Triple-negative breast cancer (TNBC) is recognized as the notoriously difficult molecular subtype of breast cancer to manage therapeutically, creating a pressing need for more effective treatment approaches. Immunochemotherapy is an emerging strategy with great clinical potential, but most focus on the tumor microenvironment itself and ignore the immune regulation of lymph nodes. Herewith, we report a dual-pronged approach of tumor-targeted paclitaxel-encapsulated nanoemulsion (PTX Emul, Phase II clinical trial) and lymph node-targeted chlorogenic acid-encapsulated self-emulsifying nanocarriers (CHA-SME) to elicit strong and selective immunogenic cell death (ICD) in the tumor and to activate immune cells in the lymph nodes, respectively, to achieve highly effective cancer immunotherapy. PTX Emul exhibited evident tumor targetability and superior tumor accumulation, induced potent ICD, and then efficiently stimulated the maturation of dendritic cells (DCs). CHA-SME demonstrates a substantial capacity to enhance drug accumulation within the mesenteric lymph nodes through the lymphatic transport pathway. Of note, PTX Emul combined with CHA-SME augmented the immunotherapeutic effects through highly efficient ICD induction within the tumor microenvironment of 4T1 orthotopic tumor, the potent DC maturation, and the effective activation of T cell-based antitumor immunity, resulting in a substantial enhancement in the inhibition of 4T1 orthotopic tumors and, notably, a reduction in lung metastasis. The dual-pronged approach of TNBC-targeted PTX Emul and lymph node-targeted CHA-SME by inducing ICD and activating lymphoid immune cells, which amplifies the systemic antitumor immune response, provides an interesting platform for potent immunochemotherapy of TNBC.

Holographic light fields offer a promising route toward high-throughput 3-dimensional (3D) nanofabrication. However, the fabrication uniformity remains limited by severe speckle noise present in many previously demonstrated hologram coding methods. Here, we address this challenge by developing a model-driven deep learning framework that enables speckle-free hologram generation with high uniformity. We demonstrate its practical feasibility for 3D nanofabrication using 2-photon lithography (TPL) and term this approach SMART HoloTPL. By establishing a polymerization model based on the broadband angular-spectrum method, self-supervised network training is guided to explore advanced hologram coding strategies without reliance on paired datasets. Tailored neural network architecture and loss functions are designed for high-uniformity hologram generation. A TPL fabrication platform powered by a femtosecond regenerative laser amplifier has been built. SMART HoloTPL achieves large-scale speckle-free 3D nanofabrication with a 120,000 voxels/s throughput and 120-nm resolution, addressing key challenges in fabrication rate and quality.

Renal cell carcinoma (RCC), a highly heterogeneous malignancy that arises from the renal tubular epithelium, has exhibited a rising incidence in recent years and has become the predominant urologic malignancy, posing a major threat to human health and life. Although our understanding of RCC has advanced, treatment remains challenging owing to low specificity and sensitivity, particularly with respect to postoperative recurrence and therapy-induced renal injury. Therefore, effective strategies that can improve therapeutic outcomes are urgently needed. In recent years, the expanding investigation of materials for biomedical applications has identified several constructs with promising clinical potential; compared with traditional drugs, these materials offer superior targeting, an improved safety profile, and a broader array of functions and synergistic effects that can effectively overcome RCC recurrence, drug resistance, and metastasis. Moreover, biomaterials can attenuate renal damage and inhibit renal fibrosis, thereby preserving renal function. In this review, we present a comprehensive examination of the current landscape and future directions of biomaterials for RCC and renal injury treatment. We propose an integrated antitumor and kidney protection strategy and establish an analytical framework rooted in the fundamental contradictions of material design, encompassing functional conflicts, stimuli-responsive activation, and metabolic safety. This approach provides novel insights into overcoming critical challenges in the field.

Periodontitis is a chronic bacterial inflammatory disease. M2 macrophage-derived exosomes (M2-exos) possess targeted immunomodulatory abilities, but their role in mitigating oxidative stress (key for periodontitis treatment) remains unclear. In this study, we engineered M2-exos loaded with indocyanine green (ICG) (ICG@M2-exos) for the treatment of periodontitis. The constructed ICG@M2-exos effectively facilitated macrophage reprogramming from the M1 to the M2 phenotype, thereby resolving chronic inflammation and enhancing periodontal tissue repair. Under near-infrared irradiation, ICG conferred potent antibacterial efficacy against Porphyromonas gingivalis (P. gingivalis). Simultaneously, the exosomes released from ICG@M2-exos mitigated oxidative stress and decreased the expression of proinflammatory factors in THP-1 cells through promoting M2 polarization. In a rat model of P. gingivalis-induced periodontitis, the sustained release of ICG@M2-exos markedly expedited periodontal bone regeneration, accompanied by elevated levels of anti-inflammatory cytokines. Collectively, ICG-engineered M2-exos represent a promising strategy for tackling inflammatory periodontal conditions. This study demonstrates the dual advantages of ICG@M2-exos in near-infrared-responsive antibacterial activity and immunomodulation that work synergistically, laying a solid foundation for future clinical applications.

Recently, immune checkpoint inhibitors (ICIs) have demonstrated substantial benefits and potential by enhancing antitumor immune responses via the normalization of host T cell activity. Nonetheless, a considerable proportion of patients were tolerant to ICI therapy, thereby restricting its broader application in cancer treatment. Identifying the key barriers responsible for resistance to ICI therapy has led to the development of combination therapies with ICIs as a promising approach to overcome these challenges, providing new directions for ICI-based cancer immunotherapy. Neutrophils within the tumor microenvironment are considered a critical factor contributing to poor responses to ICI treatment, and combining ICIs with neutrophil-targeted therapy has shown remarkable efficacy and promise. Consequently, this review discusses the diverse roles of neutrophils in cancer immunotherapy, outlines the synergistic mechanisms of targeting neutrophils in conjunction with ICIs, highlights relevant clinical trials of this combination strategy, and discusses current limitations and future directions. Overall, this review aims to provide new insights into effective strategies for ICI therapy.

To reduce mental disorder prevalence, the understanding of resilience to stress-related disorder and its neurobiological mechanisms has come into the focus of biomedical research to develop both biologically rooted prevention and innovative therapeutic approaches for stress-related disorder. While some resilience mechanisms have been exemplified on the molecular, cellular, and brain-regional level, evidence on the neural systems level is rather sparse. We present the first translational evidence of adaptive plasticity in visual microcircuits and top-down modulation onto the visual system as a neurobiological resilience mechanism at the neural systems level in both humans and mice. In humans, we demonstrate that this adaptive microcircuit plasticity is linked to interactions between neurocognitive domains—executive and perceptual—and between brain regions—frontal and occipital—in specific oscillatory frequencies (β band in frontal inferior frontal gyrus and γ band in occipital V2). Additionally, expanding upon prior resilience research, our findings offer further evidence that phenotypic resilience is associated not only with macro- and microcircuit plasticity but also with better performance in neurocognitive functions central to resilience, i.e., perceptual discrimination in mice and cognitive control in humans. In mice, using awake 2-photon calcium imaging, we observed distinct resilient and susceptible network phenotypes in mouse visual cortex. Resilient animals surpassed both susceptible animals and nonstressed controls in their ability to encode visual afferents. This suggests an improved performance supporting the concepts of posttraumatic growth and stress inoculation on a neurobiological level. Resilience at the neural systems level involves active, dynamic processes rather than being merely passive responses to stress and constitutes a first example that neural network states of resilience are metastable, self-stabilizing, and noncontinuous entities that could serve as a target for new neural network interventions for fostering resilience.

Intraoperative cancer diagnosis using Raman spectroscopy is a growing area of research, but clinical adoption is held back by relatively slow single point data acquisition. Its application to glioblastoma is particularly attractive because of the distinct spectra of malignant and healthy brain tissues, which allow detection of even diffusely invasive glioblastoma with high accuracy. Current clinical practice for intraoperative guidance uses indocyanine green (ICG) for wide-field localization, but its nonspecific accumulation beyond tumor margins leads to false-positive guidance. Critically, the strong fluorescence background from ICG under 785-nm Raman excitation overwhelms the inherently weak Raman signal, thereby preventing concurrent use of the 2 modalities. Here, we overcome this barrier by introducing a signal-processing algorithm that suppresses ICG-derived interference, enabling coregistered acquisition. We present an integrated “search-and-confirm” workflow, where ICG first identifies regions of interest and subsequent signal processing suppresses fluorescence interference, thereby enabling machine-learning-based Raman diagnosis within 3 s and achieving 85% to 90% identification accuracy in vivo. By enabling spatial correlation, we demonstrate that ICG systematically overestimates tumor extent, while Raman signatures match histopathological margins, thereby transforming Raman spectroscopy into a real-time corrective filter for clinical fluorescence guidance and offering a practical path toward precision glioblastoma resection.

The nervous system has emerged as a critical regulator of tumor biology. Over the past 2 decades, accumulating evidence has given rise to the rapidly expanding field of cancer neuroscience, revealing that neural circuits actively shape tumor initiation, progression, metastasis, prognosis, and therapeutic response. While the nervous system comprises both central and peripheral components, increasing attention has focused on the peripheral nervous system (PNS) as a key mediator of tumor–host interactions within the tumor microenvironment (TME). Autonomic (sympathetic, parasympathetic, and enteric) and sensory neural pathways interact dynamically with tumor cells, immune cells, glial cells, and other stromal components, influencing tumor growth, invasion, metastasis, and immune regulation through diverse cellular and molecular mechanisms. In addition, environmental and patient pathophysiological factors—including environmental stress, psychological states, pain, microbiota, aging, metabolic status, and lifestyle behaviors—can further modulate nerve–cancer interactions and reshape the tumor ecosystem. In this review, we systematically organize PNS–cancer interactions within the TME across 3 integrative dimensions: pathological phenotypes, cellular components, and modes of communication, thereby providing a conceptual framework for understanding the mechanistic landscape of cancer neuroscience. This structured perspective highlights the diverse modalities of nerve–tumor communication, identifies key modulatory factors influencing these interactions, and discusses emerging therapeutic strategies targeting nerve–cancer signaling.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting women of childbearing age. Infertility caused by ovulatory disorders and low follicle quality is an urgent problem. Abnormal fatty acid oxidation (FAO) contributes critically to the etiology and progression in PCOS. However, the potential mechanism by which FAO affects follicular development in PCOS patients is unclear. Here, we demonstrate that increased expression of tripartite motif-containing protein 21 (TRIM21) (an E3 ubiquitin ligase) in the prenatal anti-Müllerian hormone PCOS mouse model leads to abnormal FAO in ovarian granulosa cells. Functionally, knocking down TRIM21 increased mitochondrial membrane potential homeostasis and improved fatty acid-dependent aerobic respiration and oxidative phosphorylation functions. TRIM21 regulated the ubiquitination and degradation of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme for FAO, at the K161 site. TRIM21 is regulated by the E2 ubiquitin ligase ubiquitin conjugating enzyme E2 M (UBE2M), which enhances its protein expression and ubiquitination by TRIM21 neddylation. MLN4924 (a neddylation inhibitor) reversed the ubiquitination degradation of CPT1A by inhibiting TRIM21 neddylation. The phenotype of PCOS mice treated with MLN4924 was alleviated, and the maturation of oocytes and embryonic development improved. Together, these findings indicate that TRIM21-CPT1A plays an indispensable role in FAO of granulosa cells, and inhibiting TRIM21 neddylation may be a therapeutic strategy to improve abnormal follicular development in PCOS.

Traditional Chinese medicine (TCM), rooted in holistic philosophy, features a “multicomponent, multitarget, multipathway” therapeutic model that has long posed challenges for modern scientific interpretation due to its inherent complexity. Studies elucidating its biological mechanisms have historically relied on correlation-based analytical paradigms. Although artificial intelligence (AI) has been increasingly introduced into TCM research, most current applications remain confined to disease classification, outcome prediction, or herb–target association mining, with limited capacity to reconstruct the underlying biological logic of Zheng (TCM Syndrome) differentiation and formula compatibility. This review systematically elaborates on how network pharmacology serves as a foundational framework, constructing “herb–compound–target–disease” networks that align with TCM’s holistic nature, while AI addresses network pharmacology’s limitations—machine learning streamlines active component screening and ADME/T (absorption, distribution, metabolism, excretion, and toxicity) property prediction, and deep learning decodes spectroscopic data, complex biological interaction networks, and formula synergies. The integrated “computational prediction-experimental validation” workflow, validated across oncology, metabolic diseases, and infectious diseases, has become the gold standard for mechanistic research. Additionally, AI revolutionizes TCM quality control by linking chemical signatures to stable efficacy, integrates multiomics data to construct holistic regulatory networks, and enables translational progress through precision patient stratification, real-world evidence integration, and TCM knowledge graphs that structure fragmented knowledge. With the advancement of technology, generative AI for drug design, large language models for mining ancient texts, and multimodal “life models” promise to deepen integration. Ultimately, AI transcends being a mere tool, translating TCM’s holistic philosophy into modern scientific language, advancing its modernization and internationalization, and offering insights for multitarget drug development in global healthcare.

Expanding near-field regions in high-frequency 6G systems necessitates precise spatial-field control, yet narrow beamwidths and 3-dimensional tracking complexities create severe alignment hurdles. Here, we present an eye-tracking-driven programmable metasurface that bridges human visual intent with real-time electromagnetic responses via gaze-contingent beam steering. The system integrates a polarization-agile metasurface featuring independent 1-bit phase control for both copolarized and cross-polarized reflections. By engineering a 90° phase offset between these channels, the eye-tracking-driven programmable metasurface enables high-gain beam focusing and efficient linear-to-circular polarization conversion. Experimental results confirm that the system dynamically maps 3-dimensional gaze coordinates to metasurface coding patterns with millisecond-level responsiveness, facilitating robust near-field focusing and far-field scanning. This work establishes a “service-follows-vision” communication scenarios for intelligent wireless systems, offering distinct advantages in signal enhancement and interference mitigation.

The global pulp industry discards over 50 million tons of lignin annually, with conventional valorization strategies hindered by performance and cost barriers. We report an ion-exchange, self-catalytic strategy to upcycle the industrial lignosulfonate into high-performance bio-based adhesives. The facile ion-exchange process transforms sodium lignosulfonate into lignosulfonic acid, which acts as not only a copolymer backbone of adhesive but also an intrinsic macromolecular catalyst, autonomously driving esterification reaction with citric acid and then wood polymers, eliminating the need of fossil-derived cross-linkers and energy-intensive pretreatments. This mechanism endows it performing excellent performance in bonding strength and boiling-water resistance. Crucially, the performance gains are coupled with important economic and environmental benefits; production costs are substantially lower than conventional petrochemical resins, and a life cycle assessment confirms markedly reduced environmental impacts alongside negligible formaldehyde emissions. This work successfully resolves the performance–sustainability–cost trade-off, establishing a waste-to-wealth pathway for circular manufacturing.

Mutations in a specific protein called calcium-activated nucleotidase 1 (Cant1) cause skeletal deformities, but the role of Cant1 in these deformities remains unclear. This study shows how Cant1 acts as a key regulator of bone and cartilage health. We found that Cant1 binds to and stabilizes a protein called Wnt/β-Catenin. Wnt/β-Catenin then enters the cell nucleus to activate specific genes. One of these genes, CHSY1, is turned on to produce building blocks such as collagen and sugars that form the extracellular matrix (ECM), which acts as the scaffolding of cartilage. When Cant1 and Wnt/β-Catenin expression are suppressed, there is a reduction in glycosaminoglycans (GAGs; mucopolysaccharides) and proteoglycans (like ACAN), which create a hydrated, gel-like matrix by binding with hyaluronan and link proteins to make cartilage resistant to compression. Additionally, there is a decrease in the α-1 chain of type II collagen (COL2α1), which forms the structural mesh or framework that gives tissue its tensile strength. In summary, we identified a conserved signaling pathway, the Cant1/β-Catenin/transcription factor 4 (TCF4)–CHSY1 axis, that regulates ECM homeostasis during skeletal development. Dysfunction of this pathway is a core cause of skeletal disorders. These findings not only provide mechanistic insights into human Cant1-related skeletal diseases but also highlight potential new targets for broad-spectrum therapies aimed at correcting deficiencies in ECM biosynthesis.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide and are hallmarked by profound disturbances in energy metabolism and maladaptive tissue remodeling. Lactate, long dismissed as a metabolic waste product, is now recognized as a context-dependent central carbon source and signaling metabolite. A key recent advance is the discovery of lysine lactylation (Kla), an evolutionarily conserved posttranslational modification that couples lactate abundance to chromatin state and protein function. Here, we synthesize current knowledge on the biogenesis and enzymatic regulation of Kla, and delineate how lactate-driven histone and nonhistone lactylation remodel transcriptional and signaling networks controlling fibrosis, energy metabolism, immune and inflammatory responses, and angiogenesis. We then focus on emerging evidence that Kla is a nodal regulator across major cardiovascular pathologies—including atherosclerosis, myocardial infarction and ischemia/reperfusion injury, heart failure, valvular and arterial calcification, and pulmonary hypertension—where it can act as a context-dependent “accelerator” or “brake” of disease progression. Finally, we outline a translational framework that targets the lactate–lactylation axis at 3 levels: lactate transport, lactate production, and lactylation writers/erasers, highlighting opportunities and challenges for therapeutic intervention. Together, these insights position protein lactylation as a pivotal metabolic–epigenetic interface in the cardiovascular system and a promising entry point for precision therapies in CVDs.

Low-dimensional halides (LDHs) with self-trapped exciton (STE) emission are promising materials for scintillation applications. Nonetheless, for almost all LDHs, the measured scintillation yield is still far below theoretical value due to severe exciton–exciton/exciton–defect interaction under ionizing radiation, despite high photoluminescence quantum yield (PLQY). Here, we reported a substantial enhancement of scintillation yield in zero-dimensional (0D) Cs₃YCl₆ by structural modulation. By copper(I) alloying in Cs₃YCl₆, the delocalized excitons in [YCl₆]³⁻ octahedra convert to strongly localized excitons within [Cu₂(YCl₆)₃]⁷⁻ clusters in (Cs₈Cu)Y₃Cl₁₈, as confirmed by first-principles calculations. Temperature-dependent photoluminescence spectroscopy and kinetic results reveal a higher energy barrier for STE quenching in (Cs₈Cu)Y₃Cl₁₈ than in Cs₃YCl₆. Benefiting from the enhanced exciton confinement effect, (Cs₈Cu)Y₃Cl₁₈ exhibits a 460% enhancement in the STE-related scintillation yield. This work opens up a new strategy to enhance scintillation yield in LDHs under ionizing radiation excitation.

Ischemic stroke remains a major cause of mortality and long-term disability, with few effective neuroprotective treatments currently available. Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, is increasingly recognized as a driver of neuronal damage. However, the mitochondrial mechanisms linking ischemia to ferroptosis remain poorly defined. Here, we identify circMTCO2, a mitochondria-encoded circular RNA (circRNA), as a novel endogenous modulator of neuronal ferroptosis. circMTCO2 expression is dynamically down-regulated following cerebral ischemia/reperfusion in vitro and in vivo. Mechanistically, circMTCO2 interacts with adenine nucleotide translocase 1 (ANT1), a key regulator associated with the mitochondrial permeability transition pore (mPTP), thereby inhibiting mPTP opening and suppressing mitochondrial reactive oxygen species release. Disruption of the binding site abolishes circMTCO2–ANT1 interaction and eliminates the protective effects of circMTCO2. To restore and enhance this intrinsic defense mechanism, we developed a dual-targeting extracellular vesicle system (RVG-EV^mt-RNA) capable of delivering circMTCO2 specifically to neuronal mitochondria. Systemic administration of RVG-EV^mt-RNA decreased infarct volume, attenuated ferroptosis-associated injury, and improved neurological function in a mouse model of ischemic stroke, without inducing systemic toxicity. These findings establish circMTCO2 as a previously unrecognized mitochondrial circRNA that regulates ferroptosis by modulating mPTP activity and provide a proof of concept that organ-to-organelle circRNA delivery can be leveraged as a precision neuroprotective strategy for ischemic stroke.

This study aimed to explore the impact of treadmill running at different intensities and durations on hippocampal neurogenesis and cognitive function in mice, with a focus on the interorgan communication mechanism mediated by the extracellular vesicle (EV) cargo cathepsin B (CTSB) via the muscle–brain axis. We define the intensity of treadmill running mice based on measurements of maximum oxygen uptake. The findings from treadmill running studies at varying intensities and durations in C57BL/6J mice revealed that treadmill running improved hippocampal neurogenesis and memory in wild-type (WT) mice in an intensity-dependent manner. Omics and UK Biobank cohort analyses identified muscle-derived CTSB as a key exercise-responsive factor, whose expression may be regulated by O-linked N-acetylglucosaminylation. Overexpression of O-linked N-acetylglucosaminyltransferase (OGT) prolonged the half-life of CTSB and inhibited its ubiquitination-mediated degradation, whereas inhibition of OGT accelerated its degradation. Mechanistically, treadmill running may promote the secretion of muscle-derived CTSB into the bloodstream via EVs and its subsequent delivery to the hippocampus through activation of the OGT/CTSB signaling. In WT mice, knockdown of muscular CTSB partially reversed the treadmill-running-induced improvements in hippocampal neurogenesis and memory, while overexpression of muscular OGT further enhanced the release of muscle-derived CTSB. Moreover, in amyloid precursor protein/presenilin 1 mice, treadmill running potentially improved cognitive function, reduced amyloid-β deposition, neurofibrillary degeneration, and neuroinflammation by up-regulating muscular CTSB. Knockdown of muscular CTSB attenuated the benefits of treadmill running, while overexpression of CTSB further enhanced the exercise-induced effects. Overall, this study demonstrates that treadmill running may activate the muscular OGT/CTSB signaling axis, promoting the secretion of the myokine CTSB protein into the circulatory system via EVs and its transport to the brain, thereby improving hippocampal neurogenesis and cognitive function in both WT and amyloid precursor protein/presenilin 1 mice. These findings highlight the role of myokine CTSB as a pivotal modulator in muscle–brain axis communication mechanism, with its stability regulated by O-linked N-acetylglucosaminylation.

Decellularized extracellular matrix (dECM) leverages native architecture and bioactive components for tissue regeneration, yet its therapeutic efficacy is constrained by donor tissue maturity. While mature-tissue-derived dECM (Mat-dECM) lacks developmental signals, developmental-stage dECM (Dev-dECM) retains these cues but is limited by scarce sources and poor adaptability to adult environments. Here, we proposed postnatal maxillofacial odontogenic tissues as a novel Dev-dECM (pDev-dECM) source. Leveraging its unique trans-stage development—spanning embryonic crown formation to postnatal periodontal maturation—pDev-dECM balances developmental potency with adult environment adaptability. Multiomics comparative analysis revealed that pDev-dECM is enriched in arginylglycylaspartic-acid-containing proteins, which activate macrophage integrin αvβ5-mediated efferocytosis. This mechanism drives macrophage polarization toward regenerative M2 phenotypes, ensures adaptability to the adult environment, and reprograms mesenchymal stem cells to orchestrate developmental recapitulation. Consequently, pDev-dECM not only enabled in situ hierarchical regeneration of the periodontal complex but also facilitated cross-organ hierarchical regeneration in skin and muscle defect models. These findings demonstrate that pDev-dECM exerts spatiotemporal control over developmental recapitulation, establishing a universal biomaterial paradigm for multiscale tissue reconfiguration.

Mitochondrial DNA (mtDNA) damage and its subsequent release into the cytoplasm are strongly linked to osteoarthritis (OA), but the pathogenic mechanism remains poorly understood. Here, this study reveals that under inflammatory or oxidative stress, the down-regulation of mitochondrial base excision repair enzyme 8-oxoguanine DNA glycosylase 1 and excessive opening of the mitochondrial permeability transition pore jointly drive mtDNA escape into the cytoplasm. Activation of 8-oxoguanine DNA glycosylase 1 with TH10785 reduces the production of oxidized mtDNA and preserves mtDNA integrity, while suppression of excessive mitochondrial permeability transition pore opening with cyclosporin A prevents mtDNA translocation. The combined intervention synergistically decreases cytosolic mtDNA levels, alleviating cartilage matrix degradation and cellular senescence. Mechanistically, cytosolic mtDNA induces the senescence-associated secretory phenotype by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase–stimulator of interferon genes–nuclear factor κB signaling axis, whereas combined intervention blocks this cascade activation. Notably, intra-articular injection of the combination of TH10785 and cyclosporin A markedly reduces senescence and ameliorates the progression of the experimental OA model mice. This research reveals the dual regulatory roles of mtDNA integrity and translocation in governing cytosolic mtDNA content, providing novel insights for developing mtDNA-targeted therapeutic strategies against OA.

In single-cell microbes, primary and secondary metabolism are synergistically integrated to support survival and environmental adaptation through the biosynthesis of structurally diverse and biologically active small molecules—known as secondary metabolites (SMs) or natural products, such as penicillin. However, the therapeutic potential of microbial SMs is often limited because their biosynthetic gene clusters remain silent or weakly expressed under laboratory conditions. In this study, we employed BioNavi-NP as a guide to identify heme A synthase (ClHAS) as a novel metabolic link in Curvularia lunata, bridging primary and secondary metabolism. Surprisingly, inactivation of ClHAS led to the diversification of its characteristic indolizidine alkaloids, yielding previously unreported molecular frameworks. Mechanistically, ClHAS disruption impaired heme biosynthesis, thereby inducing oxidative stress that activated an uncharacterized basic-region leucine zipper transcription factor (A7370). A7370 binds specifically to a unique cis-element (ACGGCTGAC) in the promoter region of cuaF, a pathway-specific positive regulator of indolizidine alkaloid biosynthesis. This cascade regulation produces structurally unprecedented alkaloids, some of which show antibacterial activity equal or superior to the clinically prescribed drug, tinidazole, against a range of human pathogenic bacteria. Overall, this work reveals a conserved regulatory network that coordinates primary and secondary metabolism in fungi, providing new mechanistic insights into the complexity of fungal SM biosynthesis.

Diabetes hinders nerve recovery after spinal cord injury (SCI). The complex pathological factors of diabetes increase the difficulty of treating diabetes combined with SCI. Maintaining normal microglial function is essential for SCI recovery. However, it is unclear whether diabetes hinders nerve recovery after SCI by influencing normal microglial function. This study explored the role and regulatory mechanism of diabetes in microglial function during SCI recovery. We constructed a type 2 diabetes (T2D) combined with SCI mouse model and confirmed that T2D hinders nerve repair after SCI. T2D blocked phagocytizing function of microglia in SCI mice, which results in increased myelin debris accumulation and poor remyelination. A mechanistic study demonstrated that T2D triggers activation of NLRP3 inflammasome by activating the RAGE–ROS–TXNIP axis and then induces excessive microglial pyroptosis, which consequently leads to considerable loss of microglia after SCI. Verapamil (VRP; a TXNIP inhibitor) treatment confirmed that TXNIP is necessary for NLRP3 inflammasome activation. Conditional microglial Caspase-1 gene knockout (KO) mice also confirmed that excessive microglial pyroptosis is an important inducing event for more severe nerve damage in T2D combined with SCI mice. Moreover, this T2D effect on increased microglial pyroptosis was also effectively reversed by N-acetyl-l-cysteine (NAC; an antioxidant) and N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1; a RAGE inhibitor). In conclusion, this study revealed that T2D induces increased microglial pyroptosis by activating the RAGE–ROS–NLRP3 axis, and then blocks remyelination after SCI, which strongly suggests that microglial pyroptosis may be the key target for treating T2D combined with SCI.

The development of fast-charging anode materials is crucial for overcoming the sluggish reaction kinetics of conventional graphite electrodes in lithium-ion batteries. This work presents a kilogram-scale producible hard carbon/graphene flake (HC-GF) composite anode engineered based on an “electron Velcro” conductive network design. In this architecture, highly conductive GFs are intimately integrated with the HC matrix, creating multidimensional electron/ion transport channels while effectively minimizing interfacial resistance. The resulting HC-GF anode exhibits exceptional electrochemical performance, delivering a reversible capacity of 506.4 mAh g⁻¹ and maintaining 223.8 mAh g⁻¹ at a 10 C rate (corresponding to 6-min fast charging). Remarkably, when blended with graphite at a 20% ratio in a 5 Ah LFP//graphite + 20% (HC-GF) pouch cell, this minimal doping level substantially enhances multiple performance metrics, particularly fast-charging capability and cycling stability. The pouch cell retains 3.39 Ah after 600 cycles at 3 C, corresponding to an impressive capacity retention of 94.6%. This study provides a valuable material strategy for advancing fast-charging lithium-ion battery technologies.

A comprehensive understanding of the physiological functions of mammary glands and the mechanisms underlying breast diseases is crucial for promoting women’s health and well-being. This review systematically summarizes the development and applications of in vitro mammary gland models, focusing on key components including cell types, hydrogel matrix, and breast-on-a-chip platforms. We begin with a detailed overview of primary mammary epithelial cells, various cell lines, organoids, and multicellular coculture systems, highlighting their respective characteristics and advantages in mimicking mammary gland physiology and pathology. Next, we examine the essential role of hydrogel matrix in providing extracellular matrix support and facilitating cellular interactions. Furthermore, recent advances in breast-on-a-chip technologies are reviewed, covering their design, fabrication, and functional capabilities that enable high-throughput drug screening and disease mechanism investigations. Finally, we explore the applications of these in vitro models in mammary gland development, breast cancer research, and drug discovery, underscoring their critical role in improving prevention and treatment strategies. By integrating these state-of-the-art technologies, this review provides researchers with a comprehensive perspective to better understand and apply in vitro mammary models in innovative studies.

Mitochondrial dysfunction is pivotal in the pathogenesis of cardiac ischemia/reperfusion (I/R) injury. Restoring mitochondrial function represents a promising strategy for mitigating I/R-induced cardiac injury. Mitochondrial fission regulator 1-like protein (MTFR1L), a recently identified mitochondrial dynamics protein, is abundantly expressed in the cardiac tissues. However, its functional role in I/R injury remains undefined. Here, Mtfr1l-knockout mice and human embryonic-stem-cell-derived cardiomyocytes are utilized to investigate the role of MTFR1L in myocardial I/R injury and elucidate its contribution to mitochondrial integrity and function. MTFR1L deficiency markedly worsened I/R-induced cardiac injury and mitochondrial dysfunction. These phenotypes were partially reversed by mitochondria-anchored apoptosis-inducing factor (AIF) overexpression. Mechanistically, MTFR1L protects the heart via 2 interconnected pathways. First, MTFR1L sustains AIF dimerization and stabilizes the AIF–CHCHD4 (coiled-coil-helix-coiled-coil-helix domain containing 4) complex, thereby preserving mitochondrial contact site and cristae organizing system integrity and cristae architecture to facilitate electron transport chain supercomplex assembly, sustain mitochondrial respiration, and limit reactive oxygen species production. Second, by physically interacting with AIF, MTFR1L prevents its mitochondrial release and nuclear translocation, thereby suppressing intrinsic apoptosis. Overall, these findings identify MTFR1L as a cardioprotective protein against myocardial I/R injury through a dual mechanism, providing new insights into the functional repertoire of MTFR1L beyond its previously recognized role in mitochondrial dynamics. Targeting MTFR1L or its interactors may offer novel therapeutic strategies for alleviating mitochondrial dysfunction and myocardial injury.

The rise of multidrug-resistant bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), poses a serious threat to human health, necessitating an urgent need to develop innovative antibacterials with multifunctions for this. Here, focusing on integrating multi-antimicrobial mechanisms with visual monitoring, we report a novel phenanthro[9,10-d]imidazole fluorogen 9b, outstanding for its antibacterial effects against S. aureus and various clinical MRSA isolates (minimum inhibitory concentration = 0.5 to 1 μg/ml) with rapid bactericidal activity, high membrane selectivity, and low susceptibility to drug resistance. Further investigation revealed its dual antimicrobial mechanisms of action by concurrently disrupting bacterial cell membranes and inducing bacterial DNA degradation to accelerate bacterial death. Ultraviolet–visible and fluorescence spectroscopy studies showed that the fluorescence intensity of 9b was dramatically enhanced when it interacted with S. aureus. Notably, in vivo studies demonstrated that 9b effectively treated both skin and thigh MRSA infections, showing a favorable safety profile and superior efficacy compared to the first-line antibiotic vancomycin. The “dual-mechanism” fluorescent phenanthro[9,10-d]imidazole fluorogen 9b holds promise as a candidate for developing innovative antibacterial agents that enable simultaneous real-time diagnosis and treatment.

Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer’s disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm² yielded the optimal cognitive outcome in Alzheimer’s disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1, phosphorylated NF-κB, and necroptosis markers, alongside reductions in key pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1/NF-κB signaling.

The dynamic metaverse paradigm integrates emerging technologies and offers transformative opportunities to enhance consumer healthcare applications through immersive, connected experiences. However, this paradigm faces substantial cybersecurity challenges, such as distributed denial-of-service attacks, probing, and port scanning. This undermines the trustworthiness and resilience of healthcare analytics frameworks. To address these threats, intrusion detection systems that support proactive anomaly detection are essential for securing metaverse-based healthcare applications. Conventional anomaly detection techniques face challenges such as low interpretability, suboptimal feature selection, class imbalance, and inefficient hyperparameter tuning. These challenges limit their reliability in practical cyber threat intelligence settings. To solve these challenges, this paper presents an anomaly-detection framework for Internet of Things-enabled metaverse healthcare environments. The proposed framework leverages an off-policy proximal policy optimization (PPO) algorithm that incorporates SHapley Additive exPlanations-based feature selection and class-specific reward adjustments to address imbalance. The reinforcement learning-based off-policy PPO enables adaptive, sample-efficient learning by leveraging prior experience during policy updates. The hyperparameters of the model are optimized using the Bayesian Optimization Hyperband algorithm to accelerate training and enhance performance. This optimization technique combines Bayesian search with the Hyperband method to improve efficiency and convergence during model tuning. The performance of our model is evaluated on NSL-KDD, MAWI, and CICIoT2023 datasets. The results depict that the model outperformed its contemporaries with state-of-the-art results where accuracy, F-measure, G-means, and area under the curve reached 88.005%, 87.271%, 87.986%, and 0.870; 92.184%, 88.992%, 89.738%, and 0.873; and 89.368%, 88.312%, 89.039%, and 0.836, respectively. The results confirm the effectiveness of the framework in cyber threat scenarios. They also show their potential for explainable, trustworthy intelligence in metaverse healthcare.

Extracellular vesicles (EVs) are promising cell-free therapeutics for diabetic wound healing due to their immunomodulatory and proangiogenic properties. Nonetheless, challenges in ensuring long-term stability and achieving targeted delivery continue to impede clinical translation. Herein, we developed a 3-dimensional bioprinted methacrylated decellularized umbilical cord matrix (MDUM) patch enabling the sustained delivery of telomerase-immortalized umbilical cord mesenchymal stem cell-derived EVs (TMSC-EVs). TMSC-EVs encapsulated in MDUM maintained their structural integrity and biological functionality for more than 30 d under 4 °C storage, outperforming those encapsulated in gelatin methacryloyl (P < 0.01). In a diabetic murine wound model, our data demonstrated that MDUM could enhance the retention and delivery of TMSC-EVs and further augment the therapeutic effects for diabetic wound healing as revealed by attenuating proinflammatory cytokine levels, enhancing neovascularization, and accelerating collagen deposition. This study pioneers the integration of biomaterial engineering with immortalized cell-derived EVs, establishing a translatable platform for regenerative therapies in chronic wound management.

A full reproductive cycle (pregnancy followed by lactation and involution) imprints long-lived CD8⁺ tissue-resident-memory-like T cells in the breast. These cells restrain tumor growth in mice and are linked to a more inflamed tumor microenvironment and better outcomes in human triple-negative breast cancer.

Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, is a major and unavoidable environmental contaminant that poses serious risks to intestinal health. Lycopene (LYC), a natural carotenoid with potent antioxidant properties, has been reported to exert protective effects against oxidative stress. Phosphoglycerate mutase family member 5 (PGAM5) acts as a key signaling hub to control mitochondrial dynamics and mitophagy. This study aimed to elucidate the potential role of LYC in DON-induced intestinal damage and clarify the contribution of PGAM5. We established intestinal porcine epithelial cell models to explore the effects of DON and LYC on intestinal barrier integrity, mitochondrial function, mitophagy, and ferroptosis through assessments of cell viability, oxidative stress, iron accumulation, and autophagic activity. Mechanistic insights were validated using RNA sequencing, molecular docking, Western blotting, and immunofluorescence analyses. PGAM5 expression was modulated via plasmids and small interfering RNA. Our results demonstrated that DON disrupted barrier integrity, reduced cell motility, and induced cytoskeletal disorganization, accompanied by excessive mitophagy, lipid peroxidation, and ferrous iron accumulation, ultimately leading to ferroptosis. Notably, LYC alleviated DON-induced intestinal damage by inhibiting mitophagy and ferroptosis. Importantly, PGAM5 overexpression abolished the protective effects of LYC, indicating that PGAM5-mediated mitophagy-dependent ferroptosis plays a critical role in DON-induced intestinal damage. These findings suggest that LYC may serve as a potential therapeutic strategy for treating mycotoxin-induced intestinal disorders.

In this study, we have designed a full-function interferometer OB (optical bench) for the Taiji program and, for the first time, provided detailed parameter specifications for its interferometer system. Additionally, we constructed a first-generation Taiji interferometer OB and ground test system and conducted preliminary testing and calibration. A comprehensive analysis was carried out on the various noise sources impacting the interferometer system, including laser frequency noise, laser power noise, thermal drift noise, and angular jitter noise. The results revealed that the noise level of the interferometer system reached 1.1 pm/Hz^1/2 at 1 Hz, 5 pm/Hz^1/2 at 0.1 Hz, and 8 pm/Hz^1/2 at 0.01 Hz; these levels satisfied the requirements of the Taiji-2 mission. This work marks the first step in transitioning the Taiji program’s interferometer system from a principle prototype to an engineering prototype, playing a critical role in its future development.

The mammillary body (MB) has traditionally been regarded as a relay station for the hippocampus and plays a pivotal role in the Papez circuit. However, its molecular and cellular organization remains inadequately characterized. This study focuses on the horizontally symmetrically distributed neurotensin (Nts)-expressing and nitric oxide synthase 1 (Nos1)-expressing neurons in the MB, demonstrating that Grik4 (encoding a high-affinity kainate receptor subunit) underlies their distinct electrophysiological properties. Within neural circuits, Nts and Nos1 neurons receive excitatory inputs from the ventral subiculum and send parallel excitatory projections to the dorsomedial and ventrolateral subdivisions of the anteroventral thalamus (AV). These 2 cell type-specific circuits are essential for working memory and exhibit selective activation during the maintenance phase with a marked temporal difference. Together, our findings establish a direct link from molecular identity to circuit architecture and cognitive processing by demonstrating that molecularly distinct Nts and Nos1 neurons constitute differential circuits with convergent inputs, divergent outputs, and dissociable roles in working memory maintenance. This work thus reveals a fundamental cross-scale organizational principle—molecule, cell, circuit, function—within the MB.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, initiated by an excessive inflammatory cascade that frequently progresses to immunoparalysis characterized by immune cell dysfunction. In this review, we first provide an overview of the key elements and stages in the onset and progression of sepsis. Subsequently, we discuss the recent advances of biomaterial-based nanomedicine (including organic nanomaterials, inorganic nanomaterials, and natural bio-inspired nanomaterials) in the treatment of sepsis. The elimination of pathogens and the modulation of the immune response within the sepsis microenvironment through the design of diverse biomaterial systems were specifically summarized. Finally, we discuss the challenges and opportunities for biomaterial-based nanomedicine in the treatment of sepsis.

Effective therapy for ischemic diseases requires not only timely restoration of perfusion but also protection of ischemic tissues from secondary insults, particularly oxidative-stress-induced injury. Here, we propose the concept of “proangiogenic nanozymes” and develop an efficient screening platform by doping angiogenic elements (Mg, Co, Cu, Zn, Sr, or Eu) into an archetypal antioxidative nanozyme, Prussian blue. Systematic assessment of catalytic activity and proangiogenic performance identified Cu-doped Prussian blue (CuPB) as the lead candidate. In addition to efficiently decomposing multiple reactive oxygen species, thereby attenuating oxidative stress, reducing apoptosis, and protecting ischemic tissues from secondary injury, CuPB nanozymes also stimulated angiogenesis, thereby accelerating tissue repair. In murine models of hind limb ischemia and myocardial infarction, CuPB conferred therapeutic benefits after both local and systemic administration, underscoring its translational potential. This proangiogenic nanozyme strategy offers an integrated and effective approach to ischemic tissue regeneration, bridging catalytic nanomedicine and vascular repair.

Adipose tissue has evolved from a passive lipid store to a dynamic, heterogeneous endocrine organ, whose dysfunction is closely linked to a cluster of chronic metabolic diseases. While early studies focused on overall adiposity, emerging evidence demonstrates that depot-specific adipose tissue traits outperform body mass index alone in predicting various disease risks. Adipose tissue heterogeneity refers to the inherent differences across distinct adipose depots, which manifest at anatomical, cellular, and molecular levels, alongside functional specialization. Moving beyond descriptive characterization, this review proposes a multiscale, functionally grounded framework that translates adipose heterogeneity into precision risk management and depot-targeted therapies. We provide a holistic update to cover previously underappreciated adipose depots (perivascular, epicardial, and bone marrow adipose tissues) and integrate recent single-cell sequencing discoveries of novel cell subsets in adipose tissues. We systematically summarize the core hallmarks of adipose heterogeneity and depot-specific roles in health and disease, while assessing the strength of evidence linking cellular subsets to functional outcomes. We also discuss how emerging technologies such as spatial transcriptomics, organoid technology, and artificial intelligence-driven imaging analysis resolve pathogenic niches and build translatable risk models. Finally, we propose a translational framework to overcome key bottlenecks from preclinical validation to clinical implementation, aiming to advance personalized management of diseases related to adipose tissue dysfunction.

Photodynamic therapy (PDT) is a clinically approved therapeutic modality that uses photosensitizers (PSs) to generate reactive oxygen species (ROS) upon light irradiation, enabling disease treatment with minimal invasiveness and excellent spatiotemporal precision. Despite these advantages, conventional PDT is fundamentally constrained by the mismatch between its oxygen dependence and the intrinsically hypoxic tumor microenvironment, which markedly compromises therapeutic outcomes. In this context, type I PSs offer a promising solution because they can produce cytotoxic radicals through electron transfer pathways, thereby reducing dependence on oxygen (O₂) and improving efficacy under hypoxic conditions. Organic framework materials have recently emerged as powerful and versatile platforms for constructing type I PSs, owing to their programmable structures, high porosity, and efficient photoinduced charge separation and electron transfer. Importantly, the modular nature of these frameworks enables rational tuning of both structural motifs and compositional building blocks, allowing systematic regulation of light absorption, redox properties, and ROS generation pathways to maximize type I PDT performance. Moreover, organic frameworks can simultaneously function as nanocarriers for therapeutics, facilitating co-delivery and synergistic combinations (e.g., chemotherapy, immunotherapy, or catalytic therapies) that may achieve more durable and comprehensive tumor control. However, current studies remain fragmented, and there is still a lack of an integrated and mechanistically grounded overview that connects framework design principles with type I ROS generation mechanisms and performance optimization strategies. To address this unmet need, this review provides a comprehensive summary of the design strategies, mechanistic insights, and recent progress in organic framework-based type I PSs. We first outline the fundamental principles of type I photochemistry and the key physical and chemical processes underlying type I PDT. We then highlight rational design and modulation strategies to enhance optical properties, promote charge separation, and strengthen oxygen independence. Next, we summarize representative in vivo/in vitro disease models to demonstrate emerging diagnostic and therapeutic applications. Finally, we discuss current challenges and future opportunities for clinical translation, offering practical guidance for the development of next-generation phototherapeutic agents based on these innovative framework systems.