Abstract Oral microbial homeostasis is a stable equilibrium state of the ecological community of oral microorganisms formed through the dynamic interactions between the oral microorganisms and the host's oral ecosystem. Its disruption can lead to opportunistic pathogenic infections or refractory infectious diseases in the oral cavity. Compared to traditional antibiotic treatments, the development of materials capable of rebalancing oral microbial homeostasis is advantageous in reducing the induction of drug‐resistant bacteria and preserving the normal oral microbiota, making it a current research focus. Nanomaterials exhibit significant potential in rebalancing oral microbial homeostasis owing to their antibacterial, anti‐inflammatory, immunomodulatory, and other functions. Previous reviews have predominantly focused on the mechanisms of nanomaterials against single microbial species, overlooking their differential effects on ecological communities and ecosystems. This review adopts an ecological perspective, systematically summarizing the strategies of nanomaterials in rebalancing oral microbial homeostasis through three dimensions: population and community, ecosystem, and cross‐ecosystem, while analyzing the influencing factors involved. Finally, the limitations and future prospects of current research are discussed. This review aims to provide theoretical support for the prevention and treatment of oral infectious diseases and to offer novel design insights for the development of advanced therapeutic materials.

Neurodegenerative diseases (NDs) are a major cause of disability and the second leading cause of death worldwide. The progression of NDs is intricately linked to the disruption of immune homeostasis, which is characterized by excessive activation and infiltration of immune cells. Recent studies have uncovered the potential of nanomaterials (NMs) with immunomodulatory capabilities to effectively manage neuroinflammation and slow the progress of NDs. The review begins by elucidating the mechanisms through which NMs modulate innate and adaptive immune responses in the context of NDs. These mechanisms encompass the dampening of innate immune cell activation, particularly microglia and astrocytes, and the restriction of peripheral adaptive immune cell infiltration into the central nervous system (CNS). By doing so, NMs can alleviate neuroinflammation and promote the repair of damage induced by NDs. The review emphasizes the application of stimulus‐responsive NMs for targeted immunomodulation within the CNS. Moreover, it discusses strategies to enhance NM targeting and develop of NM‐based active immunotherapies as prospective therapeutic approaches for clinical application. Understanding the mechanisms and applications of NMs is pivotal for unlocking their full potential in immunomodulatory strategies. This knowledge will lay the foundation for novel therapies addressing the unmet clinical needs of NDs.

ABSTRACT Diabetic bone defects repair is severely hindered by impaired angiogenesis and delayed osteogenesis. Conventional tissue‐engineered scaffolds often fail to achieve effective vascularization due to the compromised angiogenic capacity of host endothelial cells in the hyperglycemic microenvironment. Here, we developed a prevascularized scaffold by encapsulating stem cells from human exfoliated deciduous teeth (SHED), which shared developmental origin to craniofacial bone, within a reduced graphene oxide (rGO)‐integrated hydrogel. rGO significantly accelerated SHED‐mediated formation of vascular networks in vitro. The scaffold's therapeutic efficacy was confirmed in a clinically relevant diabetic beagle dog mandibular defect model, which showed increased vascular density and accelerated bone regeneration. Mechanistic validation revealed that rGO activates the FAK‐Src/RELA pathway to upregulate P4HA1, subsequently enhancing collagen I synthesis and driving extracellular matrix (ECM) remodeling to create a pro‐angiogenic niche. This study demonstrates that engineering the ECM with rGO is a novel strategy to accelerate prevascularization and bone repair in diabetic conditions.

Impaired angiogenesis is a major cause of delayed healing in age-related bone defects, and dysfunction of the pro-angiogenic paracrine activity of senescent bone marrow mesenchymal stem cells (BMSCs) contributes substantially to this vascular deficiency. Here, we synthesised a tannic acid-derived nanocarbon (TANC) and investigated whether it could promote angiogenesis by restoring the pro-angiogenic paracrine function of senescent BMSCs. In an aged rat calvarial defect model treated with locally implanted TANC-loaded GelMA hydrogels, TANC significantly increased blood perfusion, CD31-positive vessel density, and VEGF expression. In vitro, conditioned medium from TANC-treated senescent BMSCs markedly enhanced endothelial proliferation, migration, tube formation, and angiogenesis-related marker expression, whereas direct TANC treatment showed little effect. Transcriptomic screening and functional validation identified Lama2 as a key paracrine mediator regulated by TANC. Lama2 knockdown in vitro and Lama2 neutralisation in vivo both markedly attenuated the pro-angiogenic effect. Mechanistically, Lama2 preferentially interacted with integrin α3β1 on endothelial cells and activated downstream PI3K/AKT signalling. Collectively, these findings show that TANC restores the pro-angiogenic paracrine function of senescent BMSCs through the Lama2/integrin α3β1/PI3K/AKT axis and represents a promising biomaterial-based strategy for age-related bone defects with impaired vascularisation.

This study aims to address the challenge of mitochondrial energy metabolism disorders induced by the hyperglycemic microenvironment of diabetic wounds. We developed an intelligent dual-responsive hydrogel and propose an innovative "internal-external synergistic" therapeutic strategy. The dynamic crosslinked network of the hydrogel responds to high glucose and reactive oxygen species (ROS) signals in the wound microenvironment, consuming these pathological factors to achieve external microenvironmental regulation while triggering the precise release of encapsulated oxidized carbon nanohorns (oxCNHs). As a "functional enhancement unit" and "mitochondrial energy restorer", oxCNHs stabilize the hydrogel network through multivalent interactions prior to signal activation, and upon signal stimulation, activate AMPKα via phosphorylation to restore mitochondrial energy metabolism. This metabolic restoration drives the assembly of F-actin stress fibers, which provide the necessary driving force for directed cell migration and angiogenesis. In vivo experiments demonstrated the hydrogel's significant efficacy in promoting wound repair. This study advances the role of oxCNHs from mere passive drug carriers to active metabolic regulators. Furthermore, it introduces an innovative paradigm for diabetic wound healing through a synergistic approach that externally modifies the microenvironment while internally reactivating the cellular energy machinery.

Redox balance is crucial for maintaining normal physiological functions. Its disruption by oxidative stress can trigger or exacerbate a series of pathological cascades, ultimately contributing to various chronic diseases, particularly inflammatory disorders. Inhibiting oxidative stress and its associated pathological cascades may alleviate these diseases, a process often linked to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Initially characterized as a redox-sensitive transcription factor, Nrf2 is now recognized as a pivotal regulator of an extensive network of antioxidant genes, effectively counteracting oxidative stress and its detrimental effects. Consequently, advances in understanding Nrf2 activators and their regulatory mechanisms have accelerated the development of Nrf2-targeted therapies, demonstrating significant potential for preventing and treating chronic inflammation diseases. Many natural phytochemicals, particularly flavonoids, have been identified as Nrf2 activators that can ameliorate inflammatory responses. Furthermore, therapy with mesenchymal stromal/stem cells (MSCs) is a highly researched treatment approach with the potential to confer immunomodulatory, anti-inflammatory, anti-apoptotic and antimicrobial effects. Owing to their superior safety profile compared to conventional therapeutics, MSCs are gaining prominence as sustainable long-term treatment options, although their precise molecular mechanisms remain to be fully elucidated. This review focuses on the activation mechanisms of Nrf2 and its clinical and preclinical inducers, with particular emphasis on the mechanistic insights and therapeutic applications of natural flavonoids and MSCs in the prevention or treatment of inflammatory diseases. More importantly, it summarizes the profound role of flavonoid-MSCs combinatorial therapy in the intervention of inflammatory diseases, pointing out novel therapeutic strategies and future prospects for modulating the Nrf2 signaling pathway in the treatment of inflammatory disorders.

In wound healing applications, conventional nanomaterials fail to precisely regulate the wound healing process because of the lack of dynamic adaptation to the wound microenvironment. Conversely, stimuli-responsive nanomaterials can respond to endogenous stimuli such as pH, enzymes, reactive oxygen species (ROS), and glucose, as well as exogenous stimuli such as light, electricity, and magnetism. Thus, stimuli-responsive nanomaterials can facilitate precise drug delivery and effectively treat wounds, and some of these materials can even achieve integrated diagnosis and treatment. Previous reviews have focused mainly on hydrogel carriers with stimuli-responsive properties. This review focuses on stimuli-responsive nanomaterials, classifies these materials on the basis of their stimulus sources, and systematically summarizes the response mechanisms, application outcomes, and design strategies of endogenous, exogenous, and dual stimuli-responsive nanomaterials applied in wound healing. Furthermore, this review explores the research gaps and future developments of stimuli-responsive nanomaterials for wound healing.

The challenge in treating neurodegenerative diseases (NDs) lies in the complexity of their pathological mechanisms. Strategies capable of synergistically regulating multiple pathological features are crucial for treating NDs. Chiral nanomaterials (CNMs), including chiral nanoparticles (CNPs) and chiral nanoassemblies (CAMs), offer a unique platform for achieving such precise multitarget regulation because of their stereoselective interactions. Strategies for synthesizing CNMs are outlined in this review, and an in-depth analysis of their core biological mechanisms for treating NDs—inhibiting and clearing pathological proteins, enhancing synaptic plasticity, alleviating neuroinflammation, selectively eliminating senescent cells and promoting the differentiation of neural stem cells—is provided. Optimization of these functions through internal chiral design and external physical field modulation is explored. Finally, we propose forward-looking concepts such as “stage-optimized chiral nanomedicines” and “intelligently responsive chiral nanomaterials” to provide guidance for next-generation precision nanomedicine for NDs. Statement of Significance The key challenge in treating neurodegenerative diseases (NDs) lies in the precise identification and coordinated regulation of multi-target pathological processes. In recent years, chiral nanomaterials (CNMs), including chiral nanoparticles (CNPs) and chiral nanoassemblies (CAMs), have emerged as innovative tools for NDs intervention owing to their unique stereoselective recognition capabilities. This review systematically categorizes CNMs and their synthesis strategies, and focuses on elucidating their core biological mechanisms, including the inhibition and clearance of pathological proteins, enhancement of synaptic plasticity, alleviation of neuroinflammation, selective elimination of senescent cells, and promotion of neural stem cell differentiation. Furthermore, strategies to optimize their functionality through internal chiral structure design and external physical field modulation are explored. Collectively, this review aims to systematically elucidate the biological mechanisms and material properties of CNMs in NDs therapy, providing a theoretical foundation and guidance for the rational design and construction of next-generation neurorepair materials.

Large maxillofacial bone defects severely impair oral function and aesthetics, and current treatments involving autologous bone grafting followed by prosthetic restoration are associated with high surgical trauma and prolonged rehabilitation. Herein, we present a tooth-bone integrated organoid (TBO) strategy that synchronously reconstructs bone and dental implant structures in vitro, aiming to achieve dual restoration of structure and function post-implantation. Bioactive glass (BG) was employed as a multifunctional "bond" that not only established effective adhesion between BG callus organoids and BG-Si3N4 implants via dual-interface bonding with soft and hard tissues, but also acted as an active stimulant and mineralization agent to accelerate the hypertrophy and ossification of callus organoids in the late stage of endochondral ossification. Simultaneously, BG enhanced the osteogenic potential and osseointegration of the dental implants through bioactive ion release and interfacial mineralization. This approach boldly confronts and attempts to resolve the dual challenges of maxillofacial bone defects repair and dental arch restoration, offering a clinically translatable pathway toward integrated structural and functional maxillofacial regeneration.

Skin and mucous membranes serve as crucial barrier tissues within the human body. Defective wound healing not only inflicts pain but also heightens the risk of infection and impairs immune function. Janus hydrogels possess two-sided distinct asymmetric structures that endow them with diverse properties such as high water absorbency, flexibility, anti-adhesion ability etc. These hydrogels also exhibit great potential in biofluid transport, drug delivery and promoting tissue repair. Currently, research efforts predominantly concentrate on the preparation techniques, properties, and biomedical applications. This review summarized its structural characteristics and different forms of designations, and focused on the possible mechanisms, the existing problems and improvement strategies for the skin and mucous tissues wound, aiming to provide new design ideas for repairing complex skin and mucous membrane tissue defects.

Responsive intelligent biomaterials, characterized by their ability to sense and respond to external or internal stimuli, have emerged as promising candidates in regenerative medicine (RM). RM aims to replace or regenerate damaged human cells, tissues, or organs to restore normal function. However, their mechanisms of action are not fully understood, especially at the molecular level. Studies on long-term stability, in vivo degradation, and tissue impact are lacking. Translation from research to clinical application faces challenges due to physiological and genetic differences between animal models and humans, and inadequate clinical data. This chapter summarizes the current applications of responsive intelligent biomaterials in RM, encompassing bone regeneration, cartilage regeneration, skin regeneration, nerve regeneration, and myocardial regeneration. This chapter aims to help overcome these hurdles and successfully apply responsive intelligent biomaterials in regenerative medicine.

The clinical translation of dental materials presents significant opportunities, driven by increasing market demand, supportive regulatory frameworks, and advancements in digital and additive manufacturing technologies. These factors facilitate enhanced personalization, improved biocompatibility, and superior aesthetic and mechanical properties of dental products. However, the path to successful translation is fraught with challenges, including funding uncertainties, gaps in clinical evaluation frameworks, and limitations in material performance, particularly concerning the long-term stability of resins and zirconia ceramics. Moreover, there is a pressing need for better integration of multidisciplinary data and artificial intelligence technologies. Future advancements in this field will depend on fostering robust collaborations between research and industry, adopting international standards, and leveraging cutting-edge technologies to accelerate innovation.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication in patients undergoing long-term bisphosphonate therapy, while our knowledge on the pathogenesis of BRONJ is far from sufficient. Gamma delta (γδ) T cells predominantly distribute in mucosal tissues and play an important role in both immune modulation and bone metabolism; however, the mechanism of γδ T cells in the pathogenesis of BRONJ has not been elucidated. Here, we induced BRONJ-like lesions in wild-type (WT) and T-cell receptor delta-deficient (TCRδ-/-) mice via intraperitoneal zoledronate injection. Our findings revealed that γδ T cells infiltrating BRONJ lesions suppressed osteoblast differentiation, whereas γδ T cell depletion in TCRδ-/- mice restored osteogenic function and significantly reduced BRONJ lesion incidence. Mechanistically, we identified matrix metalloproteinase 3 (MMP3) secreted by activated γδ T cells as a critical enzyme cleaving membrane-bound Sema4D (mSema4D) into soluble Sema4D (sSema4D). This cleavage product bound to Plexin-B1/2 receptors on osteoblasts, activating the mTOR signalling pathway to inhibit osteogenic differentiation (ALP/Runx2 downregulation). To promote the repair of BRONJ lesions, we engineered a dual-functional composite hydrogel (Gel-BG@ab) combining PLGA-PEG-PLGA with mesoporous bioactive glass (BG) and anti-Sema4D antibodies. This composite hydrogel achieved sustained antibody release, effectively neutralising sSema4D, restoring osteoblast activity and reducing the formation of BRONJ-like lesions in vivo. This study provides evidence of MMP3-Sema4D-Plexin-B1/2/mTOR crosstalk in BRONJ and introduces a targeted biomaterial strategy to disrupt pathogenic feedback loops. The Gel-BG@ab is the integration of immunomodulation and regenerative medicine, providing both theoretical and technical insights for the immune-material combination therapy of BRONJ.

The pathological microenvironment following peripheral nerve injury (PNI) comprises a dynamic interplay of cellular and molecular events that critically influence neuronal regeneration and functional recovery. Recent advances in nanotechnology have demonstrated the transformative potential of nanomaterials (NMs) in nerve repair, capitalizing on their unique physicochemical properties to engineer a pro-regenerative milieu that facilitates axonal regrowth. This review systematically explores the biological mechanisms by which NMs modulate and remodel the injury niche, thereby enhancing peripheral nerve regeneration (PNR). Specifically, this review highlights five key microenvironmental regulators, including rebuilding remyelinating Schwann cells, balancing the immune microenvironment, forming blood vessels, constructing extracellular matrix, and regulating cytokines and hormones. By analyzing these NMs-mediated therapeutic strategies, we provide novel mechanistic insights and discuss translational opportunities for next-generation nanomedicine in PNR therapy.

Orofacial pain encompasses a diverse group of disorders that pose a significant clinical challenge, often progressing from acute to chronic conditions due to a disconnect between clinical diagnosis and underlying pathophysiology. This review provides a synthesis of the mechanisms driving this transition and evaluates emerging therapeutic strategies that target them. First, we dissect the pathophysiological mechanisms of acute pain, including peripheral sensitization and transient central sensitization; and then detail how these processes can become maladaptive, leading to chronic pain states sustained by a combination of persistent nociceptive input, neuropathic alterations, and nociplastic changes involving dysfunctional descending modulation and central network reorganization. Building on this mechanistic framework, we critically appraise novel therapeutic approaches, including targeted pharmacotherapies such as selective ion channel and endocannabinoid system modulators, alongside non-pharmacotherapeutic interventions that encompass neuromodulation techniques designed to regulate central neural plasticity and psychologically grounded therapies. By integrating molecular evidence with clinical presentations, this review offers a framework for advancing towards a more precise, mechanism-based management of orofacial pain.

Diabetic wound treatment remains a worldwide clinical challenge due to key issues, including persistent oxidative stress, bacterial infections and impaired angiogenesis, which impede diabetic wound healing. In this study, a multifunctional Janus amphiphilic membrane (Nb@CCJM) was successfully prepared through a double vitrification process for diabetic wound healing. The layers of the Janus membrane were tightly connected due to the nano-interlocking interface formed between the inner Nb2C MXene-functionalized collagen vitrified membrane and the outer CMC vitrified membrane. Nb@CCJM exhibited excellent biocompatibility, outstanding mechanical properties, and appropriate degradation behavior, effectively scavenging significant amounts of ROS both in vivo and in vitro, thereby reducing oxidative stress in cells and tissues. Additionally, Nb@CCJM exhibited remarkable bactericidal activity to prevent wound infections. Owing to the hydrophilicity of the CMC layer, Nb@CCJM displays asymmetric adhesion; its outer layer effectively prevents tissue adhesion while simultaneously resisting bacterial adherence and avoiding infection. Importantly, Nb@CCJM significantly enhanced the migration and tube formation of vascular endothelial cells in vitro and efficiently promoted angiogenesis and wound healing in diabetic mouse models. Furthermore, mechanistic studies indicate that one of the mechanisms through which Nb@CCJM promotes angiogenesis involves the upregulation of SDF-1 alpha and CXCR4 gene expression, thereby activating the SDF-1 alpha/CXCR4 signaling axis along with its downstream MAPK and PI3K/AKT signaling pathways to facilitate vascular endothelial cell migration and accelerate angiogenesis. In summary, Nb@CCJM was prepared using a straightforward and safe method, effectively scavenged ROS, eliminated bacteria, resisted cell adhesion, and promoted angiogenesis, providing a cost-effective solution for accelerating diabetic wound healing.

Recent data have revealed an increased risk of respiratory exposure during the manufacturing process and application of nanomaterials, resulting in an increased incidence of neurodegenerative diseases in the general population. Zinc oxide nanoparticles (ZNPs) are among the most used nanomaterials in biomedical and manufactured consumer products. In this study, neurological dysfunction after intranasal administration of ZNPs is observed, in which the ZNPs enter the brain via the nose-to-brain pathway and accumulate in microglia but not in astrocytes or neurons. By using a coculture system of microglia and neurons, the ZNPs are found that induce microglia-derived oxidative stress injury and lead to neuronal cell PANoptosis. In this context, ZNPs induced the generation of reactive oxygen species (ROS) originating from microglial NADPH oxidase 2 (NOX2), which further induced neuronal membrane lipid peroxidation and increased Ca2+ influx and mitochondrial DNA release. The leaked mitochondrial DNA subsequently initiates PANoptosis of neurons. Importantly, inhibition of microglial NOX2 activation can significantly alleviate brain oxidative injury and rescue neuronal PANoptosis. This study can advance the understanding of the mode of neuronal cell death while underscoring the importance of the interconnections among glial cells and neurons, which is beneficial for informing effective interventions for respiratory exposure to nanoparticles.

Nanoplastic pollution has emerged as a significant environmental concern, with increasing evidence suggesting that these nanoparticles can disrupt the blood-brain barrier (BBB) and accumulate in the brain, ultimately leading to neurological impairment. However, the underlying mechanism for the toxic effects of nanoplastics on the BBB remain poorly understood. In this study, we explored the toxic effects of polystyrene nanoplastic (PSNP) on brain microvascular endothelial cells (BMECs), one of the most critical components for maintaining BBB integrity. Our results revealed that PSNP specifically accumulate in the endolysosomal system following their internalization by BMECs. This accumulation disrupts lysosomal function and blocks endolysosomal pathways, ultimately triggering methuosis—a unique form of cell death characterized by extensive cytoplasmic vacuolization. Although the endosomal sorting complexes required for transport (ESCRT) system is naturally activated as a cellular defense mechanism, it is insufficient to repair PSNP-induced lysosomal membrane damage. By enhancing ESCRT activity, we effectively restored lysosomal function, thereby preventing cellular methuosis and preserving BBB integrity. Therefore, our findings provide crucial insights into the mechanisms underlying PSNP-induced BBB disruption by focusing on methuosis in endothelial cells. These insights hold important implications for environmental toxicology and public health in the context of global plastic pollution.

With the rapid development of nanotechnology, layered double hydroxides (LDHs) have attracted considerable attention in the biomedical field due to their highly tunable composition and structure, superior biocompatibility, multifunctional bioactivity, and exceptional drug delivery performance. However, a focused and comprehensive review addressing the role of LDHs specifically in tissue regeneration has been lacking. This review aims to fill that gap by providing a systematic and in-depth overview of recent advances in the application of LDHs across various regenerative domains, including bone repair, cartilage reconstruction, angiogenesis, wound healing, and nerve regeneration. Beyond presenting emerging applications, the review places particular emphasis on elucidating the underlying mechanisms through which LDHs exert their therapeutic effects. Although LDHs demonstrate considerable promise in regenerative medicine, their clinical translation remains in its infancy. To address this, we not only provided our insights into the personalized problems that arise in the application of various tissues, but also focused on discussing and prospecting the common challenges in the clinical translation of LDHs. These challenges include optimizing synthesis techniques, enhancing biosafety and stability, improving drug-loading efficiency, designing multifunctional composite materials, and establishing pathways that facilitate the transition from laboratory research to clinical practice.