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.
Abstract Clinical stage‐adaptive treatment strategies for infected wounds face temporal challenges due to the varying demands for antibacterial, anti‐inflammatory and anti‐scarring effects during different stages of healing. In this study, a core‐shell microneedle (MN) patch with spatiotemporally programmed release was developed through controlled degradation, reactive oxygen species (ROS) and pH response, termed VP@FNV‐CuO 2 ‐MN. In the mildly acidic microenvironment of early‐stage infected wounds, the moderately crosslinkedboronic ester‐based shell loaded with nano‐copper peroxide (n‐CuO 2 ) was released first, triggering a Fenton‐like reaction that produced antibacterial ROS and pro‐angiogenic Cu 2+ ions. Concurrently, the boronic ester bonds of MN could adaptively neutralize the liberated ROS, thereby preventing excessive oxidative stress. The core of MN was structured with a highly‐crosslinked hydrogel and encapsulated fibroblast‐derived exosome‐mimetic nanovesicles (FNV) loaded with verteporfin (VP@FNV), which ensured targeted suppression of the YAP/En1 signaling pathway in fibroblasts during the late stage of wound healing. Evaluations in Sprague‐Dawley (SD) rat full‐thickness infected wound models and rabbit ear hypertrophic scar models demonstrated accelerated wound healing and scarless regeneration. These findings confirm that VP@FNV‐CuO 2 ‐MN facilitates stage‐adaptive modulation of antibacterial, inflammation resolution, angiogenesis, and extracellular matrix remodeling, offering an innovative solution for scarless healing of infected wounds.
Abstract The dynamic interplay between intratumoral bacteria and cancer progression has unveiled new avenues for precision oncology, positioning bacteria as versatile, programmable platforms for targeted therapy. This review systematically explores the dual roles of tumor‐associated microbiota‐both promoting and suppressing malignancy‐and highlights the transformative potential of engineered bacterial systems in cancer treatment. Capitalizing on their innate tropism for hypoxic tumor cores, bacteria serve as self‐propelled, living drug carriers capable of localized delivery of cytotoxic agents, immunomodulators, and prodrug‐converting enzymes. Advances in synthetic biology and nano‐biohybrid designs have further enabled the development of intelligent bacterial vectors that respond to tumor‐specific signals, thereby minimizing off‐target effects and enhancing therapeutic precision. We discuss innovative strategies in which bacteria are harnessed to remodel the immunosuppressive tumor microenvironment (TME), potentiate immune checkpoint therapies, and synergize with conventional modalities such as chemotherapy, radiotherapy, and photodynamic therapy. Emphasis is placed on bacterial‐derived components‐including outer membrane vesicles, spores, and metabolites‐that can be functionally repurposed for cancer immunotherapy and targeted drug delivery. Furthermore, we examine ongoing clinical trials that underscore the translational feasibility of bacterial therapeutics, while also addressing persistent challenges in safety, biocontainment, and manufacturing scalability. Looking forward, we envision a new paradigm in which engineered bacteria, integrated with real‐time imaging and personalized microbiome profiling, evolve from experimental tools into clinically deployable “living medicines.” By bridging synthetic biology, immunology, and materials science, bacteria‐based platforms offer a promising frontier for achieving potent, specific, and adaptable cancer therapies.
Abstract As a natural endogenous bioreactor, the dynamic microenvironment of blood clots holds significant and underappreciated potential for tissue regeneration. This review systematically delineates the clot's core pathophysiology, including its fibrin network, diverse bioactive molecules, and cellular components, along with the key regulatory factors that shape its microenvironment. This paper further clarifies the differential regulatory mechanisms of blood clots in tissue regeneration, which vary across different tissue repair processes and are influenced by various pathological conditions such as inflammation. In clinical translation, autologous blood clots and their derivatives have shown promising results in skin healing, regenerative endodontics, and bone repair. Yet, challenges like insufficient mechanical strength and variable individual efficacy persist. Concurrently, the development of biomimetic materials that mimic fibrin's topology and integrate sequential growth factor release demonstrates enhanced hemostatic and osteogenic capabilities. By analyzing these advances, this review positions the blood clot as a novel paradigm to guide future biomaterial design, offering innovative solutions for complex tissue engineering and repairs.
Abstract Neurovascular interaction plays a central role in bone development, repair and regeneration. The coordinated activity between nerves and blood vessels not only ensures the delivery of oxygen, nutrients, and regulatory signals but also modulates skeletal cell behavior and immune responses. However, traditional therapeutic strategies, such as autografts and allografts, and synthetic scaffolds often fail to replicate the native neurovascular microenvironment, limiting their regenerative efficacy. This review outlines the regulatory mechanisms of neurovascular coupling in bone regeneration. Neural inputs, mediated through neurotrophic factors and neurotransmitters, regulate bone homeostasis by influencing the activity of osteoblasts and osteoclasts, while vascular networks supply essential oxygen and nutrients to support bone maintenance and repair. We then summarize recent advances in neurovascularized biomaterials, including neurotrophic factor‐loaded scaffolds, electroconductive composites, ion‐releasing ceramics, and endogenous electroactive materials, which enable synchronous neural, vascular, and osteogenic regeneration. In addition to functional materials, cell‐ and molecule‐based approaches further enhance neurovascularized bone repair. Together, these strategies represent a shift from passive fillers to multifunctional scaffolds capable of fulfilling complex repair processes. This review aims to bridge mechanistic understanding with material design, offering insights for next‐generation bone tissue engineering.
Abstract Organ‐on‐a‐chip (OoC) is a promising technology that can be used to investigate tissue formation, organ function, and disease etiology as well as an in vitro test platform for evaluating drug and radiation efficacies along with their side effects. The OoC technology provides substantial advantages like the ability to precisely control cellular processes in microenvironments for extended periods and the ease of applying a diffusion gradient to improve pharmacokinetics and pharmacodynamics. As a precursor to personalized medicine, the OoC systems are expected to serve as a milestone technology, especially after the United States Food and Drug Administration Modernization Act 2.0, and more recently, 3.0. Of importance, the OoC platforms could be engineered to produce genetically identical or near‐identical tissue and organ models derived from an individuals' cells, enabling detailed studies of specific genetic and epigenetic phenotypes and better capturing interpersonal differences. To describe this conceptual extension, we introduce the term “clone‐on‐a‐chip (CoC)” as a conceptual warning and not to suggest technological feasibility; also referring not to whole‐organism cloning but to the replication of patient‐specific biological profiles in vitro for personalized therapeutics development and testing. This approach holds unique potential for tailoring therapeutic strategies; however, future projections may present new ethical dilemmas. A CoC ethical discussion extends beyond issues arising from the requirements for informed consent, property rights, commercialization efforts, and cell sourcing to include potentially controversial applications and societal concerns.
Abstract Ferroptosis is an iron‐dependent form of regulated cell death driven by lipid peroxidation, characterized by distinct ultrastructural alterations such as mitochondrial shrinkage and disruption of cristae. As an emerging therapeutic target in oncology, ferroptosis opens new therapeutic perspectives for a range of diseases, including cancer. Recent studies have demonstrated that ferroptosis induction exhibits superior efficacy in tumor regulation compared to certain conventional treatment modalities. However, the process of ferroptosis is intricately regulated by multiple signaling pathways involving iron metabolism, lipid metabolism, and disturbances in redox homeostasis, thereby limiting the effectiveness of single‐induction strategies. With advances in nanotechnology, a variety of nanomaterials have been engineered to induce ferroptosis through multi‐level regulatory systems or to serve as delivery vehicles for small‐molecule agents, significantly enhancing targeting capability toward tumor tissues. This review systematically summarizes recent advances in the molecular mechanisms, regulatory networks, pathological roles, small‐molecule inducers, and nanocarrier‐based targeted therapeutic strategies related to ferroptosis. It should be noted that, as a rapidly evolving research field, the application of ferroptosis in cancer therapy remains at an early stage. This article further discusses key challenges and future directions for its translation into clinical precision therapies, and concludes with critical scientific questions that demand urgent investigation in future research.
Abstract Cancer stem cells (CSCs) represent a highly plastic therapy‐resistant tumor subpopulation that drives therapy resistance, disease recurrence, and metastasis. This review critically evaluates how nanotechnology‐based strategies are gaining traction in addressing key biological and translational barriers associated with CSC targeting in the context of precision oncology. On the diagnostic frontiers, nanoplatforms enable CSC detection through biomarker‐assisted and ‐independent functional imaging approaches, as well as liquid biopsy modalities that capture CSC‐associated circulating tumor cells, circulating tumor DNA (ctDNA), and extracellular vesicles, thereby supporting non‐invasive disease stratification and monitoring. Across therapeutic modalities, nanotechnology‐assisted delivery of mono‐ and combination chemo‐, radio‐, targeted, photothermal, photodynamic and sonodynamic therapies effectively sensitizes CSCs and eliminate them by enhancing intratumoral drug accumulation. Niche‐focused nanostrategies harness stimuli‐responsive activation of nanoparticles tailored to CSC‐associated microenvironmental cues, and modulate hypoxia, redox balance, metabolic plasticity, and stemness signaling as central mechanisms for disrupting CSC maintenance. Nanotechnology‐assisted immunotherapies, including checkpoint‐directed delivery, immune modulation, nano‐vaccines, and engineered cell strategies, represent emerging approaches to reprogram CSC‐immune interactions and enhance anti‐tumor immune responses. Nanoparticle physicochemical properties, pharmacokinetics, biodistribution, and immune interactions are critical parameters that govern their therapeutic efficacy and safety. Importantly, despite strong preclinical success, the clinical translation of nanotherapeutics remains constrained by limitations of preclinical models, regulatory hurdles, manufacturing complexity, and cost‐ineffectiveness. Overall, the evidence supports the view that rational, biomarker‐informed nanoplatform design, integrated with patient‐specific tumor features, represents a viable path toward precision CSC‐targeted therapies with improved clinical responses and durable cancer control.
Abstract Copper, a classical antibacterial metal, has long been of interest and widely used in medical and public health applications. Recent findings that copper can induce programmed cell death (cuproptosis) not only in eukaryotes but also in bacteria (cuproptosis‐like death) provide a unique perspective for the development of novel antibacterial strategies. On the basis of these findings, current research is actively exploring various strategies to enhance the effects of cuproptosis‐like death, thereby improving its antibacterial efficacy. In this review, we highlight current strategies to enhance cuproptosis‐like death and potential strategies for its development, including aspects of copper transporter protein regulation, exogenous copper ion uptake, the application of nanotechnology, and combination therapy. In addition, we discuss the differences between cuproptosis‐like death and cuproptosis in terms of key events, such as copper homeostasis regulation, lipoylated protein aggregation and iron‒sulfur cluster disruption. Finally, we introduce the limitations and challenges that enhanced bacterial cuproptosis‐like death may face in future studies, which will help to deepen our understanding of the mechanisms of enhanced cuproptosis‐like death.
Abstract Over the past decades, managing tendon disorders has remained a great clinical challenge. Due to the limited endogenous healing ability of tendons, current clinical approaches often result in unsatisfactory repair. Therapies based on mesenchymal stem cells (MSCs) are promising for treating various tendon disorders; however, recent clinical trials have shown that the therapeutic benefits of exogenous MSC transplantation are still unsatisfactory. Alternatively, harnessing endogenous tendon stem/progenitor cells (TSPCs) has emerged as a promising strategy to initiate tenogenesis and restore tendon homeostasis, which can overcome the limitations of exogenous MSCs transplantation, such as low utilization rate, uncontrollable cell fate, and high costs. Meanwhile, efforts in decoding heterogeneity of TSPCs, advances in material science, and regenerative medicine have enabled precise modulation of the TSPC niche and cellular responses through the tailored design of biomaterials. Biomaterials with tailored properties, such as hydrogels, scaffolds and decellularized tendon matrix, can provide physical or chemical cues that activate endogenous TSPCs for regeneration. Moreover, drug delivery systems mediated by biomaterials like nanoparticles, hydrogels, and microneedles can directly or indirectly promote tenogenic potential of TSPCs. This review provides an updated overview of the specific markers and functions associated with various TSPC subpopulations, highlighting their roles in tendon physiology and pathology. Additionally, we summarize current biomaterial‐based strategies for modulating cellular responses of endogenous TSPCs, including activating normal tenogenic potential, inhibiting pathological differentiation, senescence and apoptosis, and improving the TSPC niche. Lastly, we present future perspectives that emphasize the need for a more comprehensive understanding and targeted modulation of TSPCs and their microenvironment. In summary, this review provides key insights into the rational design of next‐generation biomaterials aimed at TSPC modulation with the ultimate goal of advancing clinical therapies for tendon disorders.
Abstract Acute kidney injury (AKI) remains a life‐threatening condition due to the lack of tools for early‐stage detection and effective treatment. Herein, we report a fucoside‐targeted gold nanocluster‐based theranostic probe (Au 44 MBA 26 ‐Fuc NCs) that integrates near‐infrared‐II photoluminescence (NIR‐II PL) imaging with multi‐mechanistic therapy for AKI. Leveraging its strong NIR‐II emission, the probe enables non‐invasive, real‐time visualization of injured kidneys within 3 min after intravenous injection in mice. Furthermore, the probe exerts potent therapeutic effects against AKI through its multi‐enzyme‐mimetic activities, including NADH oxidase, superoxide dismutase (SOD), and glutathione peroxidase (GPx), which collectively mitigate oxidative stress, regulate inflammation via macrophage polarization, and inhibit ferroptosis by upregulating glutathione peroxidase 4 (GPX4) and restoring mitochondrial function. Transcriptomics reveal that these effects are mediated through regulation of the ferroptosis/MAPK and FoxO pathways, enhancing ferroptosis resistance and antioxidant defense. The probe also demonstrates favorable biosafety and renal clearance. This work offers a targeted theranostic strategy for precise AKI management and advances the development of metal NCs‐based platforms for oxidative‐stress‐related diseases.
Abstract Organic field‐effect transistor (OFET)‐based biosensors are promising for wearable technology due to their good flexibility and low‐cost fabrication. However, their susceptibility to signal drift from mechanical stress and environmental factors like temperature has been a major limitation. In this Commentary, we highlight a novel strategy that fundamentally redesigns the OFET biosensing circuit to eliminate the drifts.
Abstract Spinal cord injury (SCI) leads to high rates of central nervous system impairment and imposes a significant treatment burden, highlighting the need for effective repair strategies. Bioscaffolds are considered to be multifunctional materials composed of bioactive polymers and signaling molecules, showing potential comparable to tissue engineering approaches utilizing exogenous stem cells. These bioscaffolds, which act as biological frameworks, can modulate intrinsic neuronal regeneration and the external microenvironment to facilitate SCI repair. This review explores the current status and future prospects of three‐dimensional bioscaffolds for SCI repair, covering the pathophysiology of spinal cord injury, associated repair mechanisms, and key bioscaffold properties influencing repair efficiency. Notably, the review highlights new insights into the use of therapeutic bioscaffolds to promote endogenous stem cell differentiation, enhance axon growth, regulate the injury microenvironment, and support SCI repair. Finally, expert opinions are discussed, summarizing design principles for effective SCI‐repair bioscaffolds and underscoring their significant potential for clinical applications.
Abstract Liposomes have emerged as the most clinically successful nanocarriers with good biocompatibility, low immunogenicity, and facile modification potential. However, their widespread application is limited by challenges associated with suboptimal drug release kinetics and poor bioavailability under complex physiological conditions. These limitations stem from the dual paradox of maintaining circulatory stability while enabling rapid drug release at target sites. Engineering of stimulus‐responsive liposomal systems has been identified as a promising strategy for mitigating these biomedical delivery challenges. Such systems are designed to achieve spatiotemporally controlled drug release and nanomedicine in response to specific endogenous or exogenous stimulus, thereby enhancing therapeutic efficacy while minimizing systemic toxicity. A comprehensive understanding of the design principles and release mechanisms governing stimulus‐responsive liposomes is essential for the rational development of advanced drug delivery systems. Therefore, this review systematically examines the design strategies for precise, stimulus‐triggered drug release through a detailed analysis of the effects of liposome structure and composition on drug release, with particular emphasis on lipid component engineering for controlled release. Furthermore, it explores functionalization strategies, focusing on chemical modification approaches for stimulus‐responsive behavior. The component‐responsive design and functional modification strategies discussed herein provide a systematic framework for liposome research. Meanwhile, the fundamental understanding of stimulus‐responsive liposomes is significantly advanced, thereby facilitating the development of more efficient and precise drug delivery and nanomedicine.
Abstract Fiber‐type soft bioelectronics are revolutionizing wearable and implantable healthcare technologies by addressing critical clinical challenges, particularly minimizing the mismatch in mechanical stiffness between bioelectronics and biological tissues. These devices can seamlessly integrate with dynamic in vivo environments. Their inherent mechanical flexibility and structural adaptability enable applications in both confined sensitive regions and expansive highly mobile areas of the body. Beyond adaptability, fiber‐type soft bioelectronics offer multifunctionality, enabling real‐time biological signal acquisition, targeted drug delivery, and localized electrical stimulation. Moreover, fabric‐based designs offer excellent conformability, making them suitable for long‐term monitoring of physical, electrochemical, and electrophysiological signals. This article presents a comprehensive review on fiber‐type soft bioelectronics technologies, with a focus on their wearable and implantable applications in healthcare. First, the fundamental requirements for these devices are outlined, describing the foundation for their design and functional integration. Technological advancements that fulfill those requirements are described based on actual examples. The review also examines the materials used for the fibers, highlighting their mechanical, electrical, and biocompatible properties. Next, strategies for fiber fabrication are discussed, including methods for transforming fibers into fabrics. Finally, recent breakthroughs in the applications of fiber‐ and fabric‐type soft bioelectronics in health monitoring and therapeutic interventions are explored.
Gouty tophi, driven by hyperuricemia, bacterial infection, and excessive inflammation, are highly susceptible to rupture, while current therapies fail to simultaneously address these factors, often leading to chronic non-healing wounds and increased amputation risk. Herein, guided by the pathological features of the gout wound microenvironment, we developed a multifunctional nanoplatform by co-loading uricase (Uri) and catalytic carbon dots (CDs) onto highly adhesive polydopamine (PDA) nanoparticles. The resulting CDs-Uri@PDA integrates uric acid (UA) degradation, antibacterial action, and inflammation modulation into a unified three-in-one system. Under hyperuricemic conditions, Uri catalyzes UA decomposition to generate localized antibacterial H2O2 at the early stage, while the polyphenolic groups of PDA synergistically enhance the overall antibacterial efficacy and the adhesive matrix protects wounds from external contamination. Subsequently, CDs selectively eliminate residual H2O2 and excessive reactive oxygen species during the inflammatory phase, suppressing inflammatory signaling and promoting wound repair. Through this cascade of stage-dependent dual-catalytic regulation, CDs-Uri@PDA enables sequential therapy of gout wound ulcers and accelerates healing, offering a promising strategy to improve uricase-based treatments and advance clinical management of gout wounds.
Sonodynamic therapy (SDT) using inorganic sonosensitizers provides precise, noninvasive treatment for skin fungal infections (SFIs) due to deep tissue penetration and biocompatibility. However, their application is limited by inherent-wide bandgap, poor oxygen adsorption, and rapid charge recombination. Herein, we develop an iron nitride/cerium oxide (Fe2N/CeO2) narrow-bandgap Schottky heterojunction sonosensitizer embedded in microneedle (MN) patches (MN@Fe2N/CeO2) for SFIs treatment. Theoretical and experimental studies have confirmed that fast electron transfer from metallic Fe2N to semiconductor CeO2 drastically reduces the bandgap, boosts oxygen adsorption, and leads to a robust reactive oxygen species storm. Ultrasound-induced MN@Fe2N/CeO2 exhibits superior antifungal efficacy 1.50-fold higher than that of ketoconazole cream in vivo with biocompatibility and no drug resistance. Transcriptome sequencing reveals that Candida albicans is eradicated through multiple pathways, including antioxidant stress. This study pioneers high-performance SDT by integrating an advanced heterojunction design with practical MN delivery to enhance SFI treatment.
The therapeutic potential of nanozyme-mediated chemodynamic therapy (CDT) is often hindered by limited catalytic efficiency and undesirable off-target effects. To address these limitations, we engineered a cancer cell membrane-coated Au-MnOx nanozyme (Au-MnOx@CCM) engineered for near-infrared (NIR) enhanced tumor CDT. This multifunctional nanozyme exhibits both catalase-like (CAT-like) and peroxidase-like (POD-like) activities, enabling the in situ generation of oxygen (O2) to alleviate tumor hypoxia and facilitate the production of cytotoxic hydroxyl radicals (center dot OH) for selective tumor cell eradication. Concurrently, the Au-MnOx nanozyme effectively depletes intracellular glutathione (GSH), thereby amplifying oxidative stress and enhancing CDT efficacy. The biomimetic coating with homologous the cancer cell membrane (CCM) significantly improves tumor-targeting specificity, reduces off-target accumulation, prolongs systemic circulation, and minimizes immune clearance. Moreover, the application of NIR irradiation enables deep tissue penetration and precise spatial activation of the nanozyme at the tumor site, further enhancing therapeutic selectivity and potency. Collectively, this well-designed Au-MnOx@CCM nanozyme integrates CDT and photothermal therapy (PTT), offering a synergistic, tumor-specific, and minimally invasive therapeutic strategy. This platform holds considerable promise for advancing precision oncology with improved therapeutic outcomes and reduced systemic toxicity.
Synergistic radiotherapy-immunotherapy in glioblastoma (GBM) faces dual tumor resistance mediated by enhanced DNA damage repair and programmed cell death-ligand 1 (PD-L1) upregulation. Herein, we engineer a glycosylated dendrimer nanoamplifier (Gal-G5(Au)-DMC) that hijacks the DNA damage-immune crosstalk for enhanced radiotherapy-immunotherapy of orthotopic GBM. The Gal-G5(Au)-DMC was constructed by modifying demethylcantharidin (DMC) to glycosylated fifth-generation (G5) polyamidoamine dendrimers pre-encapsulated with 2.0 nm gold nanoparticles (Au NPs). The modification with DMC enhanced the stability of Gal-G5(Au)-DMC in the systemic circulation, while the galactose ensured its optimal blood-brain barrier penetration and tumor accumulation. In the tumor microenvironment, the pH-responsive release of DMC amplifies Au NPs-mediated radiosensitization via DNA repair suppression and reverses immunosuppression by reducing the protein phosphatase 2A activity of T cell population. When combined with anti-PD-L1 antibody, the synergy between radiosensitization-induced immunogenic cell death and DMC-driven immunomodulation increased the proportion of cytotoxic and regulatory T cell populations, achieving a 50% long-term survival rate in orthotopic GBM models even at day 50-twice the efficacy of conventional radio-immunotherapy. This nanoamplifier intervene in the interaction between DNA damage and the immune system, blocking repair-mediated resistance while converting radiation-induced stress signals into sustained anti-tumor immunity. Synchronizing these dual tracks yields a clinically actionable paradigm for GBM therapy.
