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Autonomous Polymer Frameworks for Sustainable Tissue‐Interfaced Plastic Bioelectronics

This review focuses on plastic bioelectronic systems integrated with autonomous polymer frameworks (auto‐POFs) and summarizes recent progress in this field. It provides an in‐depth analysis of the design strategies and operational mechanisms of auto‐POFs, highlighting their pivotal role in enhancing the sustainability and interfacial adaptability of bioelectronic systems, and outlines the future direction for the development of next‐generation wearable and implantable systems. Abstract Recent advancements in polymer science have enabled the development of plastic bioelectronics, providing soft, stretchable, and tissue‐conformable technologies for continuous health monitoring, diagnostics, and therapeutic interventions. Unlike conventional silicon‐based electronics that often exhibit mechanical mismatches with biological tissues, plastic bioelectronic systems leverage intrinsically soft and mechanically compliant organic and polymer materials to achieve enhanced conformability. This reduces interfacial stress and enables high‐fidelity signal acquisition from dynamic tissue interfaces. However, the low mechanical modulus that enables their unique advantages also makes these systems susceptible to mechanical damage, weak adhesion, and functional degradation under physiological conditions. To overcome these limitations, emerging research focuses on integrating autonomous polymer frameworks (auto‐POFs)–engineered materials that endow the polymer matrix with self‐adhesion, self‐protection, self‐healing, self‐degradation, and self‐sensing capabilities. These features enable real‐time responsiveness to stimuli and extend device lifespan without external intervention. This review provides a comprehensive overview of recent progress in auto‐POF‐based systems, including their material design strategies, functional mechanisms, and roles in enhancing the reliability and adaptability of sustainable, wearable, and implantable tissue‐interfaced plastic bioelectronics. By highlighting key material innovations and device architectures, the path is outlined toward next‐generation biomedical platforms capable of autonomous and sustainable operation in dynamic biological environments. This review focuses on plastic bioelectronic systems integrated with autonomous polymer frameworks (auto-POFs) and summarizes recent progress in this field. It provides an in-depth analysis of the design strategies and operational mechanisms of auto-POFs, highlighting their pivotal role in enhancing the sustainability and interfacial adaptability of bioelectronic systems, and outlines the future direction for the development of next-generation wearable and implantable systems. Abstract Recent advancements in polymer science have enabled the development of plastic bioelectronics, providing soft, stretchable, and tissue-conformable technologies for continuous health monitoring, diagnostics, and therapeutic interventions. Unlike conventional silicon-based electronics that often exhibit mechanical mismatches with biological tissues, plastic bioelectronic systems leverage intrinsically soft and mechanically compliant organic and polymer materials to achieve enhanced conformability. This reduces interfacial stress and enables high-fidelity signal acquisition from dynamic tissue interfaces. However, the low mechanical modulus that enables their unique advantages also makes these systems susceptible to mechanical damage, weak adhesion, and functional degradation under physiological conditions. To overcome these limitations, emerging research focuses on integrating autonomous polymer frameworks (auto-POFs)–engineered materials that endow the polymer matrix with self-adhesion, self-protection, self-healing, self-degradation, and self-sensing capabilities. These features enable real-time responsiveness to stimuli and extend device lifespan without external intervention. This review provides a comprehensive overview of recent progress in auto-POF-based systems, including their material design strategies, functional mechanisms, and roles in enhancing the reliability and adaptability of sustainable, wearable, and implantable tissue-interfaced plastic bioelectronics. By highlighting key material innovations and device architectures, the path is outlined toward next-generation biomedical platforms capable of autonomous and sustainable operation in dynamic biological environments. Advanced Science, EarlyView.

One‐Step Coaxial 3D Printing of Pre‐Vascularized Skin Organoid Models with ADSC Microspheres for Enhanced Wound Healing

A multifunctional vascular bed platform is created using coaxial 3D printing, allowing the one‐step integration of organoid microspheres with perfusable vascular structures. This strategy enables rapid and functional vascularization of organoids to support tissue repair and vascularization, providing a scalable and translationally promising approach for advancing organ regeneration therapies. Abstract Organoids are important tools for studying organ development, drug screening, and regenerative medicine, yet the absence of integrated vasculature limits their culture and translation. To address this, the PV‐XOM strategy is proposed, which achieves one‐step construction of pre‐vascularized organoids through coaxial bioprinting: the inner phase uses temperature‐responsive sacrificial material and endothelial cells to form hollow vascular channels, while the outer phase is a biomimetic hydrogel matrix containing organoid microspheres. Based on this framework, a pre‐vascularized skin organoid model (PV‐SOM) is established, in which the outer phase is loaded with adipose‐derived stem cell (ADSC) microspheres and skin fibroblasts. In vitro, PV‐SOM achieved rapid vascular closure and maturation; in vivo, it formed abundant neovessels in large skin defects, accelerated wound closure, and improved collagen remodeling. Proteomic analysis further revealed that ADSC microspheres activate the PI3K–AKT–mTOR pathway to regulate vascular formation across multiple stages. These findings show that PV‐XOM offers an effective, scalable solution to the vascularization bottleneck of organoids with strong translational potential. A multifunctional vascular bed platform is created using coaxial 3D printing, allowing the one-step integration of organoid microspheres with perfusable vascular structures. This strategy enables rapid and functional vascularization of organoids to support tissue repair and vascularization, providing a scalable and translationally promising approach for advancing organ regeneration therapies. Abstract Organoids are important tools for studying organ development, drug screening, and regenerative medicine, yet the absence of integrated vasculature limits their culture and translation. To address this, the PV-XOM strategy is proposed, which achieves one-step construction of pre-vascularized organoids through coaxial bioprinting: the inner phase uses temperature-responsive sacrificial material and endothelial cells to form hollow vascular channels, while the outer phase is a biomimetic hydrogel matrix containing organoid microspheres. Based on this framework, a pre-vascularized skin organoid model (PV-SOM) is established, in which the outer phase is loaded with adipose-derived stem cell (ADSC) microspheres and skin fibroblasts. In vitro, PV-SOM achieved rapid vascular closure and maturation; in vivo, it formed abundant neovessels in large skin defects, accelerated wound closure, and improved collagen remodeling. Proteomic analysis further revealed that ADSC microspheres activate the PI3K–AKT–mTOR pathway to regulate vascular formation across multiple stages. These findings show that PV-XOM offers an effective, scalable solution to the vascularization bottleneck of organoids with strong translational potential. Advanced Science, EarlyView.

An Engineered Solidified Peptide Hemocyte Sponge as Nanomotor Storage to Combat Bacterial Colitis

Peptides immobilized via nickel coordination can stabilize the framework structure. Following coating with red blood cell membranes, these constructs are capable of continuously sequestering endotoxins and mitigating colonic pathogenic damage by alleviating bacterial‐induced ferroptosis. Abstract The emergence of drug‐resistant bacteria has significantly heightened the urgency for effective interventions within the global public healthcare system. Furthermore, the structural diversity of endotoxins across different bacterial species poses a major limitation on the clearance efficiency of structure‐specific anti‐endotoxin antibodies. In this study, a peptide‐based material with membrane‐disrupting functionality is developed. The topological configuration of the peptide is immobilized through Ni2+ coordination, and the thrust force generated by a redox reaction is harnessed to facilitate deep tissue penetration and enhance resistance to oxidative degradation. Notably, it is discovered that the immobilized peptide‐based nanomotor storage system, coated with red blood cell membranes, can effectively mitigate colitis‐induced damage by concentrating and sequestering endotoxins while distributing the bacterial burden. This approach operates independently of molecular structure‐specific binding. Following endotoxin capture, the nanomotor storage system utilizes electrostatic interactions from immobilized peptide to adsorb endotoxins, thereby preventing excessive release of pro‐inflammatory cytokines during prolonged infection, ultimately enabling effective management of bacterial colitis. The top‐down fabrication of endotoxin storage materials presents a broadly applicable strategy against bacterial infections. The peptides immobilized via metal coordination offer an efficient pathway for bacterial and endotoxin capture, enabling the development of comprehensive storage systems. Peptides immobilized via nickel coordination can stabilize the framework structure. Following coating with red blood cell membranes, these constructs are capable of continuously sequestering endotoxins and mitigating colonic pathogenic damage by alleviating bacterial-induced ferroptosis. Abstract The emergence of drug-resistant bacteria has significantly heightened the urgency for effective interventions within the global public healthcare system. Furthermore, the structural diversity of endotoxins across different bacterial species poses a major limitation on the clearance efficiency of structure-specific anti-endotoxin antibodies. In this study, a peptide-based material with membrane-disrupting functionality is developed. The topological configuration of the peptide is immobilized through Ni 2+ coordination, and the thrust force generated by a redox reaction is harnessed to facilitate deep tissue penetration and enhance resistance to oxidative degradation. Notably, it is discovered that the immobilized peptide-based nanomotor storage system, coated with red blood cell membranes, can effectively mitigate colitis-induced damage by concentrating and sequestering endotoxins while distributing the bacterial burden. This approach operates independently of molecular structure-specific binding. Following endotoxin capture, the nanomotor storage system utilizes electrostatic interactions from immobilized peptide to adsorb endotoxins, thereby preventing excessive release of pro-inflammatory cytokines during prolonged infection, ultimately enabling effective management of bacterial colitis. The top-down fabrication of endotoxin storage materials presents a broadly applicable strategy against bacterial infections. The peptides immobilized via metal coordination offer an efficient pathway for bacterial and endotoxin capture, enabling the development of comprehensive storage systems. Advanced Science, EarlyView.

Stamping Lithography on Arbitrary Surfaces based on Self‐Assembly of Colloidal Particles

A new method called Stamping Lithography for three‐dimensional (3D) circuits manufacturing is proposed, which comprises a resist mask stamping process based on self‐assembly of colloidal particles and a subsequent etching process. It replaces the photoresist with self‐assembled particles and the exposure process with stamping, making it feasible to operate on arbitrary surfaces without the need for sophisticated equipment. Abstract Three‐dimensional (3D) circuits on curved surfaces have been widely used in conformal antennas, intelligent skins, metasurfaces, and bionic electronics. Traditional planar circuit technologies represented by photolithography are confronted with the problem of being difficult to apply to curved surfaces. To solve this problem, transfer printing technology uses planar stamps to transfer devices onto curved surfaces fabricated by photolithography, but faces the problem of over‐stretching when adapting to non‐developable surfaces. Meanwhile, in‐situ additive manufacturing technologies on curved surfaces, such as inkjet printing and laser direct writing, have low manufacturing efficiency, and the available materials are minimal. Herein, this paper proposes a new method called Stamping Lithography, which comprises a resist mask stamping process based on self‐assembly of colloidal particles (RSSA) and a subsequent etching process similar to those used in planar circuit technologies, making it possible to fabricate circuits using various materials on large‐area non‐developable surfaces. By fabricating circuits on hemispherical substrates, this approach demonstrates the potential of non‐developable surfaces. This work presents a practical strategy for the fabrication of 3D electronics on arbitrary surfaces, which can serve as a complementary technology to photolithography in the planar circuit industry. A new method called Stamping Lithography for three-dimensional (3D) circuits manufacturing is proposed, which comprises a resist mask stamping process based on self-assembly of colloidal particles and a subsequent etching process. It replaces the photoresist with self-assembled particles and the exposure process with stamping, making it feasible to operate on arbitrary surfaces without the need for sophisticated equipment. Abstract Three-dimensional (3D) circuits on curved surfaces have been widely used in conformal antennas, intelligent skins, metasurfaces, and bionic electronics. Traditional planar circuit technologies represented by photolithography are confronted with the problem of being difficult to apply to curved surfaces. To solve this problem, transfer printing technology uses planar stamps to transfer devices onto curved surfaces fabricated by photolithography, but faces the problem of over-stretching when adapting to non-developable surfaces. Meanwhile, in-situ additive manufacturing technologies on curved surfaces, such as inkjet printing and laser direct writing, have low manufacturing efficiency, and the available materials are minimal. Herein, this paper proposes a new method called Stamping Lithography, which comprises a resist mask stamping process based on self-assembly of colloidal particles (RSSA) and a subsequent etching process similar to those used in planar circuit technologies, making it possible to fabricate circuits using various materials on large-area non-developable surfaces. By fabricating circuits on hemispherical substrates, this approach demonstrates the potential of non-developable surfaces. This work presents a practical strategy for the fabrication of 3D electronics on arbitrary surfaces, which can serve as a complementary technology to photolithography in the planar circuit industry. Advanced Science, EarlyView.

Genome‐Wide by Lifetime Environment Interaction Studies of Brain Imaging Phenotypes

This study explores genome‐wide by lifetime environment interactions on brain imaging phenotypes. Gene‐environment interactions explain more phenotypic variance than main effects, pinpoint regulatory variants, and reveal exposure‐specific biological pathways. Critical sensitive periods are identified in childhood and adolescence, offering novel insights for optimizing brain health. Abstract Brain structure and function show substantial individual differences, finely controlled by genes, environments, and their interactions. Despite the increasing knowledge about genetic and environmental main effects, gene‐environment interaction effects on brain phenotypes remain elusive. This study investigates genome‐wide by environment (41 exposures) interactions on 598 brain imaging phenotypes in 7084 healthy young adults. Both univariate and multivariate analyses identify 486 significant gene‐environment interactions, scattered across the genome, exposome, and phenome. These interactions explain more variances of phenotypes than genetic and environmental main effects (100% of genetic and 96% of environmental main effects are non‐significant). Variants with interactions are enriched in intronic and intergenic regions, comprising 79 regulatory variants and 145 associated with brain gene expression. Protein‐protein interaction network analyses reveal distinct interaction networks for genes associated with air pollution (hubs: H4C6, SMARCA4, and RPS11) and urbanicity (hubs: CCND1, CALM3, and CDK2) exposures. Genes that interacted with air pollution exposures exhibit enrichment in pathways related to metal ion detoxification and homeostasis. For time‐varying exposures, 144 interactions demonstrate sensitive periods, predominantly in childhood (ages 4–7) and adolescence (ages 12–15). These findings highlight the value of genome‐wide by exposome‐wide interaction studies, which may offer crucial information for optimizing brain health outcomes. This study explores genome-wide by lifetime environment interactions on brain imaging phenotypes. Gene-environment interactions explain more phenotypic variance than main effects, pinpoint regulatory variants, and reveal exposure-specific biological pathways. Critical sensitive periods are identified in childhood and adolescence, offering novel insights for optimizing brain health. Abstract Brain structure and function show substantial individual differences, finely controlled by genes, environments, and their interactions. Despite the increasing knowledge about genetic and environmental main effects, gene-environment interaction effects on brain phenotypes remain elusive. This study investigates genome-wide by environment (41 exposures) interactions on 598 brain imaging phenotypes in 7084 healthy young adults. Both univariate and multivariate analyses identify 486 significant gene-environment interactions, scattered across the genome, exposome, and phenome. These interactions explain more variances of phenotypes than genetic and environmental main effects (100% of genetic and 96% of environmental main effects are non-significant). Variants with interactions are enriched in intronic and intergenic regions, comprising 79 regulatory variants and 145 associated with brain gene expression. Protein-protein interaction network analyses reveal distinct interaction networks for genes associated with air pollution (hubs: H4C6, SMARCA4, and RPS11 ) and urbanicity (hubs: CCND1, CALM3, and CDK2 ) exposures. Genes that interacted with air pollution exposures exhibit enrichment in pathways related to metal ion detoxification and homeostasis. For time-varying exposures, 144 interactions demonstrate sensitive periods, predominantly in childhood (ages 4–7) and adolescence (ages 12–15). These findings highlight the value of genome-wide by exposome-wide interaction studies, which may offer crucial information for optimizing brain health outcomes. Advanced Science, EarlyView.

AI‐Directed 3D Printing of Hierarchical Polyurethane Foams

Digitally guided direct ink writing, combined with AI‐generated design, enables the fabrication of hierarchical polyurethane foams with tunable multiscale porosity. This approach produces architected foams featuring interconnected open‐cell networks and tailored mechanical properties, advancing the development of adaptive, high‐performance materials for protective, structural, and wearable applications. Abstract Hierarchical porous materials enable next‐generation protective, thermal, and biomedical devices by leveraging multiscale architectures with tunable mechanical and thermal properties. Current 3D printing techniques mainly yield periodic lattices and support limited polymer types, restricting patterning possibilities and scalability. Stochastic foam architectures, with heterogeneous and interconnected pores, mimic biological structures for improved energy dissipation and functional adaptability. However, scalable additive manufacturing of such foams remains scarcely explored. Here, a direct ink writing (DIW) strategy couples static mixer‐enabled reactive extrusion and in situ polymerization to manufacture stochastic polyurethane (PU) foams at ambient conditions, eliminating post‐processing. Precise control over pore size (0.2 µm to 1.2 mm), porosity (65–95%), and open‐cell architecture delivers thermal conductivities down to 0.067 W m−1 K−1 and elastic recovery exceeding 90% after 5000 cycles. A multi‐agent artificial intelligence framework enables the patterning of spatially organized, bioinspired motifs into print‐ready CAD geometries, resulting in architecturally structured foams with tailored anisotropy and spatial thermal management. Flow‐rate modulation further tunes morphology, optimizing the balance between stiffness and damping. This manufacturing platform integrates stochastic pore formation, AI‐guided patterning, and mechanical–thermal optimization to realize scalable, customizable materials for impact protection, wearable thermotherapy, and adaptive healthcare, advancing digital manufacturing, smart materials, and personalized function. Digitally guided direct ink writing, combined with AI-generated design, enables the fabrication of hierarchical polyurethane foams with tunable multiscale porosity. This approach produces architected foams featuring interconnected open-cell networks and tailored mechanical properties, advancing the development of adaptive, high-performance materials for protective, structural, and wearable applications. Abstract Hierarchical porous materials enable next-generation protective, thermal, and biomedical devices by leveraging multiscale architectures with tunable mechanical and thermal properties. Current 3D printing techniques mainly yield periodic lattices and support limited polymer types, restricting patterning possibilities and scalability. Stochastic foam architectures, with heterogeneous and interconnected pores, mimic biological structures for improved energy dissipation and functional adaptability. However, scalable additive manufacturing of such foams remains scarcely explored. Here, a direct ink writing (DIW) strategy couples static mixer-enabled reactive extrusion and in situ polymerization to manufacture stochastic polyurethane (PU) foams at ambient conditions, eliminating post-processing. Precise control over pore size (0.2 µm to 1.2 mm), porosity (65–95%), and open-cell architecture delivers thermal conductivities down to 0.067 W m −1 K −1 and elastic recovery exceeding 90% after 5000 cycles. A multi-agent artificial intelligence framework enables the patterning of spatially organized, bioinspired motifs into print-ready CAD geometries, resulting in architecturally structured foams with tailored anisotropy and spatial thermal management. Flow-rate modulation further tunes morphology, optimizing the balance between stiffness and damping. This manufacturing platform integrates stochastic pore formation, AI-guided patterning, and mechanical–thermal optimization to realize scalable, customizable materials for impact protection, wearable thermotherapy, and adaptive healthcare, advancing digital manufacturing, smart materials, and personalized function. Advanced Science, EarlyView.

HPD is an m6A Methyltransferase that Protects Colorectal Cancer Cells from Ferroptotic Cell Death by m6A Methylating SLC7A11/GPX4

This study reveals that the tyrosine metabolic enzyme HPD functions as a previously uncharacterized, METTL3‐independent m6A methyltransferase. It promotes colorectal tumor progression by coordinately regulating the SLC7A11/GPX4 axis to suppress ferroptosis. This finding expands the family of m6A writers and reveals a promising new target for therapeutic intervention. Abstract N6‐methyladenosine (m6A) is a dynamic RNA modification, which is added by the METTL3‐METTL14 methyltransferase complex or METTL16. Unexpectedly, the tyrosine metabolism enzyme 4‐hydroxyphenylpyruvate dioxygenase (HPD) is discovered as a methyltransferase responsible for m6A modification. Unlike METTL3, which requires the assistance of METTL14 to form a complex and exert methyltransferase activity. Interestingly, it is revealed that HPD has a catalytic domain (CMI) like METTL3. Moreover, HPD recruits the universal cofactor S‐adenosylmethionine (SAM) to the substrate binding center as a methyl group donor. In particular, it is demonstrated that HPD regulates colorectal cancer ferroptosis by methylating SLC7A11/GPX4 through a moonlighting function. These findings uncover the moonlighting function of HPD in m6A‐mediated ferroptosis and underscore the potential to target the m6A methyltransferase activity of HPD for cancer treatment. This study reveals that the tyrosine metabolic enzyme HPD functions as a previously uncharacterized, METTL3-independent m 6 A methyltransferase. It promotes colorectal tumor progression by coordinately regulating the SLC7A11/GPX4 axis to suppress ferroptosis. This finding expands the family of m 6 A writers and reveals a promising new target for therapeutic intervention. Abstract N6-methyladenosine (m 6 A) is a dynamic RNA modification, which is added by the METTL3-METTL14 methyltransferase complex or METTL16. Unexpectedly, the tyrosine metabolism enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD) is discovered as a methyltransferase responsible for m 6 A modification. Unlike METTL3, which requires the assistance of METTL14 to form a complex and exert methyltransferase activity. Interestingly, it is revealed that HPD has a catalytic domain (CMI) like METTL3. Moreover, HPD recruits the universal cofactor S-adenosylmethionine (SAM) to the substrate binding center as a methyl group donor. In particular, it is demonstrated that HPD regulates colorectal cancer ferroptosis by methylating SLC7A11/GPX4 through a moonlighting function. These findings uncover the moonlighting function of HPD in m 6 A-mediated ferroptosis and underscore the potential to target the m 6 A methyltransferase activity of HPD for cancer treatment. Advanced Science, EarlyView.

In Situ Construction of Cu1+/Cu0 and Cu2+/Cu0 Pairs of Cu‐Based Catalysts for Electrocatalytic Nitrate Reduction

CuO and CuPO (Cu2P2O7 and Cu3(PO4)2) as precursors are in suit construction two distinct copper‐based active sites during the NO3RR reaction: Cu1+/Cu0 (derived from CuO) and Cu2+/Cu0 (derived from CuPO). Cu1+/Cu0 is the key to achieving high activity and high selectivity. Combining online DEMS and in situ FT‐IR spectroscopy with DFT calculations, the reaction mechanism of Cu1+/Cu0 is confirmed. Abstract Electrocatalytic nitrate reduction reaction (NO3RR) as a sustainable nitrogen cycle regulation strategy provides a new pathway to achieve carbon neutrality goals. In this study, CuO, Cu2P2O7 and Cu3(PO4)2 (CuPO) are synthesized as pre‐catalysts via a sol‐gel process for NO3RR, in which CuO exhibits excellent NH3 yields of 8.16 mg h−1 mgcat−1 (FE = 95.72%, ‐0.95 V vs. RHE) compared to Cu2P2O7 (7.33 mg h−1mgcat−1, 94.88%) and Cu3(PO4)2 (6.53 mg h−1mgcat−1, 92.04%). The combination of in situ Raman and XPS spectra reveal that the pre‐catalyst surface is reconfigured to form stable active sites of Cu1+/Cu0 (CuO‐derived) and Cu2+/Cu0 pairs (CuPO‐derived) during the NO3RR process. Tracking the evolution of intermediates using online differential electrochemical mass spectrometry (DEMS) spectra and in situ Fourier transform infrared spectroscopy (FT‐IR) spectra reveal that Cu1+/Cu0 pairs possess rapid catalytic kinetics for the conversion of *NO3− to *NO2−. Density functional theory (DFT) calculations confirm that Cu1+/Cu0 exhibits a lower potential‐determining step, and its exceptional *H generation and enrichment capabilities promote further hydrogenation reactions, thereby achieving excellent activity and selectivity in NH3 production via NO3RR. This study reveals the distinct advantages of reconstructed active sites in Cu‐based catalysts during NO3RR, providing guidance for designing other advanced catalysts. CuO and CuPO (Cu 2 P 2 O 7 and Cu 3 (PO 4 ) 2 ) as precursors are in suit construction two distinct copper-based active sites during the NO 3 RR reaction: Cu 1+ /Cu 0 (derived from CuO) and Cu 2+ /Cu 0 (derived from CuPO). Cu 1+ /Cu 0 is the key to achieving high activity and high selectivity. Combining online DEMS and in situ FT-IR spectroscopy with DFT calculations, the reaction mechanism of Cu 1+ /Cu 0 is confirmed. Abstract Electrocatalytic nitrate reduction reaction (NO 3 RR) as a sustainable nitrogen cycle regulation strategy provides a new pathway to achieve carbon neutrality goals. In this study, CuO, Cu 2 P 2 O 7 and Cu 3 (PO 4 ) 2 (CuPO) are synthesized as pre-catalysts via a sol-gel process for NO 3 RR, in which CuO exhibits excellent NH 3 yields of 8.16 mg h −1 mg cat −1 (FE = 95.72%, -0.95 V vs. RHE) compared to Cu 2 P 2 O 7 (7.33 mg h −1 mg cat −1, 94.88%) and Cu 3 (PO 4 ) 2 (6.53 mg h −1 mg cat −1, 92.04%). The combination of in situ Raman and XPS spectra reveal that the pre-catalyst surface is reconfigured to form stable active sites of Cu 1+ /Cu 0 (CuO-derived) and Cu 2+ /Cu 0 pairs (CuPO-derived) during the NO 3 RR process. Tracking the evolution of intermediates using online differential electrochemical mass spectrometry (DEMS) spectra and in situ Fourier transform infrared spectroscopy (FT-IR) spectra reveal that Cu 1+ /Cu 0 pairs possess rapid catalytic kinetics for the conversion of *NO 3 − to *NO 2 −. Density functional theory (DFT) calculations confirm that Cu 1+ /Cu 0 exhibits a lower potential-determining step, and its exceptional *H generation and enrichment capabilities promote further hydrogenation reactions, thereby achieving excellent activity and selectivity in NH 3 production via NO 3 RR. This study reveals the distinct advantages of reconstructed active sites in Cu-based catalysts during NO 3 RR, providing guidance for designing other advanced catalysts. Advanced Science, EarlyView.

Inferring Gene Regulatory Networks From Single‐Cell RNA Sequencing Data by Dual‐Role Graph Contrastive Learning

RegGAIN is a novel and powerful deep learning framework for inferring gene regulatory networks (GRNs) from single‐cell RNA sequencing data. By integrating self‐supervised contrastive learning with dual‐role gene representations, it consistently outperforms existing methods in both accuracy and robustness. Moreover, RegGAIN effectively uncovers GRN rewiring, enabling the discovery of condition‐specific and dynamic regulatory programs across diverse biological contexts. Abstract Gene regulatory network (GRN) inference is fundamental to understanding the regulatory architecture underlying cellular processes. Accurate reconstruction of cell‐type‐specific GRNs is therefore essential for elucidating the mechanisms that govern cellular identity, development, and disease. However, inferring GRNs from single‐cell RNA sequencing data remains challenging due to data sparsity, noise, and the intrinsic complexity of gene regulation. Here, RegGAIN is presented, a novel deep learning‐based model designed to infer GRNs from single‐cell transcriptomic data. RegGAIN employs self‐supervised contrastive learning to maximize consistency of gene embeddings across perturbed graph views. To characterize regulatory directionality and capture the distinct regulator‐ and target‐driven patterns simultaneously, it leverages separate encoders to learn dual‐role representations for each gene. Comprehensive evaluations demonstrate that RegGAIN achieves accurate and robust GRN reconstruction, consistently outperforming existing methods. The biological relevance of the predicted regulatory interactions is further validated using external epigenetic data. Moreover, RegGAIN enables the discovery of GRN rewiring, revealing condition‐specific and temporally dynamic regulatory programs. Together, RegGAIN offers a powerful and generalizable framework for GRN inference, paving the way for deeper insights into cellular regulation across diverse biological contexts. RegGAIN is a novel and powerful deep learning framework for inferring gene regulatory networks (GRNs) from single-cell RNA sequencing data. By integrating self-supervised contrastive learning with dual-role gene representations, it consistently outperforms existing methods in both accuracy and robustness. Moreover, RegGAIN effectively uncovers GRN rewiring, enabling the discovery of condition-specific and dynamic regulatory programs across diverse biological contexts. Abstract Gene regulatory network (GRN) inference is fundamental to understanding the regulatory architecture underlying cellular processes. Accurate reconstruction of cell-type-specific GRNs is therefore essential for elucidating the mechanisms that govern cellular identity, development, and disease. However, inferring GRNs from single-cell RNA sequencing data remains challenging due to data sparsity, noise, and the intrinsic complexity of gene regulation. Here, RegGAIN is presented, a novel deep learning-based model designed to infer GRNs from single-cell transcriptomic data. RegGAIN employs self-supervised contrastive learning to maximize consistency of gene embeddings across perturbed graph views. To characterize regulatory directionality and capture the distinct regulator- and target-driven patterns simultaneously, it leverages separate encoders to learn dual-role representations for each gene. Comprehensive evaluations demonstrate that RegGAIN achieves accurate and robust GRN reconstruction, consistently outperforming existing methods. The biological relevance of the predicted regulatory interactions is further validated using external epigenetic data. Moreover, RegGAIN enables the discovery of GRN rewiring, revealing condition-specific and temporally dynamic regulatory programs. Together, RegGAIN offers a powerful and generalizable framework for GRN inference, paving the way for deeper insights into cellular regulation across diverse biological contexts. Advanced Science, EarlyView.

Local‐to‐Nonlocal Second‐Harmonic Generation from Electrically Tunable Intersubband Polaritonic Metasurfaces

A local‐to‐nonlocal SHG process is demonstrated on an electrically tunable metasurface, combining an LSPR at the FF with a TM‐GMR at the SH to achieve independent dual tunability. Through modal‐overlap engineering of the proposed scheme, a high‐χ(2) MQW meta‐atom delivers strong nonlinearity while achieving 2‐DoF SH control with minimal trade‐offs, advancing the functionality of nonlinear nonlocal metasurfaces. Abstract Nonlinear optical metasurfaces enable subwavelength control of light‐matter interactions, yet simultaneous tunability of harmonic signal intensity and spectral response remains a fundamental challenge. Here, a local‐to‐nonlocal second harmonic (SH) generation process is presented, enabled by an electrically tunable polaritonic metasurface, allowing independent control of the SH spectral peak wavelength and intensity. The metasurface combines a localized surface plasmon resonance at the fundamental frequency with a transverse magnetic guided‐mode resonance at the SH frequency. By engineering modal overlap within a multiple quantum well layer, voltage‐controlled modulation of SH intensity and angle‐controlled spectral tuning is achieved, demonstrating two decoupled degrees of freedom associated with local and nonlocal modes. Angle‐resolved nonlinear reflection measurements confirm the independent tunability of the metasurface, validating the separation of excitation and emission pathways. This hybrid approach provides a general framework for nonlinear metasurfaces with enhanced flexibility and functional control, paving the way for applications in nonlinear signal processing, angle‐multiplexed photonics, and entangled photon‐pair generation for quantum optics. A local-to-nonlocal SHG process is demonstrated on an electrically tunable metasurface, combining an LSPR at the FF with a TM-GMR at the SH to achieve independent dual tunability. Through modal-overlap engineering of the proposed scheme, a high-χ (2) MQW meta-atom delivers strong nonlinearity while achieving 2-DoF SH control with minimal trade-offs, advancing the functionality of nonlinear nonlocal metasurfaces. Abstract Nonlinear optical metasurfaces enable subwavelength control of light-matter interactions, yet simultaneous tunability of harmonic signal intensity and spectral response remains a fundamental challenge. Here, a local-to-nonlocal second harmonic (SH) generation process is presented, enabled by an electrically tunable polaritonic metasurface, allowing independent control of the SH spectral peak wavelength and intensity. The metasurface combines a localized surface plasmon resonance at the fundamental frequency with a transverse magnetic guided-mode resonance at the SH frequency. By engineering modal overlap within a multiple quantum well layer, voltage-controlled modulation of SH intensity and angle-controlled spectral tuning is achieved, demonstrating two decoupled degrees of freedom associated with local and nonlocal modes. Angle-resolved nonlinear reflection measurements confirm the independent tunability of the metasurface, validating the separation of excitation and emission pathways. This hybrid approach provides a general framework for nonlinear metasurfaces with enhanced flexibility and functional control, paving the way for applications in nonlinear signal processing, angle-multiplexed photonics, and entangled photon-pair generation for quantum optics. Advanced Science, EarlyView.

Atomically Resolved Electron Reflectivity at a Metal/Semiconductor Interface

An atomically flat interface is achieved in the incoherent Al/Ge heterostructure using molecular beam epitaxy (MBE). Scanning tunneling microscopy (STM) reveals a laterally periodic modulation of electron reflectivity with atomic resolution at the commensurate Al/Ge interfacial lattice, originating from the local electronic states. This phenomenon provides a method for detecting buried interfacial states in heterostructures. Abstract An atomically flat interface is achieved between face‐centered cubic Al and diamond lattice Ge via molecular beam epitaxy (MBE). Based on the measurements of scanning tunneling microscopy (STM), an atomically resolved lateral periodic change of the electron reflectivity at the Al/Ge interface is demonstrated. The relative variation of electron reflectivity is up to ≈22% in a lateral 2 nm. It is speculated that the change of reflectivity results from the local electronic states at the Al/Ge interface. This phenomenon provides an atomically non‐destructive method for detecting the buried interfacial states in hetero‐structures by STM. An atomically flat interface is achieved in the incoherent Al/Ge heterostructure using molecular beam epitaxy (MBE). Scanning tunneling microscopy (STM) reveals a laterally periodic modulation of electron reflectivity with atomic resolution at the commensurate Al/Ge interfacial lattice, originating from the local electronic states. This phenomenon provides a method for detecting buried interfacial states in heterostructures. Abstract An atomically flat interface is achieved between face-centered cubic Al and diamond lattice Ge via molecular beam epitaxy (MBE). Based on the measurements of scanning tunneling microscopy (STM), an atomically resolved lateral periodic change of the electron reflectivity at the Al/Ge interface is demonstrated. The relative variation of electron reflectivity is up to ≈22% in a lateral 2 nm. It is speculated that the change of reflectivity results from the local electronic states at the Al/Ge interface. This phenomenon provides an atomically non-destructive method for detecting the buried interfacial states in hetero-structures by STM. Advanced Science, EarlyView.

Ythdc1‐p300‐Klf5 Complex‐Mediated Golgi Dysfunction Promotes Aortic Aneurysm

In their Research Article (DOI: https://doi.org/10.1002/advs.202512116* lF: 14.1 Q1), Wenli Wang and co‐workers identifies a novel lncRNA m6A modification‐dependent regulatory mechanism of vascular homeostasis, and constructs a predictive model for post‐operative short‐term death based on AD patient's features, providing a platform to be able to predict risk stratification of AD patients. The cover highlights the Ythdc1‐p300‐Klf5 complex serving as a potential therapeutic strategy to improve Golgi dysfunction and aortic aneurysm. Abstract Klf5 and Golph3l‐mediated regulation of Golgi morphology has been implicated in the apoptosis of vascular smooth muscle cells (VSMCs), which leads to aortic wall thinning and aneurysm. However, the molecular link between Klf5, Golph3l, and Golgi morphology alteration in the context of the aneurysm is unclear. Here, we show that apoptosis‐induced proliferation (AIP) in VSMCs occurs in aortic dissection (AD) and aortic aneurysm of humans and mice. Golph3l upregulation by Klf5 facilitates TNF‐α and TNFSF12 secretion from AngII‐stimulated VSMCs by inducing Golgi compaction, which is essential for AIP and aneurysm development. Mechanistically, AngII‐induced elevation of global m6A RNA level, especially m6A‐Gm40097, is responsible for Golph3l upregulation and AIP in VSMCs. Further, m6A‐Gm40097 mediates Klf5 interaction with Ythdc1 and p300 to form a transcription complex on the Golph3l promoter, thus activating transcription. Finally, a predictive website for post‐operative short‐term death is built based on AD patient's features, providing a platform to be able to predict risk stratification of AD patients. Collectively, this study identifies a novel lncRNA m6A modification‐dependent regulatory mechanism of chromatin remodeling and transcription activation. Targeting the Ythdc1‐p300‐Klf5 complex may serve as potential therapeutic strategy to improve Golgi dysfunction and aortic aneurysm. In their Research Article (DOI: https://doi.org/10.1002/advs.202512116 * lF: 14.1 Q1), Wenli Wang and co-workers identifies a novel lncRNA m6A modification-dependent regulatory mechanism of vascular homeostasis, and constructs a predictive model for post-operative short-term death based on AD patient's features, providing a platform to be able to predict risk stratification of AD patients. The cover highlights the Ythdc1-p300-Klf5 complex serving as a potential therapeutic strategy to improve Golgi dysfunction and aortic aneurysm. Abstract Klf5 and Golph3l-mediated regulation of Golgi morphology has been implicated in the apoptosis of vascular smooth muscle cells (VSMCs), which leads to aortic wall thinning and aneurysm. However, the molecular link between Klf5, Golph3l, and Golgi morphology alteration in the context of the aneurysm is unclear. Here, we show that apoptosis-induced proliferation (AIP) in VSMCs occurs in aortic dissection (AD) and aortic aneurysm of humans and mice. Golph3l upregulation by Klf5 facilitates TNF-α and TNFSF12 secretion from AngII-stimulated VSMCs by inducing Golgi compaction, which is essential for AIP and aneurysm development. Mechanistically, AngII-induced elevation of global m6A RNA level, especially m6A-Gm40097, is responsible for Golph3l upregulation and AIP in VSMCs. Further, m6A-Gm40097 mediates Klf5 interaction with Ythdc1 and p300 to form a transcription complex on the Golph3l promoter, thus activating transcription. Finally, a predictive website for post-operative short-term death is built based on AD patient's features, providing a platform to be able to predict risk stratification of AD patients. Collectively, this study identifies a novel lncRNA m6A modification-dependent regulatory mechanism of chromatin remodeling and transcription activation. Targeting the Ythdc1-p300-Klf5 complex may serve as potential therapeutic strategy to improve Golgi dysfunction and aortic aneurysm. Advanced Science, EarlyView.

Long‐Term Active Rather than Passive Restoration Promotes Soil Organic Carbon Accumulation by Alleviating Microbial Nitrogen Limitation in an Extremely Degraded Alpine Grassland

Active restoration increases soil organic carbon stocks by reducing microbial nitrogen limitation. Nitrogen availability promotes particulate to mineral‐associated organic carbon conversion by reducing microbial carbon use efficiency. Passive restoration has no effect on soil organic carbon stocks. Abstract Grassland degradation disrupts microbial nutrient cycling, yet the role of nitrogen (N) limitation in regulating soil organic carbon (SOC) dynamics during restoration remains poorly understood. Here, 10 years of active (sowing of seeds of native plants) and passive restoration (sand barrier protection) in degraded grasslands on the Qinghai–Tibetan Plateau are compared. Restoration impacts are assessed by integrating microbial metabolic traits such as stoichiometry‐based nutrient limitation and C use efficiency (CUEST) with SOC fractionation, which considers both POC and MAOC). Active restoration reduces microbial N limitation by 44–71%, driving a 291–467% increase in SOC stocks, from 0.81 to 3.15 kg m−2 in topsoil and 0.54 to 3.08 kg m−2 in subsoil. It also reduces CUEST by 54% in topsoil and 34% in subsoil, boosting POC by 483–557% and MAOC by 621–1,071%. MAOC dominates SOC accumulation, exceeding POC by 2.3–7.2 times. The CUEST reduction aids POC transformation into MAOC, stabilizing SOC storage. In contrast, passive restoration slightly reduces N limitation by 36–39% and CUEST by 10–23%, but failed to enhance C fractions or SOC stocks due to persistent nutrient constraints. The findings demonstrate that alleviating microbial N limitation by active restoration is critical for stabilizing SOC through MAOC accumulation. Active restoration increases soil organic carbon stocks by reducing microbial nitrogen limitation. Nitrogen availability promotes particulate to mineral-associated organic carbon conversion by reducing microbial carbon use efficiency. Passive restoration has no effect on soil organic carbon stocks. Abstract Grassland degradation disrupts microbial nutrient cycling, yet the role of nitrogen (N) limitation in regulating soil organic carbon (SOC) dynamics during restoration remains poorly understood. Here, 10 years of active (sowing of seeds of native plants) and passive restoration (sand barrier protection) in degraded grasslands on the Qinghai–Tibetan Plateau are compared. Restoration impacts are assessed by integrating microbial metabolic traits such as stoichiometry-based nutrient limitation and C use efficiency (CUE ST ) with SOC fractionation, which considers both POC and MAOC). Active restoration reduces microbial N limitation by 44–71%, driving a 291–467% increase in SOC stocks, from 0.81 to 3.15 kg m −2 in topsoil and 0.54 to 3.08 kg m −2 in subsoil. It also reduces CUE ST by 54% in topsoil and 34% in subsoil, boosting POC by 483–557% and MAOC by 621–1,071%. MAOC dominates SOC accumulation, exceeding POC by 2.3–7.2 times. The CUE ST reduction aids POC transformation into MAOC, stabilizing SOC storage. In contrast, passive restoration slightly reduces N limitation by 36–39% and CUE ST by 10–23%, but failed to enhance C fractions or SOC stocks due to persistent nutrient constraints. The findings demonstrate that alleviating microbial N limitation by active restoration is critical for stabilizing SOC through MAOC accumulation. Advanced Science, EarlyView.

Surface‐Associated Proteins on Extracellular Vesicles Remodel the Tumor Microenvironment by Potentiating TGF‐β Signaling in a Contact‐Dependent Manner

Extracellular vesicles (EVs) released from TGF‐β‐activated CAFs are enriched with ECM proteins such as TSG6 and THBS1, which facilitate their binding to recipient cell membranes. This EV–cell interaction promotes the clustering of CD44 and TGF‐β receptors on the target cell surface, thereby potentiating TGF‐β signaling activity. This study highlights a novel paradigm in EV‐mediated intercellular communication. Abstract Cancer‐associated fibroblasts (CAFs) are a major stromal cell type within the tumor microenvironment (TME), where they drive extracellular matrix remodeling and influence tumor progression through the secretion of bioactive molecules. Transforming growth factor‐β (TGF‐β) is a key regulator of CAF activation, yet its impact on the composition and function of extracellular vesicles (EVs) secreted by CAFs remains largely unexplored. Here, it is shown that TGF‐β activation alters the protein cargo and function of CAF‐derived EVs (TGF‐β‐EVs), leading to a distinct enrichment of surface‐associated proteins. One such protein is tumor necrosis factor‐stimulated gene‐6 protein (TSG6), which interacts with receptor CD44 and its ligand hyaluronan on EVs. The EV surface‐associated proteins facilitate EV docking to cell membranes by binding to transmembrane receptors. Elevated TSG6 on CAF‐derived EV surface promotes the clustering of the co‐receptor CD44 and TGF‐β type I receptor (TGFBR1) on recipient cells, enhancing TGF‐β signaling. Functionally, TGF‐β‐EVs further activate CAFs and contribute to CD8+ T cell immunosuppression, thereby promoting cancer progression. Overall, the findings reveal a contact‐dependent mechanism by which CAF‐derived EVs influence cellular signaling in the TME, suggesting a broader paradigm in which EV surface‐associated proteins regulate receptor clustering and downstream signaling, particularly in cells with low EV uptake. Extracellular vesicles (EVs) released from TGF-β-activated CAFs are enriched with ECM proteins such as TSG6 and THBS1, which facilitate their binding to recipient cell membranes. This EV–cell interaction promotes the clustering of CD44 and TGF-β receptors on the target cell surface, thereby potentiating TGF-β signaling activity. This study highlights a novel paradigm in EV-mediated intercellular communication. Abstract Cancer-associated fibroblasts (CAFs) are a major stromal cell type within the tumor microenvironment (TME), where they drive extracellular matrix remodeling and influence tumor progression through the secretion of bioactive molecules. Transforming growth factor-β (TGF-β) is a key regulator of CAF activation, yet its impact on the composition and function of extracellular vesicles (EVs) secreted by CAFs remains largely unexplored. Here, it is shown that TGF-β activation alters the protein cargo and function of CAF-derived EVs (TGF-β-EVs), leading to a distinct enrichment of surface-associated proteins. One such protein is tumor necrosis factor-stimulated gene-6 protein (TSG6), which interacts with receptor CD44 and its ligand hyaluronan on EVs. The EV surface-associated proteins facilitate EV docking to cell membranes by binding to transmembrane receptors. Elevated TSG6 on CAF-derived EV surface promotes the clustering of the co-receptor CD44 and TGF-β type I receptor (TGFBR1) on recipient cells, enhancing TGF-β signaling. Functionally, TGF-β-EVs further activate CAFs and contribute to CD8 + T cell immunosuppression, thereby promoting cancer progression. Overall, the findings reveal a contact-dependent mechanism by which CAF-derived EVs influence cellular signaling in the TME, suggesting a broader paradigm in which EV surface-associated proteins regulate receptor clustering and downstream signaling, particularly in cells with low EV uptake. Advanced Science, EarlyView.

ITM2B Truncation Promotes Migrasome Formation to Accelerate Renal Cell Carcinoma Growth

This study identifies truncated ITM2B as a regulator of migrasome formation in renal cell carcinoma (RCC) cells. The ITM2B truncation not only facilitates migrasome formation by recruiting TSPAN4, but also sorts active caspase‐7 into migrasomes. The internalization of active caspase‐7‐enriched migrasomes by macrophages stimulates IL‐6 secretion to promote RCC growth. Pathologically, hyperuricemia promotes ITM2B‐dependent migrasome formation to accelerate RCC progression. Abstract Integral membrane protein 2B (ITM2B), a transmembrane protein, frequently undergoes cleavage. The physiological functions of ITM2B are primarily studied in the context of neurological disorders, but their roles in cancers are largely overlooked. Here, it is demonstrated that in renal cell carcinoma (RCC) cells, N‐terminal truncation of ITM2B facilitates migrasome swelling through the recruitment of TSPAN4 and promotes migrasome formation. Moreover, ITM2B truncation acts as a carrier, sorting active caspase‐7 into migrasomes for migracytosis. The active caspase‐7‐enriched migrasomes are then taken up by macrophages, leading to caspase‐7‐induced IL‐6 secretion from macrophages, which eventually aggravates RCC growth through a feedback mechanism. Physiologically, hyperuricemia enhances ITM2B cleavage to aggravate RCC growth. Clinically, RCC tissues tend to produce ITM2B truncations compared with corresponding para‐carcinoma tissues. Moreover, compared with the urine from normal volunteers, that from RCC patients contains higher levels of ITM2B truncation‐enriched migrasomes. This study not only highlights novel functions of ITM2B truncation in migrasome formation and active caspase‐7 migracytosis but also elucidates the role of hyperuricemia in RCC progression via regulation of the ITM2B truncation–migrasome axis. This study identifies truncated ITM2B as a regulator of migrasome formation in renal cell carcinoma (RCC) cells. The ITM2B truncation not only facilitates migrasome formation by recruiting TSPAN4, but also sorts active caspase-7 into migrasomes. The internalization of active caspase-7-enriched migrasomes by macrophages stimulates IL-6 secretion to promote RCC growth. Pathologically, hyperuricemia promotes ITM2B-dependent migrasome formation to accelerate RCC progression. Abstract Integral membrane protein 2B (ITM2B), a transmembrane protein, frequently undergoes cleavage. The physiological functions of ITM2B are primarily studied in the context of neurological disorders, but their roles in cancers are largely overlooked. Here, it is demonstrated that in renal cell carcinoma (RCC) cells, N-terminal truncation of ITM2B facilitates migrasome swelling through the recruitment of TSPAN4 and promotes migrasome formation. Moreover, ITM2B truncation acts as a carrier, sorting active caspase-7 into migrasomes for migracytosis. The active caspase-7-enriched migrasomes are then taken up by macrophages, leading to caspase-7-induced IL-6 secretion from macrophages, which eventually aggravates RCC growth through a feedback mechanism. Physiologically, hyperuricemia enhances ITM2B cleavage to aggravate RCC growth. Clinically, RCC tissues tend to produce ITM2B truncations compared with corresponding para-carcinoma tissues. Moreover, compared with the urine from normal volunteers, that from RCC patients contains higher levels of ITM2B truncation-enriched migrasomes. This study not only highlights novel functions of ITM2B truncation in migrasome formation and active caspase-7 migracytosis but also elucidates the role of hyperuricemia in RCC progression via regulation of the ITM2B truncation–migrasome axis. Advanced Science, EarlyView.