Through single-cell transcriptional analysis of a calvarial defect model in diabetic rats, we observed that inflammatory progression in the diabetic group was arrested at the early stage compared to controls. Moreover, even after glycemic normalization via insulin treatment, inflammatory dysregulation in the diabetic osteogenic microenvironment failed to be completely reversed. This dysregulation mainly stems from impaired function of the pro-resolution Trem2+ macrophages (Mφ), a subpopulation that plays an important role in coordinating intercellular communication, yet whose function could not be fully restored by insulin. Intercellular communication analysis revealed that Trem2+ Mφ serve as a principal source of the GAS6-MerTK signaling axis. Enhanced efferocytosis mediated by this axis promotes inflammation resolution, thereby supporting the establishment of a microenvironment conducive to bone regeneration. Notably, GAS6 signaling from Trem2+ Mφ remained incompletely restored even after insulin treatment normalized blood glucose in diabetic rats. In vivo experiments demonstrated that combining systemic glycemic control with local GAS6 supplementation led to better diabetic bone healing outcomes compared to either strategy alone. Thus, our findings suggest that complementary immunomodulatory strategies targeting inflammation resolution, alongside glycemic control, are required to effectively restore diabetic bone healing.

Periosteum provides periosteal stem cells and a pro-regenerative microenvironment essential for intramembranous ossification, yet it is frequently damaged in maxillofacial bone defects, impairing healing. Herein, we developed a collagen hydrogel membrane with oriented fibrils and coordinated it with cerium and zinc (Ce/Zn/Col) to achieve structural and functional periosteum mimicry. The dual-ion coordination optimized the membrane's mechanical strength, swelling, and enzymatic stability to meet clinical needs, while endowing it with bioactive functions beyond structural support. Ce/Zn/Col promoted bone marrow mesenchymal stem cell (BMSC) adhesion and osteogenic differentiation. Importantly, during degradation, Ce/Zn/Col continuously released cerium and zinc to promote M2 macrophage polarization and endothelial tubulogenesis, mimicking native periosteal paracrine function to establish a pro-regenerative microenvironment. Transcriptional analysis revealed that the co-coordination activated osteogenic programs in BMSCs, particularly through Wnt signaling pathways, with a clear synergistic effect over single ion coordination. In a periosteum-deficient critical-sized cranial defect model, Ce/Zn/Col markedly enhanced vascularization, induced periosteum-like tissue regeneration, promoted osteoblast maturation, and accelerated intramembranous ossification, improving new bone quantity and quality. Collectively, Ce/Zn/Col represents a structurally and functionally biomimetic periosteal scaffold with promising therapeutic potential, especially in periosteum-deficient maxillofacial scenarios.

Nanotechnology has provided thousands of novel nano-antimicrobials possessing features uncommon in clinically available antimicrobials. Here, nanocarriers loaded with conventional antimicrobials and responding to environmental changes upon entry into oral biofilms are reviewed. Supra-gingival biofilms are characterized by acidic pH, the presence of bacterial enzymes, and the development of hypoxia in deeper layers. Sub-gingival biofilms are slightly alkaline, with hypoxia occurring over their entire depth. Upon entering biofilms, negatively charged, pH- and/or hypoxia-responsive nanocarriers become positively charged. This charge reversal leads to electrostatic double-layer attraction between positively charged nanocarriers towards negatively charged, water-filled channel walls in biofilms, enhancing their accumulation in a biofilm. Degradation of bacterial enzyme-responsive nanocarriers causes in-biofilm release of antimicrobial cargo, yielding higher local antimicrobial concentrations than can be achieved through their direct, oral administration without harming soft tissues. Enhanced antibiofilm activity after in-biofilm antimicrobial release from biofilm-responsive micelles and liposomes has been demonstrated in vitro towards single-species Streptococcus mutans and Staphylococcus aureus biofilms or in vivo using specific-pathogen-free rodents inoculated with selected pathogens. This preferential antibacterial activity regulated the microbial composition of ex vivo human oral biofilm towards a more healthy microbiome composition. Although clinical confirmation is limited, the potential benefits of stimuli-responsive, antimicrobial-loaded nanocarriers for oral biofilm control and microbiome restoration are worth further investigation towards clinical translation.

Background:Osteosarcoma (OS) is a malignant tumor originating from primitive mesenchymal cells, characterized by rapid metastasis, high invasiveness, and significant mortality. The primary challenges in OS management include the effective elimination of residual tumor cells to prevent recurrence and the repair of extensive bone defects caused by surgical intervention. Objective:This study aims to develop an innovative biomimetic 3D-printed bioactive glass ceramic (BGC) scaffold modified with two-dimensional nanosheets to address both tumor ablation and bone tissue repair. Materials and methods:The nanosheets were constructed via ellagic acid (EA) and ruthenium (Ru) coordination, leveraging the non-topological adhesion properties of catechol in EA to deposit the nanosheets onto the BGC scaffold (EARu-BGC). The therapeutic effects of EARu-BGC were evaluated in vitro and in vivo. Results:EARu-BGC sequentially responds to the local microenvironment during OS treatment. During the tumor ablation phase, EARu-BGC induced ferroptosis through the synergistic effects of photothermal and chemodynamic therapy, achieving over 90 % tumor cell ablation and significantly inhibiting tumor volume and weight. In the bone tissue repair phase, EARu-BGC exhibited adaptive ROS scavenging and facilitated a pro-healing microenvironment, promoting osteogenic differentiation. The gradual degradation of the BGC scaffold provided essential minerals and space for new bone formation. In vivo experiments demonstrated that EARu-BGC significantly enhanced osteogenesis, increasing the trabecular number to 1.51 ± 0.15/mm and reducing trabecular separation to 1.50 ± 0.04 mm. Conclusion:The EARu-BGC scaffold presents a promising multifunctional platform for OS treatment by effectively balancing antitumor efficacy with bone repair capabilities.

Implant-associated infections in diabetic patients pose critical challenges due to immune-metabolic dysregulation that exacerbates biofilm persistence and tissue damage. This study introduces a "dimensional rise" strategy integrating 3D-printed porous titanium frameworks with micro-nano hierarchical structures to establish a mechanically robust, high-capacity drug reservoir, surpassing the limitations of conventional 2D surface modifications. Copper-doped carbon quantum dots, synthesized from luteolin, synergize with polydopamine-mediated photothermal activation to disrupt bacterial copper homeostasis, inducing tricarboxylic acid cycle collapse and cuproptosis-like death via reactive oxygen species bursts and lipoylated protein aggregation. Concurrently, glucose oxidase depletes local glucose to activate adenosine 5'-monophosphate-activated protein kinase phosphorylation in host cells, restoring mitochondrial integrity and metabolic homeostasis through deacetylation. This dual-action system achieves differential regulation-targeting bacteria while protecting host tissues-and ensures therapeutic coverage across acute infection and chronic healing phases. Validated in three animal models, including Beagles with clinical-grade implants, the strategy demonstrates potent anti-biofilm efficacy, prevention of secondary infections, and accelerated diabetic osseogenesis. By upgrading surface engineering to 3D volumetric drug reservoirs, this work establishes a paradigm for differentiated multimodal therapy against implant-related infections in metabolically compromised hosts, addressing both immediate bactericidal demands and long-term tissue recovery.

Osteomyelitis exhibits bone defects in an inflammatory and acid microenvironment. As a crucial factor in this inflammation responses, the macrophage-osteoclast axis is absolutely the core to regulate. The research explored a shell-core structured biomaterial, consisting of a gelatin nanoparticle (GNP) platform loaded with bone morphogenetic protein 9 (BMP9) and coated with a metal phenolic network (TA-Ce), which exhibited adaptive sensitivity to pH values. Extracellularly, it rapidly responded to lower pH, achieving specific release in an inflammatory microenvironment. Intracellularly, it impacted the formation, function, and differentiation of osteoclasts through the macrophage-osteoclast axis, thereby promoting bone defect repair. In vivo and in vitro studies showed GNPs-BMP9@TA-Ce regulated osteoclasts to optimize osteomyelitis treatment strategies, highlighting the potential of modified nanobiomaterials for clinical application.

Objective As dental implanting becomes an increasing demand among patients with tooth loss, an efficient and effective training for students is to be necessary. In this case, we anticipate the possible application of virtual reality (VR) technology to pre-clinical implantation training (PCIT) in order to improve the students’ learning efficiency and effectiveness. Methods The study divided 20 subjects into two groups on average—VR based PCIT (experimental group) and traditional PCIT (control group) with the completion of the background survey (BS) before PCITs, to guarantee no apparent backgroud variation including learning of oral implantology and VR technology, learning habits, interests and hobbies, etc. All subjects received identical professional tests (T-1, T-2, T-3) before, in and after PCITs to assess the knowledge mastery condition and maintaining levels. Along with both PCITs, the subjective evaluation tests (SET) were distributed to collect the subjective feedback data so as to analyze the preference to each PCIT. Meanwhile the total interaction time, learning duration per subject were recorded for the performance analysis. Results The results show that from T-1 to T-2 period, the score of VR based PCIT increased significantly (p < 0.05). And the results of SET show that subjects in VR based PCIT generally obtain over one score higher than the ones in traditional PCIT as for the items of “Convenience”, “Interest”, “Comfort”, “Confidence” and “Subjective initiative” except “Precision”. During both PCITs, VR based PCIT shows a shorter learning duration and sufficient one-on-one interaction opportunities. Conclusion Compared with traditional PCIT, VR based PCIT has obvious influence on enhancing students’ knowledge mastery, study willingness and learning efficiency.

Photothermal therapy (PTT) demonstrates significant potential in cancer treatment, wound healing, and antibacterial therapy, with its efficacy largely depending on the performance of photothermal agents (PTAs). Metal-phenolic network (MPN) materials are ideal PTA candidates due to their low cost, good biocompatibility and excellent ligand-to-metal charge transfer properties. However, not all MPNs exhibit significant photothermal properties, and the vast chemical space of MPNs (over 700,000 potential combinations) complicates the screening of high-photothermal materials. To address this challenge, this study introduces machine learning (ML) methods for predicting the photothermal performance of MPNs. A database of photothermal properties of 80 modular MPNs was constructed, and the ML process was optimized through feature engineering and model training. The selected extreme gradient boosting model (XGBoost) successfully identified 1,654 high photothermal MPNs from a virtual database of 44,438. Subsequent experimental validation revealed a remarkable success rate of 70 % in predicting high photothermal MPNs. Additionally, several previously unreported high photothermal MPNs were discovered, demonstrating advantages in photothermal antibacterial applications. This study offers an innovative ML-driven approach for the efficient screening of MPN materials, providing a solid foundation for PTA design in PTT and other biomedical applications.

3D printing of ceramics or glass typically requires sacrificial organic plasticizers and high-temperature sintering, which is time- and cost-consuming, potentially cytotoxic, and may compromise the bioactivity and functionality of the inorganic components. We herein developed purely inorganic self-healing colloidal gels, consisting of electrostatically attractive silica-based hard nanospheres, to enable 3D printing of highly strong inorganic constructs via additive-free and low temperature sintering (LTS) processing. Through cross-scale analysis of the structural and mechanical features, we quantitatively described the constitutive relationship of attractive colloidal gels based on the integration of colloidal assembly theory with experimental characterizations. This mechanistic understanding further allowed us to develop considerably strong colloidal gels (maximal compressive modulus ∼2.3 MPa) without compromising the self-healing ability. We further demonstrated the excellent printability, shape-fidelity, and reprocessability of the inorganic gels, thereby facilitating additive-free inorganic 3D printing followed by LTS treatment at ∼700 °C. This "green" inorganic 3D-printing strategy enabled cost-efficient and bioactivity-preserved fabrication of bioglass-based bone substitutes, which led to improved in vivo osteogenesis and osteointegrity. In general, this work emphasizes the significance of rationale design and mechanistic understanding of self-healing colloidal gels with outstanding performances as printable inks and provides an avenue for customized fabrication of functional inorganic 3D structures toward applications in biomedical, machinery, energy, and chemical industries.

Bone traumatic injuries, enduring a prolonged healing process since it involves a series of bio events, becomes gradually challenging with increasing aging population. The integration of a home-based therapy strategy with emerging microelectronic technology holds promise for optimizing the whole long-term healing process of bone defect. Given the bioelectric properties of bone, utilizing biomedical electronics to providing external electric field (EF) is preferred for physical therapy strategies. Our study provides a wireless implantable bone-electronic interface (IBEI) based on ultrasonic-driven battery-free piezoelectric technology. The IBEI without percutaneous leads can effectively complete the process of converting ultrasonic signals into electric signals and finally into biological signals for bone repair. This system is miniatured, battery-free, wireless, controllable, biocomfortable and biosafe with high osteogenic efficiency. For the underlying mechanism, the EF can activate multicellular synergistic osteogenesis and up-regulate the Ca2+/CaMKII/CREB signal pathway in osteogenesis effector cells. The IBEI aligns with the future trajectory of home-based medicine, presenting a commendable therapy pattern for doctor-patient collaboration and offering a novel perspective in the realm of physical therapy.

Extrusible biomaterials have recently attracted increasing attention due to the desirable injectability and printability to allow minimally invasive administration and precise construction of tissue mimics. Specifically, self-healing colloidal gels are a novel class of candidate materials as injectables or printable inks considering their fascinating viscoelastic behavior and high degree of freedom on tailoring their compositional and mechanical properties. Herein, we developed a novel class of adaptable and osteogenic composite colloidal gels via electrostatic assembly of gelatin nanoparticles and nanoclay particles. These composite gels exhibited excellent injectability and printability, and remarkable mechanical properties reflected by the maximal elastic modulus reaching ∼150 kPa combined with high self-healing efficiency, outperforming most previously reported self-healing hydrogels. Moreover, the cytocompatibility and the osteogenic capacity of the colloidal gels were demonstrated by inductive culture of MC3T3 cells seeded on the three-dimensional (3D)-printed colloidal scaffolds. Besides, the biocompatibility and biodegradability of the colloidal gels was proved in vivo by subcutaneous implantation of the 3D-printed scaffolds. Furthermore, we investigated the therapeutic capacity of the colloidal gels, either in form of injectable gels or 3D-printed bone substitutes, using rat sinus bone augmentation model or critical-sized cranial defect model. The results confirmed that the composite gels were able to adapt to the local complexity including irregular or customized defect shapes and continuous on-site mechanical stimuli, but also to realize osteointegrity with the surrounding bone tissues and eventually be replaced by newly formed bones.

Infected bone defects (IBDs) exhibit impaired healing due to excessive inflammation triggered by pathogen-associated molecular patterns (PAMPs) from bacteria. As a vital factor in orchestrating immune responses, mitochondrial homeostasis maintenance is central to inflammation blockade. This research developed a chameleon-like nanoplatform by covering hydroxyapatite nanoparticles with a cerium ion coordinated tannic acid supramolecular network (HA@Ce-TA), which adaptively functions to regulate mitochondrial homeostasis based on intra- and extracellular environments. Extracellularly, acidic conditions activate HA@Ce-TA's peroxidase/oxidase-mimicking activity to produce reactive oxygen species (ROS), and external near-infrared (NIR) irradiation excites nanoscale Ce-TA to produce hyperthermia, which is found and explained by chemical computation. ROS production with photothermal therapy can eliminate bacteria effectively and reduce mitochondrial stress. Intracellularly, HA@Ce-TA remodels mitochondrial dynamics by upregulating mitochondrial fusion genes and eliminates excessive ROS by mimicking superoxidase/catalase. Consequently, this comprehensive modulation of mitochondrial homeostasis inhibits inflammasome overactivation. In vitro and in vivo studies showed HA@Ce-TA can modulate the mitochondria-centered inflammatory cascade to enhance IBD treatment, highlighting the potential of engineering nanotherapeutics to recalibrate mitochondrial homeostasis as an infected disease-modifying intervention.

Existing bone tissue engineering strategies aim to achieve minimize surgical trauma, stabilize the injured area, and establish a dynamic osteogenic microenvironment. The cutting-edge bone glue developed in this study satisfies these criteria. Inspired by the excellent adhesive properties of mussels, herein, a super osteogenic glue (L-DPZ) that integrates poly(vinyl alcohol), L-dopa amino acid, and zeolitic imidazolate framework-8 characterized by catechol-metal coordination is used to successfully adhere to hard tissue with a maximum adhesive strength of 10 MPa, which is much higher than those of commercial and previously reported bone glues. The stable hard tissue adhesion also enables it to adhere strongly to luxated or broken teeth, Bio-Oss (a typical bone graft material), and splice fragments from comminuted fractures of the rabbit femur. Then, it is testified that the L-DPZ hydrogels exhibit satisfactory biocompatibility, stable degradability, and osteogenic ability in vitro. Moreover, the ability to anchor Bio-Oss and sustained osteogenesis of L-DPZ result in satisfactory healing in calvarial bone defect models in rabbits, as observed by increased bone thickness and the ingrowth of new bone tissue. These results are expected to demonstrate solutions to clinical dilemmas such as comminuted bone fracture fixation, bone defect reconstruction, and teeth dislocation replantation.

In situ bioprinting has emerged as an attractive toolfor directlydepositing therapy ink at the defective area to adapt to the irregularwound shape. However, traditional bioprinting exhibits an obviouslimitation in terms of an unsatisfactory bioadhesive effect. Here,a portable handheld bioprinter loaded with biomaterial ink is designedand named "SkinPen". Gelatin methacrylate (GelMA) andCu-containing bioactive glass nanoparticles (Cu-BGn) serve as themain components to form the hydrogel ink, which displays excellentbiocompatibility and antibacterial and angiogenic properties. Moreimportantly, by introducing ultrasound and ultraviolet in a sequentialprogrammed manner, the SkinPen achieves in situ instant gelation andamplified (more than threefold) bioadhesive shear strength. It issuggested that ultrasound-induced cavitation and the resulting topologicalentanglement contribute to the enhanced bioadhesive performance together.Combining the ultrasound-enhanced bioadhesion with the curative roleof the hydrogel, the SkinPen shows a satisfactory wound-healing effectin diabetic rats. Given the detachable property of the SkinPen, thewhole device can be put in a first-aid kit. Therefore, the applicationscenarios can be expanded to many kinds of accidents. Overall, thiswork presents a portable handheld SkinPen that might provide a facilebut effective approach for clinical wound management.

Currently used wound dressings are ineffective. Hence, there is a need to develop introduce a high-performance medicament with multiple functions including rapid hemostasis and excellent antibacterial activity to meet the growing worldwide demand for wound healing products. Here, inspired by the strong adhesion of mussels and the enzyme-mimicking activity of nanometallic biomaterials, the authors developed an injectable hydrogel to overcome multiple limitations of current wound dressings. The hydrogel is synthesized via esterification reaction between poly(vinyl alcohol) (PVA) and 3,4-dihydroxyphenylalanine (DOPA), followed by catechol-metal coordination between Cu2+ and the catechol groups of DOPA to form a PVA-DOPA-Cu (PDPC) hydrogel. The PDPC hydrogel possesses excellent tissue adhesive, antioxidative, photothermal, antibacterial, and hemostatic properties. The hydrogel rapidly and efficiently stopped bleeding under different traumatic conditions, including otherwise-lethal liver injury, high-pressure carotid artery rupture, and even fatal cardiac penetration injuries in animal models. Furthermore, it is demonstrated that the PDPC hydrogel affected high-performance wound repair and tissue regeneration by accelerating re-epithelialization, promoting collagen deposition, regulating inflammation, and contributing to vascularization. The results show that PDPC hydrogel is a promising candidate for rapid hemorrhage control and efficient wound healing in multiple clinical applications.

The healing of infected bone defects (IBD) is a complex physiological process involving a series of spatially and temporally overlapping events, including pathogen clearance, immunological modulation, vascularization, and osteogenesis. Based on the theory that bone healing is regulated by both biochemical and biophysical signals, in this study, a copper doped bioglass (CuBGs)/methacryloyl-modified gelatin nanoparticle (MA-GNPs)/methacrylated silk fibroin (SilMA) hybrid hydrogel is developed to promote IBD healing. This hybrid hydrogel demonstrates a dual-photocrosslinked interpenetrating network mechanism, wherein the photocrosslinked SilMA as the main network ensures structural integrity, and the photocrosslinked MA-GNPs colloidal network increases strength and dissipates loading forces. In an IBD model, the hydrogel exhibits excellent biophysical characteristics, such as adhesion, adaptation to irregular defect shapes, and in situ physical reinforcement. At the same time, by sequentially releasing bioactive ions such as Cu2+, Ca2+, and Si2+ ions from CuBGs on demand, the hydrogel spatiotemporally coordinates antibacterial, immunomodulatory and bone remodeling events, efficiently removing infection and accelerating bone repair without the use of antibiotics or exogenous recombinant proteins. Therefore, the hybrid hydrogel can be used as a simple and effective method for the treatment of IBD.

Periodontitis is an inflammatory disease characterized by tooth loss and alveolar bone resorption. Bacteria are the original cause of periodontitis, and excess reactive oxygen species (ROS) encourage and intensify inflammation. In this study, a mussel-inspired and MnO2 NPs-reinforced adhesive hydrogel capable of alleviating periodontitis with improved antibacterial and antioxidant abilities was developed. The hydrogel was created by combining polyvinyl alcohol (PVA), 3,4-dihydroxy-d-phenylalanine (DOPA), and MnO2 nanoparticles (NPs) (named PDMO hydrogel). The hydrogel was demonstrated to be able to scavenge various free radicals (including total ROS─O2•- and OH•) and relieve the hypoxia in an inflammatory microenvironment by scavenging excess ROS and generating O2 due to its superoxide dismutase (SOD)/catalase (CAT)-like activity. Besides, under 808 nm near-infrared (NIR) light, the photothermal performance of the PDMO hydrogel displayed favorable antibacterial and antibiofilm effects toward Escherichia coli, Staphylococcus aureus, and Porphyromonas gingivalis (up to nearly 100% antibacterial rate). Furthermore, the PDMO hydrogel exhibited favorable therapeutic efficacy in alleviating gingivitis in Sprague-Dawley rats, even comparable to or better than the commercial PERIO. In addition, in the periodontitis models, the PDMO2 group showed the height of the residual alveolar bone and the smallest shadow area of low density among other groups, indicating the positive role of the PDMO2 hydrogel in bone regeneration. Finally, the biosafety of the PDMO hydrogel was comprehensively investigated, and the hydrogel was demonstrated to have good biocompatibility. Therefore, the developed PDMO hydrogel provided an effective solution to resolve biofilm recolonization and oxidative stress in periodontitis and could be a superior candidate for local drug delivery system in the clinical management of periodontitis with great potential for future clinical translation.

Since the microgap between implant and surrounding connective tissue creates the pass for pathogen invasion, sustained pathological stimuli can accelerate macrophage-mediated inflammation, therefore affecting peri-implant tissue regeneration and aggravate peri-implantitis. As the transmucosal component of implant, the abutment therefore needs to be biofunctionalized to repair the gingival barrier. Here, a mussel-bioinspired implant abutment coating containing tannic acid (TA), cerium and minocycline (TA-Ce-Mino) is reported. TA provides pyrogallol and catechol groups to promote cell adherence. Besides, Ce3+ /Ce4+  conversion exhibits enzyme-mimetic activity to remove reactive oxygen species while generating O2 , therefore promoting anti-inflammatory M2 macrophage polarization to help create a regenerative environment. Minocycline is involved on the TA surface to create local drug storage for responsive antibiosis. Moreover, the underlying therapeutic mechanism is revealed whereby the coating exhibits exogenous antioxidation from the inherent properties of Ce and TA and endogenous antioxidation through mitochondrial homeostasis maintenance and antioxidases promotion. In addition, it stimulates integrin to activate PI3K/Akt and RhoA/ROCK pathways to enhance VEGF-mediated angiogenesis and tissue regeneration. Combining the antibiosis and multidimensional orchestration, TA-Ce-Mino repairs soft tissue barriers and effector cell differentiation, thereby isolating the immune microenvironment from pathogen invasion. Consequently, this study provides critical insight into the design and biological mechanism of abutment surface modification to prevent peri-implantitis.

The regeneration of bone defects in patients with diabetes mellitus (DM) is remarkably impaired by hyperglycemia and over-expressed proinflammatory cytokines, proteinases (such as matrix metalloproteinases, MMPs), etc. In view of the fact that exosomes represent a promising nanomaterial, herein, we reported the excellent capacity of stem cells from apical papilla-derived exosomes (SCAP-Exo) to facilitate angiogenesis and osteogenesis whether in normal or diabetic conditions in vitro. Then, a bioresponsive polyethylene glycol (PEG)/DNA hybrid hydrogel was developed to support a controllable release of SCAP-Exo for diabetic bone defects. This system could be triggered by the elevated pathological cue (MMP-9) in response to the dynamic diabetic microenvironment. It was further confirmed that the administration of the injectable SCAP-Exo-loaded PEG/DNA hybrid hydrogel into the mandibular bone defect of diabetic rats demonstrated a great therapeutic effect on promoting vascularized bone regeneration. In addition, the miRNA sequencing suggested that the mechanism of dual- functional SCAP-Exo might be related to highly expressed miRNA-126-5p and miRNA-150-5p. Consequently, our study provides valuable insights into the design of promising bioresponsive exosome-delivery systems to improve bone regeneration in diabetic patients.