OBJECTIVES:This study aimed to develop and evaluate a targeted nanotherapeutic system to degrade the nonenzymatic form of JMJD3 and thereby restore immune balance and tissue repair in diabetic periodontitis. METHODS:A pH/reactive oxygen species (ROS)-responsive nanoplatform (P-PLGA@MM) was engineered using diselenium-bonded poly(lactic-co-glycolic acid) (PLGA) loaded with a JMJD3-targeting proteolysis-targeting chimera (PROTAC) and camouflaged with macrophage membranes. In vitro and in vivo models of diabetic periodontitis were used to assess cellular uptake, JMJD3 degradation, anti-inflammatory efficacy, and tissue regeneration. RESULTS:P-PLGA@MM exhibited macrophage-specific uptake and lysosomal escape, enabling efficient intracellular release of PROTAC. This facilitated the selective degradation of JMJD3's nonenzymatic activity through the ubiquitin proteasome pathway. In vitro, the nanoplatform suppressed macrophage M1 polarization and reduced inflammatory cytokines. In vivo, local injection of P-PLGA@MM in diabetic mice promoted collagen regeneration, reduced alveolar bone loss, and improved healing without systemic toxicity. CONCLUSIONS:This study demonstrates that targeted nano-delivery of PROTAC for JMJD3 degradation effectively alleviates inflammation and promotes periodontal regeneration in diabetic periodontitis. The P-PLGA@MM system presents a promising strategy for localized epigenetic therapy in chronic inflammatory diseases.

To address the limited bioactivity of titanium implant surfaces, particularly under compromised bone-healing conditions, this study developed a biofunctionalization strategy by constructing an OST-MVs@P-Ti system, in which osteoblast-derived matrix vesicles (OST-MVs), with inherent mineralization capability, were stably immobilized on titanium via a polydopamine (PDA) coating. This design mimics the natural bone mineralization mechanism, utilizing OST-MVs not only as bioactive signal carriers but also as direct executors of hydroxyapatite formation. The resulting surface exhibited enhanced hydrophilicity and roughness, good biocompatibility, and significantly promoted the adhesion, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro, as evidenced by upregulated Alkaline Phosphatase (ALP) activity, mineral deposition, and osteogenic gene/protein expression. In a rat femoral model, the OST-MVs@P-Ti implant demonstrated enhanced osseointegration with increased bone volume and intimate bone-implant contact. This study provides a biomimetic "actively mineralizing" surface modification strategy for dental and orthopedic implants and offers a promising platform for improving osseointegration.

Although mRNA therapy has achieved favorable outcomes, it still faces limitations such as poor stability and short duration of protein expression. In this study, we utilized a covalently closed circular RNA encoding bone morphogenetic protein-2 (BMP2 circRNA), which exhibits exceptional nuclease resistance and an extended half-life, thereby enabling sustained and efficient BMP2 protein expression. The BMP2 circRNA was encapsulated into biomimetic nanovesicles (BNVs) derived from bone marrow mesenchymal stem cells (BMSCs) using co-extrusion technology. These BNVs were then anchored onto the surface of micro-arc oxidized titanium (Ti-MAO) implants via polydopamine (PDA) adhesion, constructing a novel local gene delivery system. In vitro experiments confirmed that this system is not only efficiently internalized by cells but also evades lysosomal degradation, facilitating the sustained release of BMP2 protein. This, in turn, significantly promoted osteogenic gene expression and accelerated mineral deposition. Furthermore, in vivo animal studies demonstrated that the functionalized implant markedly enhanced bone regeneration, increasing both bone volume fraction and bone-to-implant contact. This study successfully integrated the inherent stability of circRNA with a biomimetic delivery strategy, offering an effective approach for improving implant osseointegration.

Prosthodontics is rapidly entering the digital era, with computer-aided design and manufacturing (CAD/CAM) soon becoming the mainstream method for fixed restoration design. Recent advances in image recognition, data analytics, and decision systems are accelerating the use of artificial intelligence (AI), shifting workflows from simple automation to adaptive, learning-based design. Nevertheless, clear clinical guidance remains limited. This expert consensus sets out core principles, technology categories, and priority use cases for AI in fixed restorations, and proposes Standardized Operating Procedures that span from preoperative planning, digital impression processing, tooth preparation evaluation, to functional design and personalized esthetic design. It also defines quality control checkpoints and ethical safeguards that highlight the central role of the clinician in reviewing and validating AI outputs. Recommendations are provided for data governance, including security, privacy, and auditability. Finally, the document outlines near-term development needs such as interoperable data standards, transparent model reporting, and clinically oriented validation metrics. The goal is to support standardized, safe, and effective clinical adoption of AI in fixed dental restorations.

Porcine-derived amelogenins, essential for enamel development and clinically applied in periodontal bone regeneration, faces purification challenges for its specific isoforms, limiting the understanding of their distinct functions and clinical translation. In this study, we purified P148, the most abundant isoform in porcine amelogenins, constructed a chitosan/hyaluronic acid (CS/HA) layer-by-layer coating on polydopamine-modified titanium implants, and preliminarily investigated its osteogenic effects and underlying mechanisms using in vitro and in vivo models. In vitro, the P148-functionalized surfaces exhibited favorable biocompatibility and significantly promoted cell attachment, proliferation, osteogenic gene expression, and extracellular matrix (ECM) production compared to unmodified titanium. Moreover, this modification activated the MAPK-ERK1/2 pathway, a key signaling axis regulating BMSC differentiation. In vivo rat experiments further verified enhanced peri-implant new bone formation, underscoring the translational promise of the P148/CS/HA coating for improving osseointegration. Taken together, these findings suggest that this bioactive surface holds broad application potential for clinical bone regeneration.

Postoperative bone reconstruction after tumor resection remains challenging due to tumor recurrence and poor osteogenesis. Although photothermal scaffolds can ablate tumors (via high heat) and stimulate bone formation (via mild heat), balancing these effects is difficult-excessive heat damages tissue, while insufficient heat fails to eliminate tumors. Here, we develop an injectable Mn3O4-enhanced hydrogel (GM/OD/Mn3O4) to address this. Mn3O4 nanosheets, firstly synthesized via biomineralization, exhibit high photothermal efficiency and enzyme-mimetic activity (glucose oxidase/peroxidase-like). The hydrogel adapts to irregular defects and releases Mn3O4 in acidic tumor microenvironments. Through catalytic cascades, it depletes ATP and inhibits heat shock proteins, overcoming tumor thermoresistance and enabling effective ablation at mild temperatures (43 °C). Lower NIR power (40 °C) further enhances osteogenesis. In vivo, the hydrogel suppresses tumor recurrence while promoting bone regeneration, offering a dual-functional strategy for postoperative bone repair.

Digital technologies have become an integral part of complete denture restoration. With advancement in computer-aided design and computer-aided manufacturing (CAD/CAM), tools such as intraoral scanning, facial scanning, 3D printing, and numerical control machining are reshaping the workflow of complete denture restoration. Unlike conventional methods that rely heavily on clinical experience and manual techniques, digital technologies offer greater precision, predictability, and efficacy. They also streamline the process by reducing the number of patient visits and improving overall comfort. Despite these improvements, the clinical application of digital complete denture restoration still faces challenges that require further standardization. The major issues include appropriate case selection, establishing consistent digital workflows, and evaluating long-term outcomes. To address these challenges and provide clinical guidance for practitioners, this expert consensus outlines the principles, advantages, and limitations of digital complete denture technology. The aim of this review was to offer practical recommendations on indications, clinical procedures and precautions, evaluation metrics, and outcome assessment to support digital restoration of complete denture in clinical practice.

Diabetic wound healing is critically impaired by dysregulated macrophage polarization, compromised endothelial angiogenic function, and diminished fibroblast proliferation/migration under persistent hyperglycemia. Current therapies, predominantly focused on single-cell targeting, lack coordinated modulation across these key cellular components. We developed a novel triple-targeting core-shell nanoparticle (miR-RPC) leveraging the shared integrin αvβ3 receptor on macrophages, endothelial cells, and fibroblasts to address this limitation. miR-RPC features an RGD/phosphatidylserine (PS)-modified lipid shell encapsulating a chitosan/​​miR-146a-5p​​ core. This miRNA was selected as a model RNA because of its widely recognized beneficial role in three key cell types in wound healing. The RGD peptide enables specific αvβ3-mediated triple-targeting. The anionic lipid PS facilitates core-shell assembly via electrostatic interaction with the cationic chitosan/RNA core and mimics apoptotic signals to enhance macrophage phagocytosis and phenotypic transition. miR-RPC effectively reprogrammed macrophages towards the M2 phenotype, restored endothelial angiogenic capacity under high glucose, and stimulated fibroblast proliferation, migration, and collagen secretion. Incorporated into a gelatin methacrylate (GelMA)/oxidized hyaluronic acid (OHA) double cross-linked hydrogel (GelO), miR-RPC@GelO significantly accelerated diabetic wound healing in rat models, demonstrating reduced inflammation, increased vascular density, and enhanced collagen deposition. This innovative triple-targeting system achieves coordinated diabetic wound repair through synergistic “immunomodulation-angiogenesis-collagen deposition” mechanisms, offering a promising therapeutic approach. Furthermore, the successful preparation of miR-RPC expands the application of anionic lipids in RNA delivery systems and highlights its potential as a versatile gene delivery vector.

Rapid osseointegration of titanium implants remains challenging under pathological conditions. This study develops an engineered exosome-based mRNA delivery system for osteogenic regulation. Through co-transfection with BMP2 and Paip2 plasmids, Exosomes (Exo en ) loaded with untranslated  Bmp2  mRNA are generated, exhibiting an eight-fold increase over naive exosomes and a three-fold enhancement compared to BMP2-only exosomes. These vesicles are functionalized with a cholesterol-anchored E7 peptide for BMSC targeting and immobilized on a titanium implant via a mussel adhesive protein coating (Exo en -E7@TiM). The system enables targeted, sustained delivery of  Bmp2  mRNA to BMSCs. Once internalized, the mRNA utilizes an internal ribosome entry site (IRES) to initiate translation, effectively bypassing the original suppression and driving robust BMP2 protein expression. Exo en -E7@TiM significantly enhanced osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs) in vitro, upregulating key markers and accelerating mineralization. In rat tibiae, it substantially improved new bone formation and bone-implant contact vs controls. This integrated strategy combines exosome-mediated nucleic acid delivery, biological targeting, and bioadhesive immobilization to significantly enhance osseointegration, showing considerable promise for clinical applications in compromised bone healing.

Toll-like receptors (TLRs) play important roles in immune responses against pathogens and tumors. Recently, TLR8 has gained attention because of its association with multiple inflammatory diseases, infections and antitumor responses. TLR8 senses the degradation products of single-stranded RNA from microbes and self-released RNA to induce type I interferons, inflammatory gene expression and nucleotide-binding and oligomerization domain-, leucine-rich repeat- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. So far, the understanding of TLR8 function in vivo is still limited, partially because of lacking a reliable rodent animal model. Murine Tlr8 cannot sense the ligands of human TLR8. In mammals, TLR8 distinguishes live bacteria from dead bacteria to regulate the magnitude of immune responses. Recently, TLR8 has been reported to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA to induce inflammatory responses, suggesting that TLR8 participates in coronavirus disease 2019 (COVID-19). In this review, we discuss the mechanism of ligand recognition by TLR8, TLR8-mediated signaling pathways and signaling crosstalk between TLR8 and other molecules, and untangle the contribution of TLR8 to inflammatory diseases, infectious diseases, antitumor immunity and vaccination.

Atherosclerosis is characterized by inflammation in the arterial wall, which is known to be exacerbated by diabetes. Therapeutic repression of inflammation is a promising strategy for treating atherosclerosis. In this study, we showed that diabetes aggravated atherosclerosis in apolipoproteinE knockout (ApoE(-/-)) mice, in which increased expression of long-chain acyl-CoA synthetase 1 (Acsl1) in macrophages played an important role. Knockdown of Acsll in macrophages (M phi(shAcsl1)) reprogrammed macrophages to an anti-inflammatory phenotype, especially under hyperglycemic conditions. Injection of M phi(shAcsl1) reprogrammed macrophages into streptozotocin (STZ)-induced diabetic ApoE(-/-) mice (ApoE(-/-) + STZ) alleviated inflammation locally in the plaque, liver and spleen. Consistent with the reduction in inflammation, plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages. Taken together, our findings indicate that increased Acsl1 expression in macrophages play a key role in aggravated atherosclerosis of diabetic mice, possibly by promoting inflammation. Adoptive transfer of Acsl1 silenced macrophages may serve as a potential therapeutic strategy for atherosclerosis.

Objectives: Poor oral health status may increase the risk of cardiovascular disease. However, whether a specific association exists between tooth loss and hypertension is inconclusive. Accordingly, a quantitative systematic review was conducted to investigate the relationship between tooth loss and hypertension. Methods: Systematic search, data analysis and quality assessment were conducted on relevant literature published in PubMed, Embase, Web of Science and Cochrane Libraries until October 2021. Odds ratio (OR) with 95% confidence interval (CI) was used as effect size to evaluate the association between tooth loss and hypertension. Meta-regression and subgroup analyses were performed to identify whether difference was associated with studylevel factors. Results: Of the 56 studies selected, 28 studies in 16 different countries involving 1,224,821 individuals were eligible for the systematic review. After adjustment for confounding factors, individuals with tooth loss had a higher risk for hypertension (OR 1.20; 95%CI 1.10-1.30, I2 = 40.02%). With respect to the risk of hypertension on tooth loss, individuals with hypertension still had a higher risk for tooth loss (OR 1.35; 95%CI 1.07-1.62, I2 = 51.10%). Age limitation of the included population is the major source of heterogeneity. However, studies in which the population was limited to the elderly did not report an increase in association between tooth loss and hypertension compared with studies without age limitation. Conclusions: The results suggest a bidirectional association between tooth loss and hypertension. Future longitudinal prospective studies are required to establish causality between tooth loss and hypertension. Clinical significance: Subjects with severe tooth loss should be carefully monitored for the manifestation of hypertension. The oral health status of hypertensive patients should also be meticulous maintained to prevent unwarranted tooth loss.

Extracellular vesicles (EV)-based delivery of therapeutic mRNAs is challenged by the low loading efficiency. In this study, we designed a DNA aptamer consisting of two parts: the single strand part recognized the AUG region of target mRNA, preventing mRNA from translation and ribosome assembly; and the double strand part containing the elements recognized by the CD9-ZF (zinc finger) motifs, sorting DNA aptamer-mRNA complex into CD9-ZF engineered EVs. In vitro and in vivo studies revealed that the system could efficiently load functional mRNAs to the EVs. Furthermore, adipose specific delivery of loaded Pgc1α mRNA via the strategy could efficiently induce white adipocyte browning. Similarly, delivery of interleukin-10 (Il-10) mRNA via the strategy had potent anti-inflammatory effect in inflammatory bowel disease (IBD) mouse model. Together, our study has proposed an efficient strategy to load therapeutic mRNAs of interest into EVs, which could be used as a promising strategy for gene therapy.

Cancer is one of the leading causes of death and a major public health problem all over the world. Immunotherapy is becoming a revolutionary clinical management for various cancer types. Restoration of aberrant immune surveillance on cancers has achieved markable progress in the past years by either in vivo or ex vivo engineering of the immune cells. Here, we summarized the central roles of immune cells in tumor progression and regression, and the existing and emerging strategies for different immune cell-based immunotherapies. In addition, the current challenges and the potential solutions in translating the immunotherapies into the clinic are also discussed.

Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women. Under chronic inflammatory conditions caused by estrogen deficiency, activated T cells contribute to elevated levels of proinflammatory cytokines, impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells (BMMSCs), and disturbed regulatory T cell (Treg)/Th17 cell balance. However, therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed. Here, we produced T cell-depleting nanoparticles (TDNs) that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized (OVX) mice. TDNs consist of monocyte chemotactic protein-1 (MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand (FasL) as the corona. We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo. Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state, further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype. Mechanistically, we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles (ApoEVs), which promoted macrophage transformation towards the M2 phenotype. These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.

Although the effects of tricalcium silicate-based cements (TSCs) on osteogenesis have been extensively investigated, their immunomodulatory role on bone regeneration remains elusive. The present study investigated how TSCs modulate bone regeneration by inducing macrophage polarization. The ex vivo part of the study evaluated the effects of two TSCs on mouse bone marrow-derived macrophages (mBMDMs), and on the osteogenic potential of mouse bone marrow mesenchymal stromal cells (mBMMSCs) that had been co-cultured with TSC-exposed mBMDMs. The in vivo part of the study utilized a rat mandibular defect model to investigate the osteogenic effects of the TSCs on healing of bone defects. Immunofluorescence and immunohistochemistry were used to identify polarization of the macrophages adjacent to bone defects and their cytokine secretion in vivo . The TSCs induced mBMDMs to polarize into the M2 phenotype ex vivo . Osteogenic differentiation of mBMMSCs was enhanced when these cells were co-cultured with mBMDMs that had been exposed to either TSC at non-cytotoxic concentrations. In vivo observations of more profuse new bone formation, presence of defect-adjacent macrophages with M2 phenotype and expression of osteogenesis-related cytokines are indicative of the immunomodulatory role played by TSCs on bone regeneration. This is achieved via induction of macrophage polarization into the M2 phenotype. (c) 2021 Elsevier Ltd. All rights reserved.

Immune suppressive microenvironment in tumor emerges as the main obstacle for cancer immunotherapy. In this study, we identified that HIF1α was activated in the tumor associated macrophages and acted as an important factor for the immune suppressive microenvironment. Epigenetically silencing of Hif1α via histone H3 methylation in the promoter region was achieved by CRISPR/dCas9-EZH2 system, in which histone H3 methylase EZH2 was recruited to the promoter region specifically. The Hif1α silenced macrophage, namely HERM (Hif1α Epigenetically Repressed Macrophage) manifested as inheritable tumor suppressing phenotype. In the subcutaneous B16-F10 melanoma syngeneic model, intratumoral injection of HERMs reprogrammed the immune suppressive microenvironment to the active one, reducing tumor burden and prolonging overall survival. Additionally, HERMs therapy remarkably inhibited tumor angiogenesis. Together, our study has not only identified a promising cellular and molecular target for reverting immune suppressive microenvironment, but also provided a potent strategy for reprogramming tumor microenvironment via epigenetically reprogrammed macrophages.

Inflammatory response plays a critical role in myocardial infarction (MI) repair. The neutrophil apoptosis and subsequent macrophage ingestion can result in inflammation resolution and initiate regeneration, while the therapeutic strategy that simulates and enhances this natural process has not been established. Here, we constructed engineered neutrophil apoptotic bodies (eNABs) to simulate natural neutrophil apoptosis, which regulated inflammation response and enhanced MI repair. The eNABs were fabricated by combining natural neutrophil apoptotic body membrane which has excellent inflammation-tropism and immunoregulatory properties, and mesoporous silica nanoparticles loaded with hexyl 5-aminolevulinate hydrochloride (HAL). The eNABs actively targeted to macrophages and the encapsulated HAL simultaneously initiated the biosynthesis pathway of heme to produce anti-inflammatory bilirubin after intracellular release, thereby further enhancing the anti-inflammation effects. In in vivo studies, the eNABs efficiently modulated inflammation responses in the infarcted region to ameliorate cardiac function. This study demonstrates an effective biomimetic construction strategy to regulate macrophage functions for MI repair.

Sox9 is an intrinsic transcription factor related to the determination and maintenance of chondrogenic lineage of bone marrow mesenchymal stem cells (BMSCs). In recent research, we have proved that fragmented chondrocyte aggregates (cell bricks) could promote chondrogenesis of BMSCs in vivo. However, it is still unknown whether the ratio of BMSCs/chondrocyte bricks has a significant influence on 3-D cartilage regeneration and related molecular mechanism. To address this issue, the current study subcutaneously injected three groups of cell complex with different rabbit BMSCs/chondrocyte bricks’ ratios (1 : 2, 1 : 1, and 2 : 1) into nude mice. Gross morphology observation, histological and immunohistochemical assays, biochemical analysis, gene expression analysis, and western blot were used to compare the influence of different BMSCs/chondrocyte bricks’ ratios on the properties of tissue-engineered cartilage and explore the related molecular mechanism. The constructs of 1 : 1 BMSCs/chondrocyte bricks, (B1CB1) group resulted in persistent chondrogenesis with appropriate morphology and adequate central nutritional perfusion without ossification. The related mechanism is that increased expression of Sox9 in the B1C1 group promoted chondrogenesis and inhibited the osteogenesis of BMSCs through upregulating Col-II as well as downregulating RUNX2 and downstream of Col-X and Col-I by upregulating Nkx3.2. This study demonstrated that BMSCs/chondrocyte bricks 1:1 should be a suitable ratio and the Sox9-Nkx3.2-RUNX2 pathway was a related mechanism which played an important role in the niche for stable chondrogenesis of BMSCs constructed by chondrocyte bricks and PRP.