Dental defects, ranking among the most prevalent diseases globally, pose a serious threat to human health, with extensive defects involving dentin leading to complications such as pulp and periodontal diseases, as well as maxillofacial dysfunctions, significantly impairing quality of life. Current clinical treatments primarily rely on rigid materials such as metals, composite resins, and ceramics for macroscopic filling. However, their inherent limitations, differences in compositional and structural characteristics from natural dentin, mismatched mechanical properties, and interfacial adhesion instability, fail to meet the clinical demand for long-term and stable restoration of natural dentin. In situ dentin regeneration, inspired by the complex composition and hierarchical structure of natural dentin, aims to induce the autonomous repair of dentin. This approach effectively overcomes the traditional limitations, shifting from traditional passive filling to active regenerative repair. Based on the growth direction and mineralization pattern of the repair layer, current research focuses on three strategies: “inward growth”, “outward growth”, and “synchronized inward-outward growth”. This review primarily focuses on the roles and clinical applications of key bioactive materials in these strategies, providing a feasible basis for future material and performance optimization of dentin in situ regeneration.

Extracellular vesicles (EVs) secreted by stem cells have become a promising cell-free approach in regenerative medicine, with significant potential for the repair and treatment of musculoskeletal tissues and disorders. However, the limited bioactivity and scalability of EV production pose significant challenges for commercial production and clinical translation. To overcome these challenges, researchers have started exploring how the cellular microenvironment can modulate EV characteristics and enhance their therapeutic efficacy. While the microenvironment's biochemical facets have been the primary focus of prior investigations, the influence of biophysical factors on EV characteristics remains relatively underexplored. This review consolidates the existing research investigating the effects of biophysical features of the cellular microenvironment on EV production and function, with a particular emphasis on applications in musculoskeletal regeneration. By providing a comprehensive understanding of how biophysical factors impact EVs, this review seeks to enhance the development of effective strategies that harness the power of EVs for large-scale production and their successful application in regenerative therapies for musculoskeletal disorders. Ultimately, such insights could greatly assist patients who require innovative, cell-free regenerative treatments, thereby propelling advancements in musculoskeletal tissue engineering and in regenerative medicine.

Nanozymes including noble metals, metal oxides, metal-organic frameworks, carbon-based nanomaterials, and layered double hydroxides (LDHs) have undergone rapid development in recent years. In addition to the cost-effectiveness, high stability, and superior catalytic capabilities of common nanozymes, LDHs have unique characteristics such as extensive surface area, anion exchange capacity, adjustable composition/structure, and low toxicity. Leveraging these properties, LDH-based nanozymes (LDHzymes) with enzyme-like activity demonstrate significant potential for applications, particularly in biomedicine. This review summarizes the preparation methods for LDHzymes with different morphology and elucidates their catalytic activities (including peroxidase-, oxidase-, superoxide dismutase-, and catalase-like activity) and mechanisms. Subsequently, the applications of LDHzymes across biomedical fields are examined, including biosensing and detection, antimicrobial properties, treatment of tumors, and reactive oxygen species-related diseases. Finally, future research directions for LDHzymes are proposed, including the design of high-performance LDHzymes, intelligent therapeutic applications, and the expansion of application fields, which provide a framework for the development of novel LDHzymes for biomedical applications.

Biofilm infections pose a significant clinical challenge largely due to the limited penetration of a variety of antibacterial agents, making traditional antibiotic therapies ineffective. In this study, we develop a pH-responsive, charge-reversal liposomal system (TPA-ICN/LVF@Lipo-PyB) loaded with the phototherapeutic agent TPA-ICN and the antibiotic levofloxacin (LVF) for multimodal synergistic therapy of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections. The surface-grafted pyridine betaine group enables charge reversal of TPA-ICN/LVF@Lipo-PyB through rapid and efficient protonation to enhance its penetration capability in the acidic microenvironment of biofilms. Upon laser irradiation, the liposomal system exhibits both photodynamic and photothermal properties to inactivate bacteria within the biofilm. Simultaneously, the photothermal effect effectively disassembles the liposome due to the presence of thermosensitive phospholipids to trigger LVF release, ensuring the effective eradication of residual bacteria. Remarkably, the multimodal synergistic therapy demonstrates exceptional in vitro bacterial eradication, achieving a 99.99% reduction in MRSA biofilms. Furthermore, TPA-ICN/LVF@Lipo-PyB significantly accelerates the healing of MRSA-infected wounds by reducing inflammation, promoting angiogenesis, and enhancing collagen regeneration. These outstanding therapeutic results highlight the potential of this approach for the safe and effective clinical management of wound infections.

Posterior segment eye diseases (PSEDs) remain a leading cause of irreversible blindness, with the eye's dynamic and static barriers posing challenges to effective drug delivery through different administration routes. Currently, treatment options available for PSEDs are limited, with invasive intravitreal injection being the predominant choice. However, frequent injections carry a high risk of complications, and are associated with low patient compliance. The rapid advancement of nanomaterials has sparked intense interest in nanoconstructed drug delivery systems as potential solutions to overcome these bottlenecks. Experimental studies have demonstrated that diverse nanocarriers can accommodate different therapeutic agents and circumvent ocular barriers through multiple mechanisms, including prolonged drug residence, enhanced tissue permeability, to name a few. In addition, nanomaterial-based delivery systems also offer advantages in improving posterior segment drug delivery efficiency and therapeutic practicality. In this review, the multiple ocular barriers and traditional administration routes are presented first. Then, we focus on the promise held by nanoplatforms for barrier penetration and summarize key mechanisms involved. Meanwhile, the review highlights the value of nanocarriers in achieving efficient drug delivery and treatment of PSEDs with illustrative examples and tables. Finally, current challenges and future prospects are also discussed here to encourage basic research and clinical transformation.

Periodontitis is a common and frequent oral disease which is characterized by persistent loss of periodontal supportive tissue and seriously affects the physical and psychological health. Existing clinical diagnostic indicators are incapable of accurately diagnosing periodontitis patients at an early stage, while traditional treatment methods are unable to promote the periodontal bone regeneration stably. It is vital to explore more sensitive methods for aided diagnosis and precise treatment to improve clinical efficacy. Exosomes are nano-sized extracellular vesicles that are produced by all kinds of cells. In recent years, many studies have revealed that exosomes are abundant in complex biogenetic materials that participate in cell signaling, immunomodulation, and tissue regeneration. Furthermore, their enormous potential in disease diagnosis and treatment is gradually explored. Here, we review the current impact of exosomes on the development and progression of periodontitis. We briefly describe some studies that discovered that the amount and component of exosomes are altered during the pathogenesis of periodontitis, demonstrating their potential as indicators for aided diagnosis. We also categorize the application of various cell and plant-derived exosomes, as well as the research progress of some novel engineered exosomes, which provides some new directions for designing personalized therapeutic strategies for periodontitis patients.

The tumor microenvironment (TME) plays a crucial role in cancer progression and treatment, particularly in the field of immunotherapy. Composed of diverse cell types and extracellular matrix components, the TME collectively contributes to cancer pathogenesis and resistance to treatment. In recent years, innovative strategies targeting the TME have emerged as promising therapeutic approaches for cancer treatments. This review focuses on the latest advancements in engineered nanomaterials designed to modulate the immune-suppressive characteristics of the TME, including hypoxia, reactive oxygen species levels, high interstitial fluid pressure, and acidity. By strategically manipulating the TME with nanomaterials, we hold promise for creating a more conducive environment for immune cell activation and destruction of tumor cells, thereby enhancing the efficacy of immunotherapy. The development of these nanomaterials represents a significant leap forward in our battle against cancer by offering a novel approach to overcome challenges posed by immune-suppressive TME.

With the occurrence of terrorist incidents and the intensification of war situations, concerns about biological and chemical warfare agents (BCWAs) created by mankind are growing due to their chilling characteristics such as high toxicity, high fatality rate, mass destruction, imperceptibility to senses, rapid dissemination, and even easy availability. In most cases, even slight exposure to these BCWAs can be a disaster because of their lethal or incapacitating effects on humans. Hence, it is urgently demanding to develop effective methodologies for sensitive detection and efficient neutralization of BCWAs in a specific scenario. Among various techniques, micro/nanorobots (MNRs), which can transfer energy from surroundings into kinetic energy for self-propelled or field-powered movement, have emerged as state-of-the-art tools to actively combat biological and chemical threats. In this review, the latest research progress in MNRs for sensing and detoxification of BCWAs is presented. Toxins and pathogenic bacteria have been selected as the representatives for biological warfare agents, whereas nerve agents were chosen as typical chemical warfare agents. Besides, the working principles of MNRs based on their locomotion features (e.g., velocity changes) and constructed material characteristics (e.g., fluorescent on/off switch, photocatalytic effect, adsorption, and antibody-antigen recognition) in terms of sensing and detoxification are summarized. Finally, current challenges and future perspectives for the development of fuel-powered and field-driven MNRs and their application in sensing and removing BCWAs are discussed.

Spinal cord injury (SCI) presents significant challenges due to the profound damage it causes to motor functions and sensory. The post-trauma environment, characterized by the formation of cystic lesions and the absence of extracellular matrix, hinders neural regeneration and compromises the survival of transplanted cells. Biomaterials offer a promising avenue by providing a supportive environment for nerve repair. Silk fibroin (SF), a natural protein extracted from the cocoons of Bombyx mori silkworms, stands out for its exceptional biodegradability, biocompatibility, and adjustable mechanical properties. SF can be fabricated into various formats, including sponges, hydrogels, and fibers, making it highly adaptable for numerous biomedical applications such as tissue engineering, wound healing, and drug delivery. Recent advancements in SF-based biomaterials have highlighted their potential in SCI repair by mimicking the native cellular microenvironment, promoting axonal growth, and facilitating tissue repair. This review focuses on the structure and properties of SF, its environmentally friendly processing methods, and the strategies for designing composite scaffolds using SF-based biomaterials for SCI repair. It also examines future challenges and prospects in this promising field.

Oral and craniomaxillofacial tissues are essential for maintaining oral functions, including respiration, mastication, swallowing, and speech. They also play a pivotal role in facial aesthetics and overall health. However, the intricate anatomy, co-existence of diverse tissue types, and high demand for functional recovery make regeneration a challenging process. Traditional 3D printing technology is limited to fulfilling morphological requirements and cannot meet the complex demands of multi-tissue regeneration and functional restoration in the oral and craniomaxillofacial regions. In contrast, 3D bioprinting technology enables the creation of biologically functional cell-laden living scaffolds that are highly compatible with defect sites. This advanced approach effectively promotes post-transplantation tissue integration and significantly enhances therapeutic outcomes. This review focuses on the utilization of 3D bioprinting in oral and craniomaxillofacial tissue regeneration. It highlights advancements in biomaterial application and printing technology, and current achievements and challenges in preclinical and clinical research, aiming to facilitate the translational and innovative applications of this technology in oral and craniomaxillofacial repair and reconstruction.

Stimuli-responsive nanomaterials offer significant potential for enhancing diagnostic accuracy, optimizing therapeutic efficacy, and advancing precision theranostics. Hydrogen sulfide (H₂S) was found to be upregulated in colorectal cancer, which endows it with an ideal endogenous trigger for tumor targeting. Here, we introduce a novel class of H₂S-activated metal-organic framework (MOF) systems specifically designed for targeted colorectal cancer imaging and synergistic copper-induced tumor regression. The Cu-MOF nanoplatform demonstrated a rapid response to H₂S at the tumor site, producing copper sulfide with strong near infrared absorption and activated PA signals. In vivo studies demonstrated remarkable tumor inhibition in an orthotopic colon cancer model with minimal side effects. The copper-based MOFs theranostic nanosystem effectively reduced protein lipoylation and Fe-S cluster protein levels (FDX1), triggering cuproptosis. This study presents a novel strategy for designing multifunctional nanoparticles for synergistic PA/CDT/PTT/cuproptosis theranostics.

Microglia-mediated neuroinflammation can lead to progressive neuronal damage, accelerating the development of neurodegenerative changes or existing neurological disorders. Regulating microglial activation to reshape the inflammatory microenvironments has increasingly become a promising therapeutic target for the treatment of neurological diseases. Retinoic acid, a natural small-molecule compound, holds potential neuroprotective and immunomodulatory properties. However, its poor water solubility poses a challenge to its bioavailability. In this study, calcium retinoate nanoparticles (Ca-RA NPs) were proposed and synthesized through a coordination reaction between retinoic acid molecules and calcium ions, which were proved to be easily endocytosed by microglia and rapidly decomposed into small molecule/ion storms in lysosomes. In vitro experimental results demonstrated that Ca-RA NPs can inhibit lipopolysaccharide (LPS)-induced M1 polarization of microglia while promoting their polarization toward the M2 phenotype. Furthermore, the mechanism underlying the anti-inflammatory effects of Ca-RA NPs on microglia is closely associated with the inhibition of mitogen-activated protein kinase and NF-κB signaling pathways. Notably, cell co-culture experiments revealed that Ca-RA NPs mediated immune microenvironment can indirectly promote neuronal differentiation of neural stem cells (NSCs) by selectively modulating microglial M1/M2 polarization. In vivo experimental results further demonstrated that Ca-RA NPs can not only alleviate the local inflammatory microenvironment but also promote the neuronal differentiation of endogenous NSCs to repair damaged neurons, thereby improving the behavioral functions of LPS-induced neuroinflammatory mice. These findings highlight the potential of Ca-RA NPs as a promising therapeutic approach for neuroinflammation by targeting microglia.

Lysosomal entrapment is a formidable bottleneck for the delivery of clustered regularly interspaced short palindromic repeat/CRISPR-associated protein (CRISPR/Cas9) gene editing systems. To address this, we developed a nanoneedle platform that are self-assembled by CRISPR/Cas9 encoding plasmids, triggered by existent cellular metabolic metal ions in tumor cells, leading to lysosomal disruption for effective gene delivery. Based on this, a CRISPR/Cas9 plasmid delivery system termed PlaMnB, was further developed by encapsulation of CRISPR/Cas9-expressing Plasmid and MnO₂ in a Bacterial cell membrane system derived from genetically engineered Escherichia coli that are transformed by tumor-homing-peptide (THP) genes for tumor targeting and vascular permeation. Once targeted delivered to tumors by the bacterial membrane vehicles decorated by THP, PlaMnB releases manganese ion in the acidic and glutathione-enriching environment in tumors, leading to the formation of metal plasmid coordination nanoneedles and enhanced lysosomal escape. In addition, a tumor-specific promoter, telomerase reverse transcriptase was integrated in the CRISPR/Cas9 plasmid, allowing it to exclusively express Cas9 and sgRNA in tumors, but not in normal cells. The integrated rational design of different functional modules in the PlaMnB achieved an efficient and precise intracellular delivery of CRISPR/Cas9 for enhanced vascular permeation, effective lysosomal escape, and minimal off-target of gene editing.

Diabetic wounds affect millions of people globally, posing significant clinical and socioeconomic challenges due to their prolonged healing times and risk of complications. This review provides a comprehensive examination of the pathophysiology underlying delayed wound healing in patients with diabetes, focusing on key mechanisms such as hyperglycemia, oxidative stress, vascular insufficiency, and chronic inflammation. Impairments in angiogenesis, growth factor signaling, and tissue regeneration create a complex therapeutic landscape that demands multifaceted approaches. Accordingly, this review critically examines current clinical interventions such as topical growth factors, antioxidant therapies, and hyperbaric oxygen. Furthermore, it explores innovative solutions, such as advanced wound dressings, bioengineered materials, and stem cell therapy, which offer enhanced wound healing outcomes. We provided a comprehensive analysis of innovative platforms, such as nanoparticle-loaded hydrogels and 3D printing, shedding light on their transformative potential to revolutionize wound care through personalized multifunctional therapies. This review concludes by identifying critical gaps and proposing a roadmap for future research and clinical innovations to enhance diabetic wound management and improve patient outcomes.

Patients with large-area bone defects are highly prone to infection, which significantly hinders healing. This study presents an innovative strategy that combines exogenous physical signals with implantable materials to achieve programmed immune modulation by dynamically regulating macrophage M1/M2 polarization, striking a balance between antibacterial activity and bone regeneration. Specifically, we synthesized HAp@MXene nanocomposites by integrating hydroxyapatite nanorods with MXene nanosheets, resulting in multifunctional materials with unique magnetoelectric properties and controlled Ca²⁺ release. These nanocomposites exert their effects through cellular internalization, where magnetoelectric induction generates intracellular currents to promote macrophage M1 polarization, initiating a pro-inflammatory response to mitigate infection risk. Subsequently, calcium ions are released within lysosomes, driving macrophage M2 polarization to facilitate anti-inflammatory response and promote tissue regeneration. This dual-modality mechanism achieves the precise programmatic regulation of macrophages, accelerates and optimizes the process of bone defect repair, and underscores the immense potential of HAp@MXene nanocomposites in synergistic antibacterial and bone regeneration therapies.

The detection of antibiotic residues in environmental water sources represents a critical ecological challenge with significant implications for public health. Conventional immunoassays for antibiotics often suffer from limitations in sensitivity and efficiency, primarily due to the lack of high-performance detection antibodies and the complexity of current operational procedures. In this study, we introduce a novel approach by bioengineering a florfenicol (FF) and thiamphenicol (THF) bispecific rabbit monoclonal antibody (rmAb) for the first time, which has been integrated into an automated microfluidic biosensor. This innovative biosensor employs an AuPtCu@HRP-hapten composite nanozyme-bioenzyme, demonstrating exceptional peroxidase-mimic catalytic activity. The automated immunosensor operates within a single microfluidic chip, enhancing both the simplicity and efficiency of the detection process. The rmAbs are non-destructively immobilized on protein A-functionalized agarose microspheres, serving as effective immunoreactive carriers. By introducing a smartphone sensing strategy, our biosensor achieved the detection of FF and THF residues in river water at remarkably low concentrations of 0.014 and 0.015 ng/mL within just 30 min, respectively. The method exhibits average recoveries between 96.58% and 104.50%, with standard deviations consistently below 5.34%. This sensing strategy not only significantly reduces detection time compared to traditional direct competitive immunoassays but also enhances sensitivity and accuracy. This user-friendly biosensor represents a promising advancement in antibiotic detection technology, making it well-suited for on-site applications and paving the way for future development of robust antibiotic sensing platforms.

Early, non-invasive detection of esophageal cancer at sub-millimeter resolution is critical for tailoring precise therapeutic strategies. While ultra-high-field (UHF) magnetic resonance imaging (MRI) offers exceptional spatial resolution, the lack of optimized contrast agents capable of enhancing sensitivity for detecting microscopic tumors remains a significant challenge. Here, we report a cyclo-RGD peptide-conjugated antiferromagnetic nanoparticle (RANP) as a novel targeted T1 contrast agent, specifically designed to improve in vivo imaging of esophageal tumors at the micrometer scale. The RANP integrates an antiferromagnetic core with low magnetization, minimizing T2 decaying effects, while the cyclo-RGD peptide enhances its targeting ability by specifically binding to integrin α_vβ₃, a biomarker highly expressed on tumor vasculature. This targeted conjugation improves the probe's selective accumulation at the tumor site and facilitates superior T1 relaxation of water protons. Under 9 T MRI conditions, the RANP exhibits an r1 value of 1.88 mM⁻¹ s⁻¹ and a low r2/r1 ratio of 1.84, enabling the detection of primary esophageal tumors as small as 0.8 mm. This study significantly advances the sensitivity of current imaging techniques, pushing the detection limit of in vivo esophageal cancer diagnosis into the sub-millimeter range. Our results demonstrate the promising potential of RANP-enhanced UHF MRI for early detection, monitoring, and therapeutic intervention in esophageal cancer, offering a powerful tool for more effective clinical management.

The intrinsic scarcity of bioactive groups in bacterial cellulose (BC), which is characterized by its nanofiber network structure and superior physicochemical properties, limits its application predominantly to physical wound care. This limitation renders it inadequate for effectively addressing the intricate microenvironment associated with chronic wounds, including diabetic ulcers. Hence, a copper-doped borosilicate bioactive glass (BBG) coating was successfully fabricated on the nanofiber surface of BC by the sol-gel synthesis and hydrolysis reaction, resulting in a functional dressing termed copper-doped BBG-modified BC (Cu²⁺@BBG/BC). The characterization results showed that the Cu²⁺@BBG coating was successfully deposited onto the BC fibers. At the same time, the nanoporous network structure of BC was retained, as well as high porosity and rapid water absorption rate. Furthermore, the incorporation of the Cu²⁺@BBG coating improved the mechanical properties of the BC-based composite. Notably, ions from the Cu²⁺@BBG coating could release continuously for 48 h in a PBS solution at 37°C, which indicated that the stability of the Cu²⁺@BBG coating can meet clinical needs. Importantly, the Cu²⁺@BBG coating conferred the modified BC with excellent antibacterial properties, anti-inflammatory activities, cytocompatibility and angiogenic potential. In vivo results further demonstrated that Cu²⁺@BBG/BC-0.38 dressing, with an optimal copper content, could effectively inhibit MRSA-induced infection, mitigate the inflammatory response, enhance collagen deposition and angiogenesis, and accelerate wound healing. These findings illustrate that the developed Cu²⁺@BBG/BC-0.38 dressing holds significant promise for clinical applications and provides an innovative strategy for modifying BC nanofiber surfaces.

Mild photothermal therapy (MPTT) has emerged as a promising approach for cancer treatment. However, the rapid overexpression of heat shock proteins (HSPs) in cancer cells reduces its therapeutic efficacy. While strategies to suppress HSP expression or induce alternative cell death mechanisms, such as ferroptosis, show potential, overall outcomes remain suboptimal. In this study, we propose a triad material comprising defect-engineered single-site catalysts (DMOF), sodium nitroprusside, and HSP-targeting siRNA. Upon light exposure, this DMOF-SNP-siRNA (DSS) catalyst efficiently generates reactive species, suppresses HSP expression, and depletes intracellular glutathione, thereby inducing strong apoptotic and ferroptotic responses simultaneously. Compared to a defect-free metal-organic frameworks catalyst, the DSS single-site catalyst demonstrates significantly enhanced photothermal and catalytic properties, leading to remarkable tumor-killing capability while minimizing systemic toxicity. Notably, in a subcutaneously grafted tumor model, 60% of treated mice achieved complete remission after just two treatment sessions. Our findings establish a pioneering approach in the design of high-performance triad materials for advanced MPTT applications.

Electrical excitability, long regarded as a defining property of neurons, is now increasingly recognized in cancer cells, particularly within phenotypically heterogeneous tumor subpopulations. A recent Nature study revealed that the neuroendocrine (NE) subpopulation of small cell lung cancer exhibits neuron-like excitability, capable of generating action potentials and forming intercellular signaling networks that enhance malignancy and metastasis. This discovery highlights how electrical excitability can arise in cancer cells through metabolic reprogramming and dynamic interactions within the tumor microenvironment. Moreover, heterogeneous tumor subpopulations may cooperate to sustain excitability via metabolic coupling. These findings challenge conventional views of tumor biology, establishing a new paradigm in which cancer heterogeneity drives electrophysiological diversity and functional plasticity, fundamentally reshaping our understanding of tumor behavior, communication, and progression.