Advanced Science最新文献

Pituitary adenoma (PA) are common intracranial tumor types that have harmful effects on human health. However, the pathogenesis of PA remains unclear yet. The intratumoral microbiome has been reported playing an important impact on the occurrence, metastasis, immune monitoring, and drug resistance of various tumors. While normal dopamine receptor D2 (DRD2) expression is enriched in the apical junction of pituitary epithelium and colonic enterocytes, various factors-induced drd2 loss dampened its expression at both sites. DRD2 deficiencies are characterized by chronic hyperprolactinemia, pituitary lactotroph hyperplasia, and prolactinomas in mice, but the role of intratumoral microbiome in prolactinomas is not known. We employed specific pathogen-free (SPF) and germ-free (GF) mice models and patient samples of pituitary adenoma. In the mice pituitary tumor model, we used mice that developed prolactinomas following estradiol treatment or DRD2 deficiencies. Pituitary tumor samples from patients with nonfunctional pituitary adenoma or prolactinomas were obtained after surgical excision. Various molecular, cellular, and sequencing techniques were used to determine the role of intratumoral microbiome in pituitary adenoma. We demonstrate that human patients or murine bearing estradiol-induction or DRD2 loss are all characterized by the presence of live intratumor bacteria in the pituitary adenoma. Using metagenomic next-generation sequencing and mass spectrometry techniques, we confirm that the bacterial species of pituitary tumor tissues is Escherichia coli. In vitro tracing and immunofluorescence assay results showed that the pathobiont Escherichia coli translocates from the gut into the pituitary gland along with DRD2 loss while the blood pituitary barrier were both destroyed in mice. The Escherichia coli are phagocytosed by the microglial cells in the pituitary gland, then activate GSDMD protein releasing HMGB1, and promote the tumorigenesis of pituitary adenoma by activating the MAPK pathway. The depletion of bacteria systemically, microglial depletion or HMGB1 inhibitor ethyl pyruvate rescued prolactinomas. Our findings suggest that DRD2 deficiency underlies pituitary adenoma dependent on Escherichia coli translocation from the gut and activating microglia GSDMD/ HMGB1/MAPK pathway, and provide a novel preclinical rationale for antimicrobial agents, microglial depletion, or HMGB1 inhibitor ethyl pyruvate for the treatment of pituitary adenoma.

Glioblastoma (GBM) presents significant challenges in treatment due to the presence of the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment (TME). Here, we developed a novel metal-supramolecular delivery system (FLM@VC) that empowers meningeal lymphatic vessels (MLVs)-bridged intracranial-peripheral dual immune modulation to reverse GBM immune suppression. Using coordination-driven self-assembly of lipoic acid (LA), iron ions (Fe³⁺), and bovine albumin (BSA), we engineered nanoassemblies with Verubecestat (MK-8931) encapsulated and with vascular endothelial growth factor C (VEGF-C) and c(RGDfK) conjugated. Subcutaneously delivered FLM@VC hijacks the MLVs for brain delivery bypassing the BBB, overcoming the limitations of conventional intravenous administration. Upon tumor accumulation, GSH-responsive disassembly releases MK-8931 to reprogram TAMs from the pro-tumoral M2 to the anti-tumoral M1 phenotype, thereby eliciting proinflammatory cytokine secretion and enhancing phagocytic clearance of GBM cells. Concurrently, VEGF-C-mediated MLV expansion enhances dendritic cell (DC) trafficking to deep cervical lymph nodes (dCLNs), potently priming CD8⁺ T cell responses. This MLVs-bridged intracranial-peripheral dual immunomodulation strategy effectively transforms immunologically "cold" GBM into "hot" tumors, resulting in potent tumor eradication and significantly prolonged survival in orthotopic GBM models. It not only presents a novel paradigm for synergistic GBM immunotherapy but also provides an alternative brain drug delivery approach.

This study investigates the influence of post-processing techniques on lipid nanoparticles (LNPs) designed for miRNA delivery in in vitro transfection models. We compared blank and miRNA-loaded LNPs (LNP-miRNA) in terms of size, polydispersity index, zeta potential, electrophoretic mobility, and conductivity. miRNA encapsulation increases lipid particle size by 43.6%, due to structural rearrangements. Post-processing methods, including sonication, filtration, dialysis, and thermal treatment, significantly alter particle characteristics. Sonication and filtration decrease particle size and improve uniformity, enhancing colloidal stability. Dialysis further refines the particle size but decreases its electrophoretic mobility. Non-dialyzed, sonicated, and filtered LNP-miRNA samples demonstrate the most favorable electrokinetic profile, maintaining low conductivity (0.003 mS/cm) and high electrophoretic mobility (3.16 ± 0.22 µm cm/V·s), suggesting optimal stability for gene delivery. Zeta potential measurements show that sonication and filtration increase the surface charge of LNP-miRNA formulations from +18.9 to +29.3 mV, enhancing colloidal stability, while dialysis reduces it to +1.9 mV. Although sonicated and filtered LNP-miRNA samples exhibited more favorable physicochemical properties, the dialyzed formulations modulate intracellular trafficking, resulting in earlier intracellular availability and prolonged persistence of delivered miRNA. This work establishes a framework for optimizing non-viral miRNA delivery by showing how post-processing shapes LNP stability and transfection performance.

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. Here, we identify xanthatin, a sesquiterpene lactone from Xanthium species, as a potent inhibitor of TNBC cell growth with minimal toxicity to normal cells. Transcriptomic analyses revealed that xanthatin activates ferroptosis, evidenced by elevated ROS, lipid peroxidation, and Fe^{2 +} accumulation, together with GSH depletion and downregulation of SLC7A11 and GPX4. Target identification by drug affinity responsive target stability and mass spectrometry uncovered CDGSH iron sulfur domain 1 (CISD1) as the direct binding partner of xanthatin. Cellular thermal shift assay, surface plasmon resonance, and dynamics simulations consistently demonstrated that tryptophan-75 is the critical residue mediating this interaction. Functionally, xanthatin promotes CISD1 ubiquitination and proteasomal degradation, thereby disrupting mitochondrial iron homeostasis and inducing ferroptosis. CISD1 destabilization further impaired mitochondrial integrity and activated PINK1/Parkin-dependent mitophagy, establishing a dual ferroptosis-mitophagy mechanism. Importantly, genetic knockdown of CISD1 markedly attenuated the anticancer activity of xanthatin, confirming its essential role. In an orthotopic TNBC mouse model, xanthatin significantly suppressed tumor growth without causing systemic toxicity. Collectively, our findings provide the first demonstration that xanthatin directly targets CISD1 at the Trp-75 site to trigger ferroptosis and mitophagy, highlighting its promise as a therapeutic candidate for TNBC.

Integrating high-nickel cathodes with lithium metal anodes enables ultrahigh-energy-density batteries but remains challenged by electrolyte instability under extreme temperatures. Here, we design an anion-dominated loose solvation structure, where fluorine-rich weak solvents occupy coordination sites. γ-Valerolactone (GVL) serves as the primary solvent, assisted by two weakly coordinating co-solvents: difluoroethylene carbonate (DFEC) to modulate solvation and ethyl trifluoroacetate (ETFA) to reduce viscosity and freezing point. This balanced solvation environment enhances ionic transport, interfacial stability, and desolvation kinetics. Consequently, Li||NCM811 cells deliver stable cycling at 100°C, exceeding 90 cycles, negligible capacity loss at -40°C, and 90.4 mAh g^-1 at -60°C. Full cells (N/P ≈ 1.8) retain 90.3% capacity after 130 cycles. This work offers a viable solvation design for high-voltage lithium metal batteries operating across extreme temperatures.

This study explores tunable sound absorption using a bilayer configuration of phase-gradient acoustic metasurfaces. By carefully adjusting the cavity length between two metasurface layers, the proposed system can modulate its acoustic response between highly reflective and perfectly absorptive states without changing the internal geometry of the unit cells. The underlying mechanism results from evanescent-wave coupling, which becomes significant at sub-wavelength cavity length and is strongly influenced by the phase gradient and integer parity of each metasurface. To analyze the scattering behavior of the bilayer system, an analytical model based on coupled-mode theory is developed, identifying the conditions that ensure both reflection and transmission are effectively suppressed. Theoretical predictions are validated by full-wave simulations using bilayer metasurfaces realized with space-coiling structures. The results demonstrate broadband tunability in sound absorption, with optimal configurations achieving an absorption coefficient exceeding 95%. Owing to its structural simplicity and high tunability, the proposed approach offers an effective solution for dynamic sound control in applications such as tunable noise barriers and reconfigurable sound-absorbing devices.

Bronchopulmonary dysplasia (BPD) disrupts the process of alveolar development, characterized by damage to alveolar epithelial type II cells (AEC II). The present study aims to evaluate the impact of the tryptophan-derived metabolite indole-3-propionic acid (IPA) on postnatal pulmonary development in BPD. Metabolomics indicated that tryptophan metabolic dysfunction is associated with BPD, with IPA emerging as a key metabolite that co-varies at neonatal levels in both clinical and experimental BPD. Supplementation with IPA protected against hyperoxia-induced alveolar simplification, which was characterized by increased pro-proliferative, anti-apoptotic, and pro-transdifferentiation activities. Mechanistically, we evaluated circular dichroism (CD), molecular docking, surface plasmon resonance (SPR), and immunoprecipitation techniques, and speculated that IPA exerted its inhibitory effect on phosphorylation of vesicle associated membrane protein 8 (VAMP8) through direct molecular binding. This interaction influenced the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex and subsequently promotes autophagosome-lysosome fusion. In summary, IPA alleviates hyperoxia-induced alveolar arrest by promoting autophagosome-lysosome fusion via inhibition of VAMP8 phosphorylation, which is suggestive of a promising therapeutic target of BPD.

Aberrant Notch signaling has been identified as a key driver of cancer development. Genetic studies in Drosophila showed that the knockout of strawberry notch (sno) mimics the loss of notch. Here, we found that Strawberry Notch 1 (SBNO1) is upregulated in several cancer entities and elucidated the role of SBNO1 in liver cancer development. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), SBNO1 protein was significantly increased and localized to the nucleus suggesting its involvement in gene regulation. SBNO1-inhibition reduced cell viability, colony formation and migration and induced distinct expression patterns in HCC and CCA cell lines. However, BioID revealed that SBNO1 similarly modulates gene regulation in HCC and CCA by binding to general transcription factors TAF4 and TAF3. Deletion of Sbno1 in murine liver cancer cells Hep55.1C reduced tumor growth in vivo. In addition, inhibition of Sbno1 significantly reduced liver tumor development in three different mouse models of HCC and CCA. Furthermore, Sbno1-deletion reduced biliary differentiation and angiogenesis in the tumor margin, underscoring the necessity of Sbno1 in Notch-driven CCA formation. Thus, we identified SBNO1 as a transcriptional regulator required for liver cancer development and progression.

Bioprinting is a powerful tool for engineering living grafts, however replicating the composition, structure and function of native tissues remains a major challenge. During morphogenesis, cellular self-organization and matrix development are strongly influenced by the mechanical constraints provided by surrounding tissues, suggesting that such biophysical cues should be integrated into bioprinting strategies to engineer more biomimetic grafts. Here, we introduce a novel bioprinting platform that spatially patterns mesenchymal stem/stromal cell (MSC)-derived microtissues into mechanically tunable support baths. By modulating the bath's mechanical properties, we can precisely control the physical constraints applied post-printing, directing both filament geometry and cellular behavior. Support bath stiffness regulated mechano-sensitive gene expression and microtissue phenotype, with softer matrices favoring chondrogenesis and stiffer environments promoting (myo)fibrogenic differentiation. In addition, the physical properties of the non-degradable support bath modulated microtissue fusion and extracellular matrix organization, with increased collagen fiber alignment in stiffer baths. Leveraging these findings, it was possible to engineer either articular cartilage, meniscus, or ligament grafts with user-defined collagen architectures by simply varying the physical properties of the support bath. This platform establishes a foundation for bioprinting structurally anisotropic and phenotypically distinct constructs, thereby enabling the scalable engineering of a range of different musculoskeletal tissues.

The ongoing demand for high-thrust turbine engines necessitates the advance of next-generation structural materials capable of withstanding higher temperatures. Commercial MCrAlY alloy, used as bond coats crucial for thermal barrier coating (TBC) systems, face a fundamental temperature ceiling of ∼1100 °C due to accelerated oxidation and spallation. Here, we design a novel Y and Hf co-doped NiCoCrAl-type multi-principal element alloy (MPEA) that achieves exceptional 1200 °C oxidation resistance primarily through lattice distortion-induced diffusion suppression. Compared with typical NiCoCrAlY alloy, the MPEA exhibits 59% lower in thermally grown oxide (TGO) growth rate, as well as negligible TGO spallation after 500 h at 1200°C. This performance stems from a significantly refined eutectic structure enabling rapid formation of a protective Al₂O₃ scale during initial oxidation, coupled with lattice distortion that elevates vacancy formation energy and Al migration barriers within the Al-depletion zone (ADZ), drastically reducing sustained diffusion rates. This co-design strategy, integrating tailored microstructure and lattice distortion, establishes a new paradigm for ultra-stable performance in extreme environments.