Advanced Science最新文献

Metallothionein 3 (Mt3) is crucial for cellular homeostasis and neuroprotection, with accumulating evidence linking it to amyloid-beta (Aβ) clearance by astrocytes. This study developed a CRISPR activator (CRISPRa) system using lipid nanoparticles to selectively upregulate Mt3 in astrocytes, aiming to enhance Aβ endocytosis in an Alzheimer's disease (AD) mouse model. To directly assess the therapeutic potential of Mt3 activation in a specific brain region, stereotaxic injection is utilized to deliver the CRISPRa lipid nanocomplexes. This approach enabled precise in vivo brain delivery and Mt3 activation. The findings reveal that CRISPRa lipid nanocomplex-mediated Mt3 upregulation significantly boosts Aβ uptake by astrocytes, leading to a marked reduction in Aβ plaque accumulation in AD mouse brains. These results highlight CRISPRa lipid nanocomplex-mediated Mt3 targeting as a promising strategy to enhance endogenous Aβ clearance, presenting a novel therapeutic avenue for AD.

Postharvest preservation urgently demands innovative solutions bridging atomic precision with practical scalability. Here, a distinctive photocatalysis-driven self-assembly strategy is presented that fundamentally diverged from conventional high-temperature syntheses by enabling precise single-atom coordination under ambient conditions. This approach, utilizing α-lipoic acid (α-LA) as coordination ligand, achieved the mild assembly of S-coordinated Cu single-atom nanozymes (Cu/CNS) while significantly enhancing their enzymatic activity. The resulting material demonstrated unprecedented multi-enzyme mimetic activities (catalase-, oxidase-, and glutathione oxidase-like) with catalytic efficiency surpassing conventional nanozymes by orders of magnitude. The Cu/CNS exhibits near-perfect antimicrobial efficacy against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Botrytis cinerea (B. cinerea) through synergistic mechanisms. When integrated into chitosan-gelatin films (Cu/CNS@CS-Gel), it forms active packaging with pH-responsive behavior, exceptional barrier properties, and mechanical strength. Crucially, the synthesis is simple, scalable, and environmentally adaptable. Using strawberries and kiwifruits as representative examples, Cu/CNS@CS-Gel more than doubled the shelf life while efficiently maintaining nutritional quality. Beyond food packaging, this coordination chemistry platform is generalizable to other metal-ligand systems, offering a versatile toolbox for sustainable agriculture. By bridging atomic-level design with practical feasibility, the work advances sustainable nanozyme implementation in food systems.

Magnetic anisotropy modulation is central to spintronics. 2D ferromagnetic materials (2D FMs), with their atomic-level thickness, tunable electronic structures, and high sensitivity to external stimuli, provide unprecedented opportunities for precise magnetic control. Particularly, the van der Waals (vdW) gap holds promise for effective magnetic anisotropy modulation. However, the microscopic mechanisms remain elusive. Here, it is demonstrated that epitaxial growth of α-Al₂O₃/Fe₄GeTe₂ induces a pronounced expansion of the vdW gap (up to 0.51 Å) at the interface, leading to a robust enhancement of in-plane magnetic anisotropy (IMA) and suppression of the spin reorientation temperature (T_SR) from 288 K to undetectable levels. This counterintuitive behavior contrasts with conventional thickness-dependent perpendicular magnetic anisotropy (PMA). Combined experimental and theoretical analyses reveal that vdW gap expansion reduces Te p_x/p_y orbital overlap, diminishing their contribution to magnetocrystalline anisotropy energy and suppressing PMA. These findings establish interface gap engineering as a novel route for tailoring magnetic anisotropy in 2D FMs, advancing the design of next-generation spintronic devices.

This paper presents a novel design methodology for automatically constructing soft robots with modular, LEGO-like origami actuators. By assembling these modular soft actuators, intricate robotic systems can be created. The key innovation of the work lies in the incorporation of thickness accommodation into kinematics models and the optimization-based assembly strategy standardizing the design process. This approach has been validated through two LEGO-like origami actuators, which are then assembled guided by the assembly strategy. A robot arm built by these actuators showcased a remarkable position accuracy, deviating by only 3 mm at the tip over a 400 mm span. Furthermore, two soft robots are successfully designed, built, and tested for manipulation and tight space inspection, and a bipedal walking robot, confirming the feasibility of the design algorithm for functional robotic systems. This work offers a comprehensive design framework that standardizes the assembly of LEGO-like origami actuators into accurate and functional robotic systems.

Evidence on pre-transplant metabolic therapy remains limited. We evaluated whether concurrent glucagon-like peptide-1 receptor agonist (GLP-1 RA) plus sodium-glucose cotransporter 2 inhibitor (SGLT2i) use before solid-organ transplantation is was associated with post-transplant outcomes in adults with obesity and type 2 diabetes. A target trial is emulated using de-identified electronic health records from TriNetX US. Dual therapy is compared with GLP-1 RA, SGLT2i, and usual care using 1:1 propensity-score matching. The primary outcome is all-cause mortality at 12 months; kidney graft failure, rejection, complications, and infections are secondary. Sensitivity analyses included the global network, landmark, extensions at 24 and 36 months. Three matched cohorts are constructed, dual versus GLP-1 RA (n = 4718 pairs), dual versus SGLT2i (n = 4282), and dual versus usual care (n = 3787). At 12 months, dual therapy is associated with lower mortality versus GLP-1 RA (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.57-0.85), SGLT2i (0.59, 0.48-0.72), and usual care (0.52, 0.43-0.64). Infection endpoints are neutral or lower. Estimates are consistent across sensitivity analyses. In transplant candidates with obesity and type 2 diabetes, pre-transplant GLP-1 RA+SGLT2i use is associated with lower mortality than monotherapy or usual care. Prospective evaluation is warranted.

Colorectal cancer (CRC) progression is regulated by an immunosuppressive tumor microenvironment, but the epigenetic mechanisms governing this milieu remain unclear. This study identifies the histone demethylase KDM6B as a key regulator of myeloid-derived suppressor cells (MDSCs) recruitment in CRC. Intestinal epithelial-specific KDM6B deletion promotes tumor growth by increasing MDSCs-mediated immunosuppression. Mechanistically, KDM6B directly transcriptionally activates solute carrier family 10 member 2 (SLC10A2), whereas its loss increased H3K27me3 repression at the SLC10A2 promoter, activating the ERK/AP-1 pathway and subsequent CXCL/CXCR2-dependent MDSC recruitment. Clinically, KDM6B expression positively correlated with SLC10A2 levels and inversely correlated with MDSC infiltration in human CRC specimens. More importantly, KDM6B knockdown conferred resistance to anti-PD-1 therapy in CRC, whereas its overexpression synergized with anti-PD-1 therapy. In conclusion, this study establishes the KDM6B-SLC10A2 axis as a novel epigenetic immune checkpoint, highlighting its potential as a therapeutic target for reprogramming the immunosuppressive microenvironment in CRC.

The sluggish kinetics of the oxygen reduction reaction (ORR) remain a major bottleneck for energy conversion systems such as fuel cells and metal-air batteries. Here, the synthesis of molybdenum single-atom catalysts (Mo SACs) derived from abundant and low-cost Kraft lignin is reported. By tuning nitrogen incorporation during carbonization, agglomerated Mo carbide clusters are progressively converted into atomically dispersed Mo active centers anchored on N-doped carbon. Extensive spectroscopic analyses confirm this structural evolution, while density functional theory calculations reveal that the optimized Mo coordination environment downshifts the d-band center, enabling the balanced adsorption of oxygen intermediates and thereby improving the intrinsic ORR activity. Electrochemical measurements demonstrate enhanced half-wave potential, near-four-electron transfer pathway, superior selectivity, and excellent durability, with ≈85% current retention over 50 h. Beyond performance, the use of minimally processed Kraft lignin underscores both the economic and environmental advantages of this approach, offering a scalable and sustainable pathway to practical ORR electrocatalysts.

Targeted protein degradation (TPD) represents a transformative therapeutic paradigm that harnesses the cellular degradation machinery to pharmacologically eliminate disease-causing proteins with aberrant expression. This work here reports the first design of an HSP70 interactome-mediated proteolysis targeting chimera (HSP70-PROTAC) for the degradation of the intracellular therapeutically relevant proteins via dual processes of ubiquitin-proteasomal degradation (UPS) and chaperone-mediated autophagy (CMA). By hijacking the highly expressed heat shock cognate protein (Hsc70) isoform complex in tumor tissues to glutathione peroxidase 4 (GPX4) protein, this work successfully develops an HSP70-PROTAC molecule GDAz-3 that potently and rapidly eliminates GPX4 in HT1080 cells, thereby triggering ferroptosis with high selectivity. Correspondingly, GDAz-3 exhibits a remarkable tumor-inhibitory effect in the HT1080 xenograft tumor mouse model without obvious toxicity. In addition, this work demonstrates the versatility of HSP70-based PROTACs by effectively degrading additional endogenous bromodomain-containing protein 4 (BRD4) in cancer cells. More importantly, the degradation of GPX4 mediated by GDAz-3 occurs with comparable efficiency in CRBN/VHL-knockdown cells and 786-O cells intrinsically lacking VHL expression, which facilitates expanding the application scope and overcoming drug resistance of traditional PROTAC. These findings suggest that HSP70-PROTAC is a novel and feasible strategy for the future development of TPD technology.

Depression, a common neuropsychiatric disorder, profoundly disrupts individuals' daily lives. Although the pathogenesis of depression is intensively investigated for decades, its underlying mechanisms remain elusive. Here, dysfunctional adenylyl cyclase 8 (Adcy8) is identified as a critical risk factor for the development of depression. Adcy8 expression is selectively decreased in the hippocampus, but not in the cortex, thalamus, and hypothalamus, of mice exposed to chronic stress. Adcy8 conditional knockout (CKO) in excitatory neurons, particularly dorsal CA1 (dCA1) neurons, resulted in pronounced depressive-like behaviors. Depletion of Adcy8 in dCA1 neurons reduces neuronal excitability and glutamatergic neurotransmission. Further mechanistic studies reveal a remarkable inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway by Adcy8 CKO, which downregulates parathyroid hormone 2 receptor (PTH2R) level in the hippocampus. Knocking down Pth2r with AAV-shRNA duplicates the impairments in neuronal excitability, glutamatergic neurotransmission and depressive-like behaviors. In contrast, overexpression of PTH2R in Adcy8 CKO hippocampus rescues these deficits. Chronic infusion of TIP39, the endogenous ligand for PTH2R, into the hippocampus also alleviates depressive-like behaviors of Adcy8 CKO mice. Taken together, these results uncover critical roles of Adcy8 in suppressing depressive-like behaviors, likely by maintaining the excitability and glutamatergic neurotransmission of dCA1 neurons through TIP39-PTH2R signaling pathway.