Advanced Science最新文献

The molecular mechanisms linking type 2 diabetes to increased neurodegenerative risk remain poorly defined. Given the critical involvement of microglial dysfunction in neurodegeneration, we constructed a temporal single-cell atlas integrating transcriptomic and epigenomic profiles of microglia from diabetic (db/db) and control (db/m) mice across the lifespan. We delineated a nonlinear, diabetes-specific pathological trajectory characterized by early inflammatory activation, a mid-stage inflection in neurodegeneration-associated signaling and metabolic stress, and late-stage dysfunction. Chromatin accessibility profiling revealed early and persistent epigenomic priming of neurodegeneration-associated pathways, accompanied by stage-specific enhancer rewiring. Pseudotime analysis identified a disease-associated microglial (DAM) state as a candidate transition node, characterized by biased polarization and accelerated maturation under diabetic conditions. Targeted validation using freshly isolated microglia and primary microglial cultures further supported the early expansion of the DAM population, a bias toward homeostatic-to-DAM activation, and Arhgap15-dependent regulation of phagocytic activity. Together, these findings identify microglial states and candidate regulatory pathways that may link diabetes to neurodegenerative vulnerability.

Tumor starvation therapy is a promising metabolism-targeting intervention, yet its efficacy is largely counteracted by lipid droplet (LD)-driven compensatory metabolism in malignant cells. Existing LDs-targeted approaches are further hampered by off-target systemic metabolic disturbances and inherent immunosuppressive adverse effects. Here, we construct a zeolitic imidazolate framework-8 (ZIF-8)-based nanomedicine loaded with 2-deoxy-D-glucose (2-DG) and surface-decorated with copper-tannic acid (Cu-TA, ZIF-8/2-DG@Cu-TA). This nanosystem reroutes intracellular LDs from tumor cells to adjacent cancer-associated fibroblasts (CAFs) to realize synergistic tumor starvation and immunotherapy. In the acidic tumor microenvironment, the degradable Cu-TA coating activates connexin 43 (Cx43) hemichannels on CAFs. After internalization by tumor cells, ZIF-8/2-DG releases 2-DG to suppress glycolysis, while dissociated zinc ions disrupt mitochondrial bioenergetics and further trigger Cx43 hemichannels activation on tumor cells. Fully assembled Cx43 gap junctions mediate directional LDs trafficking from tumor cells to CAFs, restricting intracellular lipid energy pools sustaining malignant metabolic demands. Simultaneous blockade of glycolysis, mitochondrial respiration and lipid metabolism induces profound tumor-cell metabolic collapse. The resulting metabolic stress strongly amplifies antitumor immunity and markedly suppresses both subcutaneous and orthotopic MOC1 tumors. Overall, this study establishes a gap-junction-driven triple metabolic starvation paradigm and offers mechanistic insights for next-generation metabolic immunotherapies.

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in the elderly, and geographic atrophy (GA) represents its advanced atrophic form. While C5 and C3 inhibitors have shown efficacy in slowing GA progression, the precise pathogenic roles of individual complement effectors and the optimal inhibition strategy remain subjects of ongoing debate. This study employs an in vitro model using A2E-laden retinal pigment epithelium (RPE) cells and normal human serum to systematically investigate complement-mediated RPE degeneration and compare the protective effects of different complement-targeting strategies. We demonstrate that C5 blockade, while preventing lytic cell death caused by the membrane attack complex (MAC), fails to fully restore mitochondrial function or prevent phagolysosomal damage. Crucially, these C5-independent pathologies involve C3 activation products. In contrast, upstream C3 inhibition comprehensively protects RPE cells by ameliorating these diverse pathological processes. Our findings provide a detailed mechanistic understanding of complement-driven RPE degeneration and support a mechanistic rationale for an upstream C3-targeting strategy in GA secondary to AMD.

Non-thermal food preservation demands catalytic platforms that achieve potent antimicrobial efficacy without compromising heat-labile nutrients. Yet whether a sonocatalyst merely seeds bubble nucleation or actively channels transiently concentrated acoustic energy into chemical work has remained unresolved, and the violent, opaque nature of cavitation further precludes operando observation of catalyst surfaces. Herein, an MXene/TiO₂ Schottky heterointerface is engineered with the aim of localizing cavitation collapse at the catalyst-liquid boundary through three cooperatively acting determinants: a built-in electric field for charge separation, hierarchical surface roughness for energy focusing, and pre-existing oxygen vacancies for dynamic defect modulation. A convergent multi-proxy evidence chain, comprising passive cavitation imaging, single-bubble computational fluid dynamics, chronoamperometry, quasi-in situ spectroscopy, and ab initio molecular dynamics (AIMD), supports a working model of this interface-confined cavitation regime. Under 40 kHz ultrasound without external heating, the interface delivers 3-log inactivation of the tested indicator bacteria (E. coli and S. aureus) at the laboratory scale, while preserving 82% of vitamin C and 88% of total anthocyanin content in juice. This work thus proposes interface-confined cavitation as a transferable design rationale for sonocatalytic interfaces, with operando validation of the active interface as the decisive next step.

Myofiber hypertrophy is central to economically important agricultural traits and vertebrate development, yet the underlying cellular and molecular programs remain elusive. Chickens have undergone substantial divergence in muscle growth following decades of artificial selection, making them a unique model for dissecting these mechanisms at single-cell resolution. Here, we performed singlenucleus RNA sequencing on 91 144 nuclei from postnatal chicken pectoralis major. Eight major conserved cell populations were resolved, with temporal dynamics exhibiting divergence between fast-growing broilers and slow-growing layers. A novel terminally differentiated myocyte subpopulation (AK1⁺ myocytes) was markedly enriched in slow-growing birds. Analysis revealed that accelerated myoblast expansion and delayed terminal differentiation are primary drivers of myofiber hypertrophy, supported by a pro-growth niche involving IGF-signaling FAPs and macrophage-myogenic crosstalk. Further comprehensive analyses identified CREM as a master repressor of myofiber hypertrophy. Mechanistically, CREM directly binds and transcriptionally activates the JUN promoter, and both factors cooperatively sustain the expression of growth inhibitors MSTN, FBXO32, and TRIM63. In vivo and in vitro functional validation confirmed that CREM deletion promotes myofiber hypertrophy, increasing pectoralis major weight and percent by 29.96% and 20.50%, respectively. This study uncovers CREM as a novel brake on myofiber hypertrophy, offering fundamental insights into vertebrate skeletal muscle development.

Improving therapeutic efficacy and antitumor immune responsiveness in BRCA1-mutant ovarian cancer remains challenging. Here, we developed a BRCA1 mutation-guided tetrahedral framework nucleic acid nanosystem, FBOA-tFNA, for coordinated intracellular delivery of the PARP inhibitor olaparib and the WEE1 inhibitor adavosertib. After folate receptor-mediated uptake, FBOA-tFNA recognizes BRCA1 mutant RNA through toehold-mediated strand displacement, enabling mutation-selective beacon activation, while drug release is independently regulated by reduction-responsive disulfide cleavage. Coordinated PARP/WEE1 inhibition amplified DNA damage, impaired G2/M checkpoint protection, and promoted tumor-cell killing in BRCA1-mutant ovarian cancer models. Resulting DNA damage-associated intracellular dsDNA signals activated STING-associated signaling, type I interferon responses, immunogenic cell death (ICD)-associated stress, dendritic-cell maturation, and CD8⁺ T-cell activation. Engineered patient-derived ovarian cancer organoids expressing a BRCA1^2594delC-containing transcript further supported the mutation-selective recognition and therapeutic potential of FBOA-tFNA ex vivo. In vivo, FBOA-tFNA showed tumor-associated fluorescence accumulation, BRCA1 mutant-transcript recognition-associated beacon activation, enhanced antitumor efficacy, and preliminary repeated-dose tolerability. Moreover, FBOA-tFNA enhanced antitumor immune responses and improved the response to anti-PD-1 therapy, accompanied by increased effector and memory-like T-cell populations. This programmable DNA nanoplatform provides a personalized combination strategy for coordinated DNA-damage therapy and immunomodulation in BRCA1-mutant ovarian cancer.

Flexible sensing technology based on hydrogel-based smart gloves enables accurate gesture recognition in complex environments, but such gloves degrade in dry, high-temperature, and underwater conditions, and their complex assembly limits practical usability. Here, a smart glove monitoring system is developed by integrating a poly(benzyl methacrylate-co-2-hydroxyethyl acrylate)/ionic liquid (P(BZMA-co-HEA)/IL) ionogel sensing layer with a flexible printed circuit board (FPCB). The ionogel is constructed through a network-constrained ionic soft-space regulation strategy, where HEA-rich segments strengthen the network, IL provides deformation-adaptive ionic soft spaces, and BZMA-rich hydrophobic segments suppress water penetration. The optimized ionogel combines stretchability (up to 1100%), weight retention (98.86% at room temperature and 95.25% at 65°C), favorable adhesion, anti-swelling behavior, and stable sensing performance under multiple environmental conditions. The FPCB enables a detachable and reconfigurable sensor array, ensuring stable interfacial contact and wearing flexibility. By further combining multi-channel signal acquisition, fully connected neural network (FCNN)-assisted gesture classification, and real-time alert feedback, the smart glove functions as an integrated sensing-recognition-warning platform, achieving 99.92% gesture recognition accuracy and enabling reliable underwater communication and safety warning. This work establishes an effective material design and integration strategy for environmentally adaptive smart gloves.

Ischemic postconditioning (IPostC) mitigates myocardial ischemia/reperfusion (I/R) injury, but its regulation of mitochondrial dynamics in the aged heart remains unclear. This study investigates the underlying mechanisms by evaluating PIWI-interacting RNA (piRNA) expression profiles after I/R injury. Functional assays using piR-4913 silencing assess its impact on infarct size, mitochondrial ATP production, and oxidative stress. Mechanistic analyses identify that piR-4913, a cardiac-enriched piRNA markedly upregulated in aged hearts following I/R injury, is effectively suppressed by IPostC. Silencing piR-4913 confers cardioprotection by limiting infarct size, enhancing ATP production, and reducing oxidative stress. Mechanistically, piR-4913 acts as a key facilitator that promotes the recruitment of OGT to Drp1, thereby catalyzing the O-GlcNAcylation modification of Drp1 at Thr604. This modification promotes Drp1 mitochondrial translocation and Fis1 interaction, driving excessive mitochondrial fission and dysfunction. In vivo validation using a Drp1-T604A mutant demonstrates profound resistance to I/R injury, confirming the critical role of Thr604 O-GlcNAcylation in age-related cardiac damage. Collectively, IPostC exerts cardioprotection in the aging heart by restraining the piR-4913/OGT/Drp1 axis, thereby restoring mitochondrial proteostasis and dynamics. This pathway represents a promising therapeutic target to improve clinical outcomes in elderly patients with myocardial infarction.

Intervertebral disc degeneration (IVDD) is a major cause of low back pain, driven largely by nucleus pulposus cell (NPC) senescence under chronic hypoxia and nutrient stress. Serine metabolism regulates senescence, but its role in IVDD remains unclear. Here, transcriptomic profiling reveals that the glycine-serine-threonine pathway is downregulated in senescent NPCs, with marked reduction of the serine synthesis rate limiting enzyme PHGDH. This is confirmed by single cell RNA sequencing of human discs, aged rat tissues, and degenerated human samples, accompanied by decreased intracellular serine. PHGDH silencing or serine deprivation inhibits NPC proliferation, induces senescence, and suppresses matrix anabolism. Mechanistically, PHGDH deficiency lowers α ketoglutarate, impairing histone demethylation and increasing H3K27me3 occupancy at the Rap1b promoter, which silences Rap1b and activates mTORC1, thereby blocking autophagic flux. Additionally, serine starvation depletes glutathione, elevates ROS, and promotes apoptosis. In vivo, AAV mediated PHGDH overexpression alleviates puncture induced IVDD, while a serine deficient diet exacerbates degeneration. Collectively, we uncover a PHGDH/Rap1b/mTORC1/autophagy cascade linking serine deprivation to NPC senescence, and propose that restoring PHGDH or serine availability may be a viable strategy to combat age related disc degeneration.

Active three-dimensional sensing requires accurate light delivery and sufficient return-signal strength, while complex scenes require a tunable balance between local power concentration and illumination coverage. Collimated beam illumination supports a longer maximum detectable distance by concentrating optical power, whereas expanded beam illumination improves angular sampling efficiency by increasing coverage per projection. Existing active-illumination approaches typically use fixed illumination patterns or predefined scanning trajectories, making it difficult to balance local power concentration for maximum detectable distance with illumination coverage for sampling efficiency. Here we propose an adaptive active-illumination method based on translationally and axially tunable cascaded metasurfaces (TATCMs). TATCMs control the beam output angle within the field of view (FoV) through lateral translation and tune illumination coverage through axial-spacing tuning. At an operating wavelength of 905 nm, the implemented TATCMs demonstrate continuous beam-output-angle control across an approximately 70°×70° FoV under a ±300 µm lateral stroke, while increasing the interlayer spacing by 2.64 mm expands collimated beam illumination with a measured divergence of 0.06° to provide continuous coverage across the FoV. Adaptive three-dimensional reconstruction further demonstrates the potential of TATCMs as a compact planar illumination platform for scene-adaptive three-dimensional sensing in autonomous vehicles, unmanned aerial vehicles, and industrial robotics.