Apoptotic extracellular vesicles (ApoEVs) are important mediators of intercellular communication in a broad spectrum of physiological and pathological processes, playing a central role in immunomodulation and the maintenance of cellular homeostasis. However, the exact function and fundamental mechanisms underlying tendon stem/progenitor cell (TSPC)-derived apoEVs in tendinopathy remain elusive. Here, we demonstrated that TSPC-apoEVs enhance macrophage efferocytosis and promote anti-inflammatory M2 polarization by activating the PPAR-γ coactivator 1α-nuclear respiratory factor 1-mitochondrial transcription factor A signaling, thereby restoring mitochondrial homeostasis and suppressing oxidative stress under inflammatory conditions. To optimize local delivery, we engineered porous gelatin microspheres to load apoEVs (GM@ApoEVs), which combined the immunomodulatory effects of apoEVs with the sustained-release properties of microspheres. Notably, GM@ApoEVs also regulated the lineage differentiation of TSPCs, promoting tenogenic differentiation and suppressing aberrant osteochondral fates. In a rat model of Achilles tendinopathy established via collagenase induction, GM@ApoEVs injection markedly improved tendon regeneration, as evidenced by aligned collagen matrix, reduced inflammatory infiltration, and diminished heterotopic ossification. Our findings revealed that TSPC-apoEVs, especially delivered by gelatin microspheres, represent a promising bioactive strategy for immunomodulation and tendon repair in tendinopathy.
Chronic wounds resulting from burns, infections, and/or diabetes represent a significant clinical challenge due to impaired healing processes, which can lead to severe complications and even amputation. Growth factors (GFs) play crucial roles in all stages of wound healing. However, their therapeutic efficacy is compromised by rapid proteolytic degradation within the wound microenvironment, while excessive concentrations can induce detrimental side effects. Hydrogels, with their three-dimensional network structure, serve as an ideal carrier for GF delivery, protecting bioactivity and enabling controlled release. This review first summarizes the key roles of different GFs in wound healing. It then focuses on hydrogel-based GF loading strategies (noncovalent and covalent binding) and the integration of stimuli-responsive mechanisms for on-demand spatiotemporal release. Additionally, the potential of synergistic therapy combining drugs or scaffold materials with hydrogel-GF systems is discussed. Finally, the application prospects of this technology in other regenerative fields are explored.
Microplastics can traverse human physiological barriers, infiltrate and accumulate in critical organs and tissues (e.g., brain, blood, and heart) over extended periods, posing significant threats to human health. While microplastic degradation in aquatic environments (e.g., contaminated water) has been extensively studied, research on bloodstream microplastic degradation remains largely unexplored, leaving a critical gap in remediation strategies. To fill this gap, we pioneered the fabrication of biocompatible magnetically driven Fe 3 O 4 @polydopamine (PDA)-lipase microrobots by functionalizing Fe 3 O 4 nanoparticles with PDA and lipase for blood-borne microplastic degradation. In vitro blood experiments confirmed that this platform holds promise for future detoxification of circulating microplastics. The microrobots integrate synergistic functions: Fe 3 O 4 enables magnetic responsiveness for precise movement control; PDA provides adhesive properties for robust microplastic binding; and lipase mediates enzymatic microplastic degradation. Guided by an external rotating magnetic field, the microrobots achieve targeted microplastic capture and in situ enzymatic degradation in blood without releasing harmful substances, addressing a pivotal safety concern for biomedical applications. Performance evaluations showed ~25% microplastic degradation efficiency in blood after 7 days of incubation. Additionally, the microrobots can be effectively recycled via magnetic separation postdegradation, reducing residuals and improving practicality. Hemolysis assays using rabbit blood and toxicity evaluations using human umbilical vein endothelial cells and immunofluorescence experiments confirmed their excellent biocompatibility and immunogenicity, an indispensable prerequisite for potential in vivo translation. As a proof-of-concept study, this work provides a promising biocompatible approach for blood microplastic degradation and clearance, simultaneously overcoming the technical challenge of blood-specific targeted degradation and meeting safety requirements, thus laying a foundation for microrobot-based mitigation of microplastic health hazards.
As one of the most malignant tumors, metastatic melanoma essentially requires the regulation of the lysosomal cation channel, transient receptor potential mucolipin channel 1 (TRPML1), which is also involved in the participation of various ions especially zinc ions. This perfectly aligns with the advanced therapeutic approach based on nanomaterials, because nanomaterials can easily integrate multiple metal elements to disrupt the internal homeostasis of various ions, eventually inhibiting the cell growth of metastatic melanoma. Hence, based on our previously proposed metalloposis strategy, herein, zinc gallate-based nanoclusters (ZGOCs) containing both zinc and gallium were developed, capable of inducing metalloposis. Responded to weakly-acid tumor microenvironment (TME), ZGOCs could effectively release gallium ions that triggered ferroptosis through depleting glutathione (GSH) and increasing lipid peroxidation (LPO) levels. Moreover, the released zinc ions co-treated with ML-SA5, a TRPML-specific agonist, further promoted lysozincrosis. In addition, ZGOCs exhibited rechargeable afterglow luminescence, which facilitated in vivo clearer diagnostic images with high contrast for more accurate detection of tumor boundaries. Collectively, ZGOCs in combination with ML-SA5 significantly suppressed tumor growth with favorable biosafety, providing a promising metalloptosis-based strategy for the treatment of metastatic melanoma.
Skin wound healing remains a significant clinical challenge, with traditional therapies often facing issues such as infection and secondary trauma. Thermoelectric (TE) materials possess the unique ability to convert thermal energy into electrical energy. Electrical signals generated by these materials can accelerate skin wound healing by reconstructing endogenous electric fields, modulating the inflammatory microenvironment, and promoting angiogenesis. Despite their substantial potential, a comprehensive understanding of the mechanisms, biocompatibility, antimicrobial properties, and practical applications of TE materials in skin wound healing is still lacking. This review aims to highlight recent advancements in wound healing using TE materials, while integrating considerations of flexibility, biocompatibility, and antimicrobial performance to optimize TE device design. Strategies for enhancing thermoelectric performance, such as carrier concentration modulation, band engineering, and lattice thermal conductivity reduction, are discussed to balance conductivity and the Seebeck coefficient. Although challenges in biosafety and room-temperature performance regulation of inorganic materials persist, future developments in multimodal synergistic therapy, intelligent monitoring systems, and novel material design are expected to drive the clinical translation of TE materials for treating refractory wounds.
Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degradation, synovial inflammation, and abnormal subchondral bone remodeling. Current therapeutic approaches primarily alleviate OA symptoms rather than slow its progression, underscoring the unmet need for etiology-directed therapies. Specific silencing of disease-driving genes using siRNA-based technology has received attention as a potential treatment strategy for OA. Candidate siRNA targets in OA include proinflammatory cytokines, catabolic enzymes, and signaling pathways that collectively drive cartilage destruction and synovitis. This review provides an in-depth exploration of the pathological features of OA and current treatment strategies, along with a comprehensive overview of the potential therapeutic benefits and challenges in clinical application. Building on recent advances in siRNA-based therapeutic targets and delivery systems, there is a valid conceptual foundation for the future development of novel siRNA-based diagnostic and therapeutic strategies for OA. Contemporary high-resolution and high-throughput technologies, especially single-cell sequencing and organoid-based drug screening, also facilitate the transition of siRNA-based therapies from experimental frameworks to clinical applications, offering a promising paradigm shift in disease-modifying treatment for OA.
Postoperative metastatic recurrence and wound infection pose significant threats to survival after breast cancer surgery. To address these challenges, an ideal therapeutic strategy should incorporate minimally invasive multifunctional biomaterials capable of simultaneously preventing tumor recurrence and promoting wound healing. Herein, we report a novel two-stage microneedle (MN) platform engineered via the integration of nanotechnology and tumor-microenvironment-responsive design. This system is fabricated using a stepwise casting strategy and features tip-to-base architecture equipped with on-demand smart nanocarriers for synergistic therapy against postoperative breast cancer recurrence and wound complications. The MN consists of a photo-crosslinked hydrogel tip encapsulating chitosan-based self-assembled nanocarriers and a gelatin–polydopamine hydrogel backing layer. Owing to its hierarchical structural design, the MN exhibits excellent mechanical strength with a compression force of up to 4.48 N per needle, sufficient for efficient skin penetration. Moreover, the platform demonstrates sustained pH-responsive behavior and specific tumor microenvironment targeting, enabling controlled drug release. The MN also displays outstanding biocompatibility and multi-functional therapeutic properties, including antibacterial adhesion, self-healing capability, swelling performance, and biodegradability, greatly broadening its potential as a precision medicine tool. Both in vitro and in vivo studies validated the robust and integrated therapeutic efficacy of the MN system in suppressing metastatic breast cancer recurrence and enhancing infected wound healing. This work provides a significant advance in the design of smart two-stage MNs with comprehensive functionality for minimally invasive adjuvant therapy after breast cancer surgery.
Solid tumors are characterized by dense stroma, abnormal vasculature, persistent hypoxia, and an immunosuppressive microenvironment, all of which impede therapeutic penetration and limit treatment efficacy. While photodynamic therapy has shown promise in superficial lesions, its application in deep-seated tumors is restricted by poor photosensitizer accumulation and oxygen dependency. To overcome these barriers, we developed a photothermal nanozyme-mineralized Chlorella biohybrid via the in situ biomineralization of gold nanoparticles on the cell surface. The surface-mineralized gold nanoparticles serve a dual function: acting as a photothermal agent and possessing glucose oxidase-mimicking nanozyme activity. Under 808 nm irradiation, the biohybrid generates mild photothermal heating (42-43 °C), which triggers chlorophyll release, reduces cancer-associated fibroblasts, and softens the extracellular matrix to facilitate deep tumor infiltration. Concurrently, the nanozyme catalyzes the oxidation of intratumoral glucose to produce hydrogen peroxide. This self-supplied hydrogen peroxide fuels a hypoxia-tolerant photodynamic cascade where, upon subsequent 660 nm irradiation, the released chlorophyll reacts with hydrogen peroxide to amplify reactive oxygen species generation approximately threefold compared to chlorophyll alone. In three-dimensional tumor spheroids, this sequential irradiation strategy achieved deeper chlorophyll penetration and approximately 95% cell death. Furthermore, the biohybrid significantly suppressed tumor growth and prolonged survival in both subcutaneous and orthotopic colorectal cancer models compared with control groups. This work presents a bio-abiotic integration strategy that combines stromal remodeling, catalytic hydrogen peroxide generation, and light-responsive activation to significantly expand the therapeutic window of hypoxia-tolerant photodynamic therapy, offering a promising therapeutic strategy for deep-seated and refractory solid tumors.
Bacteria, with their inherent targeting capabilities and biocompatibility, are often limited by issues such as toxicity and environmental susceptibility, while nanozymes, despite their catalytic efficiency and stability, face selectivity and functional simplicity. Bacteria-nanozyme composites synergistically integrate the unique advantages of bacteria and nanozymes to address critical challenges in therapeutic applications. This review systematically explores the classification of bacteria and their derivatives involved in the preparation of nanocomposites, as well as the classification of nanozymes. It also summarizes the common methods and principles for preparing the composites. The applications and significant therapeutic effects of bacteria-nanozyme composites in the treatment of gastrointestinal diseases, cancer, and antibacterial therapy are emphasized. In addition, the application effects of composites in other medical fields are also mentioned. This review provides a comprehensive framework for advancing bacteria-nanozyme composites, bridging microbiology and nanotechnology to revolutionize precision medicine and sustainable healthcare solutions.
Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide, often progressing to heart failure due to inadequate tissue repair and adverse remodeling. Conventional therapeutic strategies, including pharmacological interventions and surgical procedures, exhibit limited efficacy in restoring cardiac function, highlighting the urgent need for innovative approaches. Hydrogel microneedles (MNs) have recently emerged as a groundbreaking technology for MI treatment, combining the advantages of minimally invasive delivery, targeted therapy, and multifunctional integration. Furthermore, the integration of therapeutic agents into hydrogel MNs enable sequentially controlled release within the infarcted myocardium, addressing key pathological processes such as oxidative stress, inflammation, and fibrosis. Additionally, the incorporation of conductive components into hydrogel MNs facilitate the restoration of electrical signal propagation, promoting synchronized cardiomyocyte contraction and mitigating arrhythmic. This article briefly surveys the latest advancements in hydrogel MN for cardiac repair. Key issues and challenges, as well as recommendations for future research, are also discussed.
Gastrointestinal inflammatory diseases have a significant impact on human health and quality of life, underscoring the urgent need to develop novel treatment strategies. As emerging biomaterials, nanozymes combine the advantages of nanomaterials with enzyme-like catalytic activities, demonstrating considerable potential for managing gastrointestinal inflammation. To provide researchers with a clear and concise overview of recent advances and future directions in this area, this review systematically summarizes and discusses the progress in nanozyme applications for treating gastrointestinal inflammatory disorders, including inflammatory bowel disease, Helicobacter pylori infection, and the like. We begin by elucidating the catalytic mechanisms underlying the major types of nanozymes, including metal-based, metal–organic framework (MOF)-based, and carbon-based nanozymes. Subsequently, we explore nanozyme designs that enable multifaceted therapeutic effects-including antioxidant, anti-inflammatory, microbiota regulation, and barrier repair functions-through strategies such as multi-enzyme mimicry, targeted delivery, and stimulus-responsive activation. While challenges related to targeting precision and biosafety remain, nanozymes offer promising opportunities to overcome the limitations of conventional therapies. The review also discusses future prospects, such as AI-assisted design, which may accelerate the development of next-generation nanozymes. We believe this work provides a valuable theoretical foundation for the design of efficient and safe nanozyme-based treatments for gastrointestinal inflammation.
Wound infection remains a critical challenge in clinical practice, frequently leading to delayed healing and increased risks of complications. Herein, we first screened Ag NWs with excellent antibacterial, antioxidant, and cell migration-promoting properties from silver-based nanomaterials with distinct dimensional morphologies, including Ag nanowires (NWs), Ag nanoparticles (NPs), nitrogen-doped graphene (NGC) supported Ag nanoparticles (Ag NPs/NGC) and Ag single atoms (Ag 1 /NGC), as candidates for wound dressing applications. To further enhance therapeutic efficacy, we developed a composite film (Ag NWs@SF) by incorporating Ag NWs into silk fibroin (SF). Under near-infrared (NIR) light, it generates localized heat to provide a synergistic antibacterial effect to accelerate wound healing. Interestingly, the robust electrical stimulation responsiveness of Ag NWs endows the film with the potential for real-time wound monitoring. This composite film demonstrates outstanding antibacterial activity against common wound pathogens, which maintains biocompatibility and fostering tissue regeneration. In vitro and in vivo studies reveal that the Ag NWs@SF membrane accelerates wound closure by stimulating cell migration, mitigating bacterial infection, and reducing inflammatory responses. These findings offer a novel approach for effective clinical wound management, potentially addressing the unmet clinical needs in infection combating and wound healing promoting.
Electrical stimulation can serve as a therapeutic modality accelerating the healing of soft tissue wounds. However, endogenous electric fields are frequently found to be attenuated in chronic wounds. Consequently, exogenous electrical stimulation devices have been explored to supplement and enhance endogenous electric fields, thereby promoting faster and more robust healing of soft tissue injuries. This review outlines the generation of endogenous electric fields in wounds, the molecular mechanisms by which electric fields facilitate healing, and the roles of endogenous electric fields across various stages of tissue repair. It further highlights recent advancements in applying exogenous electrical stimulation to wound sites. Finally, we discuss the challenges and future directions for the widespread clinical implementation of exogenous electrical stimulation in soft tissue wound management.
Traditional medical material development relies on trial-and-error experimentation and lengthy clinical trials, resulting in prolonged cycles, high costs, and limited success rates. This model not only severely hampers R&D efficiency but also struggles to rapidly address the urgent demand for new materials in the medical field. Artificial intelligence technology, by integrating multimodal data with advanced algorithms, is breaking through this bottleneck. This paper systematically reviews the application progress of AI across the entire medical material development chain, focusing on three core scenarios: “AI-driven molecular material design,” “biocompatibility prediction,” and “personalized material customization.” Through comparative analysis of differences in technical approaches and methodological frameworks among global research groups, it deeply elucidates the key challenges currently facing the field and offers forward-looking perspectives. biocompatibility prediction,“ and ”personalized material customization." By comparing and analyzing differences in technical approaches and methodological frameworks among global research groups, it deeply elucidates key challenges in the field and prospectively outlines future directions for the convergence of AI and medical materials. This aims to provide a systematic framework for innovative development in medical materials.
Piezoelectric interfaces are emerging as powerful tools for autonomous and personalized biomedical diagnostics by enabling real-time sensing and energy harvesting from physiological activities. Among them, piezoelectric nanogenerators (PENG) exemplify the integration of mechanical-to-electrical transduction with wearable and implantable applications, supporting self-powered operation without external power supplies. This review summarizes the fundamental principles of piezoelectricity and the development of representative materials, including inorganic ceramics, organic polymers, and hybrid composites, all tailored for biomedical use. Advances in fabrication strategies such as nanoscale patterning, multilayer assembly, and additive manufacturing have enhanced the flexibility, sensitivity, and biocompatibility of PENG-based systems. These devices have shown significant promise in applications such as cardiovascular and respiratory monitoring, neuromuscular sensing, and wound healing, where continuous and accurate physiological tracking is essential. Despite these advances, challenges remain in improving energy conversion efficiency under low-frequency biological motions, ensuring stable long-term biocompatibility, and integrating energy harvesting with storage and signal processing. Future directions include the incorporation of artificial intelligence for intelligent data analysis and the adoption of sustainable materials to enable next-generation diagnostic tools that are autonomous, eco-friendly, and suitable for precision medicine.
Urothelial carcinoma (UC), particularly in its advanced and metastatic stages, poses major treatment challenges. Platinum-based chemotherapy remains the standard front-line treatment due to its superior initial disease control. However, its long-term efficacy has frequently hampered by chemoresistance. Immune checkpoint inhibitors (ICIs) have transformed the treatment of UC, offering durable responses, particularly in the metastatic urothelial carcinoma (mUC) setting. The strategic integration of ICIs, like avelumab in the first-line maintenance setting following chemotherapy, has significantly improved overall survival, representing a key shift in treatment sequencing. Concurrently, advancements in tumor molecular profile have enabled the development of novel targeted therapies for mUC, including fibroblast growth factor receptor inhibitors, Poly (ADP-ribose) polymerase (PARP) inhibitors, anti-HER2 agents, and antibody–drug conjugates specifically targeting Nectin-4. Furthermore, numerous ongoing clinical trials are actively exploring additional molecular targets and pathways to further enhance treatment options for mUC. This review outlines the evolving therapeutic landscape of mUC, emphasizing the limitations of ICI monotherapy, the promise of maintenance strategies, and the emergence of rational combination regimens for improved patient outcomes. Advances in biomarker-guided approaches, including circulating tumor DNA, tumor mutational burden, and ligand programmed death-1 expression, along with emerging biomarkers, such as T-effector gene signatures, ApolipoproteinB mRNA editing enzyme catalytic (APOBEC) mutagenesis patterns, and tumor microenvironment, are also discussed as essential tools for optimizing personalized treatment in the era of precision immunotherapy.
