography showing increased bone volume (bone volume/total volume). Histology revealed mature bone formation and higher expression of collagen-1, ALP, CD31, and vascular endothelial growth factor in the hAMSCs-sEVs group vs controls. In vitro, 12 Gy irradiation significantly inhibited osteogenic differentiation in BMSCs and angiogenesis in HUVECs. hAMSCs-sEVs were internalized by irradiated cells and reversed these inhibitions in a concentration-dependent manner. A concentration of 1010 particles/mL significantly upregulated osteogenic markers (collagen-1, ALP, runt-related transcription factor 2, osteopontin) in BMSCs and angiogenic markers (vascular endothelial growth factor, CD31) in HUVECs. RNA sequencing revealed that hAMSCs-sEVs reactivated the phosphatidylinositol 3-kinase/protein kinase B pathway in BMSCs and the Wnt/beta-catenin pathway in HUVECs, which were inhibited by radiation. These effects were blocked by pathway inhibitors Ly294002 and MSAB, respectively. CONCLUSION hAMSCs-sEVs promote the repair of ORNJ by partially reversing radiation-induced inhibition of osteogenesis and angiogenesis, potentially through reactivation of the phosphatidylinositol 3-kinase/protein kinase B and Wnt/beta-catenin signaling pathways.

INTRODUCTION:The association between breastfeeding status and early childhood caries (ECC) remains inconclusive. Few studies evaluate the breastfeeding status including both duration and exclusivity according to the WHO recommendations on breastfeeding. This study aimed to investigate the association between breastfeeding status and ECC. METHODS:This prospective cohort study comprised 3,666 children whose breastfeeding status was precisely evaluated. Poisson regression models and multivariable linear regression models were employed to analyze the associations of breastfeeding status with risk of ECC, and mean decayed, missing, and filled primary tooth surfaces (dmfs) in 3-year-old children, respectively. The data were collected from 2014 to 2020, and the analysis was conducted in 2023. RESULTS:The prevalences of ECC in offspring breastfed for <6 months, 6-11 months, 12-24 months, and >24 months were 9%, 12%, 17%, and 23%, respectively. Offspring breastfed for 12-24 months and over 24 months had a 1.82 times (95% CI, 1.40-2.37; p < 0.001) and 2.48 times (95% CI, 1.63-3.75; p < 0.001) higher risk of ECC, compared to those breastfed for less than 6 months. Offspring breastfed for 12-24 months showed a mean dmfs increase of 0.32 (95% CI, 0.21-0.44; p < 0.001), while those breastfed for over 24 months had a mean dmfs increase of 0.51 (95% CI, 0.27-0.74; p < 0.001), compared to those breastfed for less than 6 months. Among offspring breastfed for over 24 months, those exclusively breastfed for at least 6 months had significantly lower mean dmfs compared to those exclusively breastfed for less than 6 months (p for heterogeneity = 0.003). A significant interaction was observed between breastfeeding duration and exclusive breastfeeding duration on the association with mean dmfs (p for interaction <0.001). CONCLUSION:Our findings suggest that breastfeeding for over 12 months was associated with increased risk of ECC. Preventive interventions for dental caries should be implemented as early as possible, as breastfeeding is beneficial to children's health. The associations between breastfeeding duration and exclusivity with ECC should be investigated more thoroughly, particularly with adjustments for accurately measured sugar consumption.

Temporomandibular joint osteoarthritis (TMJOA), sometimes combined with type 2 diabetes (T2DM-TMJOA), has a restricting effect on quality of life and currently has few efficacious treatment options. As such, this project sought to determine the role of p16INK4a (p16) in T2DM-TMJOA development. In vivo, p16 knockout (P16KO) mice experienced less condylar bone loss and altered macrophage polarities from the inflammatory M1 to anti-inflammatory M2. In vitro, p16 knockdown (P16KD) or MS37452 treatment of THP-1 cells under high glucose and high palmitoleic acid conditions inhibited inflammatory angiogenesis and lymphangiogenesis, and supported osteogenic differentiation, respectively. Mechanistically, P16KD modelling restored mitochondrial functionality, limited intracellular iron accumulation, and polarized M2 macrophages through glutathione (GSH). Collectively, these data identify p16 as a critical regulator of T2DM-TMJOA and provide evidence for a future treatment strategy by therapeutic inhibition of p16.

Oral diseases include periodontal and oral tumors. Current treatment methods rely largely on surgical interventions and mechanical cleaning, with a lack of targeted pharmacological therapies. Regardless, natural active compounds have now become a new focus of research for the treatment of oral diseases owing to their low toxicity, favorable biocompatibility, and multi-target effects. This review summarizes the research progress regarding the role and application potential of natural active compounds, such as berberine and curcumin, in the prevention and treatment of oral diseases.

Delayed tooth extraction socket (TES) healing can cause failure of subsequent oral implantation and increase socioeconomic burden on patients. Excessive amounts of M1 macrophages, apoptotic neutrophils (ANs), and neutrophil extracellular traps (NETs) impair alveolar bone regeneration during TES healing. In the present study, we first discovered that conditioned medium (CM) collected from berberine-treated human bone marrow mesenchymal stem cells (BBR-HB-CM) accelerated TES healing. BBR-HB-CM contained bioactive materials that promoted the polarization of macrophages from M1 to M2, impeded the formation of ANs and NETs, and modulated M2 macrophage efferocytosis in vivo and in vitro. Mechanistically, BBR-HB-CM promoted bone formation by inhibiting macrophage-myofibroblast transition and reprogrammed macrophage polarization through p85/AKT/mTOR pathway-dependent autophagy. The 3-methyladenine abolished the therapeutic effects of BBR-HB-CM. Further studies revealed that BBR-HB-CM accelerated TES healing in rats with type 2 diabetes mellitus. Overall, our results demonstrated that BBR-HB-CM had high potential to promote rapid TES healing.

Diabetic periodontitis (T2DM-CP, type 2 diabetes mellitus-associated chronic periodontitis) is exacerbated by iron overload and macrophage imbalance, but therapeutic strategies remain limited. We analyzed macrophage polarization and iron metabolism markers in T2DM-CP patients and high glucose-treated macrophages, then evaluated deferoxamine (DFO) and chitosan hydrogel containing black phosphorus (BP) nanosheets and Dl-3-n-butylphthalide (NBP) (CH-BPNs-NBP) as targeted therapies. Clinical T2DM-CP samples and high glucose-stimulated macrophages showed increased M1 markers (iNOS) with decreased M2 markers (ARG-1), along with iron dysregulation (elevated TfR1, reduced FPN1 and GPX4). High glucose conditions induced ferroptosis, evidenced by mitochondrial damage and lipid peroxidation. While DFO treatment partially restored macrophage balance and iron homeostasis, CH-BPNs-NBP demonstrated more comprehensive therapeutic effects by effectively scavenging reactive oxygen species, promoting macrophage polarization toward the M2 phenotype, normalizing iron metabolism markers, and reducing alveolar bone loss as measured by CEJ-ABC distance. These findings establish iron overload and macrophage polarization as key pathological mechanisms in T2DM-CP and identify CH-BPNs-NBP as a promising multifunctional therapy capable of simultaneously addressing oxidative stress, iron dysregulation, and inflammatory imbalance in diabetic periodontitis. The superior efficacy of CH-BPNs-NBP suggests strong potential for clinical translation in managing this diabetic complication.

HMGA1 plays an important role in a variety of biological processes. However, it is still unclear what role HMGA1 plays in HNSCC. By integrating multi-omics data from public and private cohorts, we conducted a comprehensive analysis. The results showed that HMGA1 expression was significantly higher in HNSCC tumor tissue, correlated with poor prognosis. Increased HMGA1 expression indicated distinct somatic mutations and heavier tumor mutation burden, meanwhile, had significant interaction with several immune checkpoints. Single-cell analysis suggested that HMGA1 was highly enriched in malignant cells. In-vitro and in-vivo experiments also suggested that HMGA1 promoted the proliferation, migration and activation of HNSCC cells. Upstream analysis showed that cg25207224HMGA1 tested by oral rinse specimen maybe a non-invasive in-vitro predictive marker for prognostic prediction of HNSCC. Our study revealed the impact of HMGA1 on tumorigenesis, prognosis and immune microenvironment in HNSCC from a multi-omics perspective and provided a therapeutic target for HNSCC patients.

Delayed tooth extraction socket (TES) healing is a significant complication in patients with poorly controlled type 2 diabetes mellitus (T2DM). Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has been implicated in various T2DM-induced pathologies; however, its role in TES healing remains unclear. This study aimed to investigate the mechanisms of ferroptosis induced by a high-glucose environment in T2DM, focusing on its effects on human bone marrow mesenchymal stem cells (HBMSCs), iron content, and ferritinophagy. Additionally, we evaluate the therapeutic potential of a chitosan (CS) hydrogel delivery system loaded with Dl-3-n-butylphthalide (NBP) and black phosphorus (BP) nanoparticles (NBP@BP@CS) in promoting TES healing under diabetic conditions. Our findings demonstrate that ferroptosis is activated in the alveolar bone of T2DM rats, contributing to delayed TES healing. In vitro, high glucose and palmitic acid impaired osteogenesis and induced ferroptosis in HBMSCs. Both in vivo and in vitro experiments revealed that nuclear receptor coactivator 4 knockdown and treatment with iron chelators (deferoxamine and 3-methyladenine) alleviated ferroptosis and osteogenic impairment, highlighting ferritinophagy (autophagic degradation of ferritin) as a key driver of T2DM-induced ferroptosis. Furthermore, the NBP@BP@CS hydrogel demonstrated potent reactive oxygen species scavenging properties, significantly accelerating TES healing in T2DM. These findings showed ferritinophagy-dependent ferroptosis as a novel mechanism underlying delayed TES healing in T2DM and proposed NBP@BP@CS as a promising therapeutic strategy for diabetes-associated complications.

Background Deregulated Hippo signaling has been uncovered to be intricately involved in tumorigenesis. Transcriptional factor TEADs serve as key mediators of Hippo signaling and have been increasingly appreciated as putative oncogenes driving cancer initiation and progression. However, its expression pattern and oncogenic role of TEAD4 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Methods TEAD4 mRNA expression in HNSCC was determined by data mining and analyses from TCGA dataset and four independent cohorts with transcriptional profiling data publically available. The protein abundance of TEAD4 was measured by immunohistochemistry in 105 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The oncogenic roles of TEAD4 was further determined by 4-nitroquinoline 1-oxide (4NQO)-induced animal model, both knockdown/overexpression assay and TGF-β1-induced epithelia-mesenchymal transition (EMT) in vitro. Results Both mRNA and protein abundance of TEAD4 were significantly increased in HNSCC as compared to its non-tumor counterparts. Overexpression of TEAD4 significantly associated with high pathological grade, cervical node metastasis, advanced clinical stage and reduced overall and disease-free survival. In the 4NQO-induced HNSCC mouse model, increased TEAD4 immunostaining was found associated with disease progression. TEAD4 knockdown significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in HNSCC cells, while its overexpression resulted in opposite effects and EMT. Moreover, TEAD4 was critically involved in TGF-β1-induced EMT in HNSCC cells. Conclusions Our findings reveal that TEAD4 serves as a novel prognostic biomarker and putative oncogene for HNSCC by promoting cell proliferation, migration and invasion, and EMT.

BACKGROUND:Monoamine oxidase B (MAOB), a flavin monoamine oxidase, regulates biogenic and xenobiotic amine oxidative deaminization. We demonstrate MAOB expression in head and neck epithelium and its biological importance in head and neck squamous cell carcinoma (HNSCC) development. METHODS:First, we found a possible MAOB downregulation in HNSCC using bioinformatic analysis. Second, we validated MAOB expression changes in vitro and assessed its tumorigenicity in HNSCC. Finally, preclinical xenograft models further confirmed our findings. RESULTS:Results proved that MAOB was significantly reduced in HNSCC tissues and cell lines. By comparing MAOB localization in patient specimens, we found that epithelial basal cells express MAOB and that it changes throughout HNSCC development. We observed that MAOB overexpression inhibited HNSCC cell malignancy via lentiviral transfection. We additionally discovered that selegiline partly counter-regulated MAOB overexpression-induced phenotypes in HNSCC cells. CONCLUSIONS:We found that MAOB is a potent biomarker and a unique and essential indication of HNSCC carcinogenesis.

Periodontitis, a prevalent inflammatory condition in the oral cavity, is closely associated with oxidative stress-induced tissue damage mediated by excessive reactive oxygen species (ROS) production. The jaw vascular unit (JVU), encompassing both vascular and lymphatic vessels, plays a crucial role in maintaining tissue fluid homeostasis and contributes to the pathological process in inflammatory diseases of the jaw. This study presents a novel approach for treating periodontitis through the development of an injectable thermosensitive gel (CH-BPNs-NBP). The gel formulation incorporates black phosphorus nanosheets (BPNs), which are notable for their ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator that promotes lymphatic vessel function within the JVU. These results demonstrate that the designed thermosensitive gel serve as a controlled release system, delivering BPNs and NBP to the site of inflammation. CH-BPNs-NBP not only protects macrophages and human lymphatic endothelial cells from ROS attack but also promotes M2 polarization and lymphatic function. In in vivo studies, this work observes a significant reduction in inflammation and tissue damage, accompanied by a notable promotion of alveolar bone regeneration. This research introduces a promising therapeutic strategy for periodontitis, leveraging the unique properties of BPNs and NBP within an injectable thermosensitive gel.

Four to eight percent of patients with head and neck cancer will develop osteoradionecrosis of the jaw (ORNJ) after radiotherapy. Various radiation-induced tissue injuries are associated with reactive oxygen and nitrogen species (RONS) overproduction. Herein, Fe doping is used in VOx (Fe-VOx) nanozymes with multienzyme activities for ORNJ treatment via RONS scavenging. Fe doping can induce structure reconstruction of nanozymes with abundant defect production, including Fe substitution and oxygen vacancies (OVs), which markedly increased multiple enzyme-mimicking activity. Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzyme-like performance of Fe-VOx can effectively reprogram jawbone microenvironment to restore mitochondrial dysfunction and enhance mitophagy. Moreover, the surface plasmon resonance (SPR) effect of Fe-VOx made it a good photothermal nanoagents for inhibiting jaw infection. Thus, this work demonstrated that Fe-VOx nanozymes can efficiently scavenge RONS, activate mitophagy, and inhibit bacteria, which is potential for ORNJ treatment.

Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

The excess production of reactive oxygen species (ROS) will delay tooth extraction socket (TES) healing. In this study, we developed an injectable thermosensitive hydrogel (NBP@BP@CS) used to treat TES healing. The hydrogel formulation incorporated black phosphorus (BP) nanoflakes, recognized for their accelerated alveolar bone regeneration and ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator aimed at enhancing angiogenesis. In vivo investigations strongly demonstrated that NBP@BP@CS improved TES healing due to antioxidation and promotion of alveolar bone regeneration by BP nanoflakes. The sustained release of NBP from the hydrogel promoted neovascularization and vascular remodeling. Our results demonstrated that the designed thermosensitive hydrogel provided great opportunity not only for ROS elimination but also for the promotion of osteogenesis and angiogenesis, reflecting the "three birds with one stone" concept, and has tremendous potential for rapid TES healing.