bims-enlima Biomed News
on Engineered living materials
Issue of 2025–12–21
forty-nine papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. Noise-Guided Design of Synthetic Protein Waves in Living Cells.
  2. Programmable cell differentiation in budding yeast uncouples reproductive and metabolic tasks.
  3. Eukaryotic-like Synthetic Cells with Chemically Controlled Protein Localization.
  4. Hierarchically structuralized hydrogels with ligament-like mechanical performance.
  5. Living Hydrogel Bioreactors With Liquid Cavities Stabilize Microbial Consortia for Sustainable Algal Lipid Biomanufacturing.
  6. Materials reach new levels of frustration.
  7. Multimaterial 3D printed soft robots with embedded actuation and sensing.
  8. Engineering living bio-hybrid materials for sustainable l-threonine production.
  9. Multiscale hierarchical design of tough hydrogels: from natural to biomimetic.
  10. A synthetic cell phage cycle.
  11. Solution-Processable, Elongated Liquid Metal Particles for Composites with Enhanced Thermal Management.
  12. Ultrasound-Triggered Self-Assembly of Discrete Oligourethanes into Supramolecular Gels: Importance of Stereocenter Sequence.
  13. Force Transmission by Minimal Focal Adhesion Complexes Induces Synthetic Cell Deformation.
  14. MultiCell: geometric learning in multicellular development.
  15. Embedded 3D Printing of Graphene Oxide-Containing, Chemically Crosslinkable Poly(Ethylene Glycol) Inks.
  16. Modular Parallel Plate Flow Chamber with Tunable Substrate Mechanics and Defined Shear Stress.
  17. Multistep genomics on single cells and live cultures in subnanoliter capsules.
  18. Cell-free protein synthesis in microcompartments towards cell-cell communication.
  19. Integrating synthetic biology to understand and engineer the heart, lung, blood, and sleep systems.
  20. 4D-Printable, Smart Lubricious Pickering Emulsion Gels Fabricated with Reversibly Assembled Nanogel Surfactants.
  21. Peptide passports: Programmable import fuels novel protein building blocks.
  22. Soft electronics based on particle engulfment printing.
  23. Reconstituting transcription-translation-coupled DNA replication within complex in vitro biological systems.
  24. Transient hepatic reconstitution of trophic factors enhances aged immunity.
  25. SpaceBar enables single-cell-resolution clone tracing with imaging-based spatial transcriptomics.
  26. Filomicelle-Embedded Composite Hydrogels for Localized Gelation Within the Anterior Chamber of the Eye.
  27. A Chemically Switchable Synthetic Condensate Platform for Reversible Protein Sequestration and Release.
  28. Thermodynamic and Molecular Origins of Crack Resistance in Polymer Networks.
  29. Thermodynamics of microphase separation in a swollen, strain-stiffening polymer network.
  30. Programmable acoustofluidic engineering for creating gradient biomaterials.
  31. Ribozyme-Enabled Tissue Specificity (RETS): A System for Precise Gene Expression without Specialized Promoters.
  32. Development of biobased dynamic thiol-acrylate photopolymers: 3D-printed self-healing and shape memory materials.
  33. DNA nanodevice for analysis of force-activated protein extension and interactions.
  34. Low-Cost, Rapid Fabrication of Customizable Polyethylene Glycol-Based Cell Culture Devices.
  35. MechanoMR microparticle (M 3 ) sensors reveal dynamic stress loading as a driver of epithelial-mesenchymal transition.
  36. Functionalized nanopipettes for pH-gated single cell DNA delivery.
  37. Photodegradable Hydrogels Formed by Thiol-Norbornene Photopolymerization of Poly(ethylene glycol)-Norbornene-Carboxylate.
  38. Building dynamical models of multi-step state transitions from single cell gene expression trajectories.
  39. Engineering mammalian protein secretion: Toward the convergence of high-throughput biology and computational methods.
  40. Machine learning-driven optimization of metabolic balance for β-carotene production.
  41. LARIS enables accurate and efficient ligand and receptor interaction analysis in spatial transcriptomics.
  42. Antibody-lectin chimeras for glyco-immune checkpoint blockade.
  43. A chemically inducible, leakless Cre recombinase by split-protein-based efficient and enhanced degradation (SPEED).
  44. Nascent RNA profiling reveals genome-wide productive reiterative initiation regulating gene transcription in bacteria.
  45. Decoding the architecture of living systems.
  46. On-surface polymerization of natural amino acids: substrate engineering and monomer design.
  47. Reversibly Damping Protein Fibers with High Strength and Self-Recovery Capacity Enabled by Dual Dynamic Bonding Networks.
  48. RAPMS 2.0 Improves Specificity and Throughput for Proteomic Identification of RNA Binding Proteins.
  49. Moth-Wing-Inspired Multifunctional Metamaterials.
  1. ACS Synth Biol. 2025 Dec 16.
    Noise-Guided Design of Synthetic Protein Waves in Living Cells.
    Dennis T Bolshakov, Elliott W Z Weix, Thomas M Galateo, Rohith Rajasekaran, Scott M Coyle.
      Protein circuits organize cell biology, but synthetic dynamics are challenging to engineer due to stochastic genetic and biochemical variation. Genetically encoded oscillators (GEOs) built from bacterial MinDE-family ATPases and activators generate synthetic protein waves that act as novel frequency-domain imaging barcodes in eukaryotic cells, providing a platform for understanding, engineering, and applying synthetic protein dynamics. Using budding yeast, we disentangle how expression levels and expression noise govern the GEO waveform and encodability. While the GEO amplitude is sensitive to extrinsic noise, the GEO frequency is stably encoded by the activator:ATPase ratio. By integrating GEO components into the yeast modular cloning toolkit, we developed different noise-guided expression strategies that act like filters on the GEO waveform. We paired these filters with hundreds of biochemically distinct GEO variants to engineer clonal populations that oscillate at distinct frequencies and to design waveform libraries with customizable spectral features and tunable waveform variation. Our work establishes a robust platform for precision genetic encoding of synthetic GEO oscillations and highlights the utility of noise-guided strategies for dynamic protein circuit design.
    Keywords:  expression noise; imaging barcodes; protein circuits; protein oscillations; signal processing; synthetic dynamics
    DOI:  https://doi.org/10.1021/acssynbio.5c00599
  2. bioRxiv. 2025 Dec 09. pii: 2025.12.04.692473. [Epub ahead of print]
    Programmable cell differentiation in budding yeast uncouples reproductive and metabolic tasks.
    Jacob Guidry, Grant R Bowman.
      High-yield biomanufacturing requires large cell populations and a mechanism for directing metabolic resources towards product synthesis. However, the resources that support population growth are the same as those that drive productivity, creating a conflict that limits production yields. To overcome this fundamental limitation, we apply the principle of division of labor to separate reproductive and metabolic tasks into distinct cell types within an isogenic Saccharomyces cerevisiae culture. We introduce MiSTY (Microbial Stem Cell Technology in budding Yeast), a genetic platform that exploits natural asymmetric cues to control cell differentiation. Leveraging bud cell-specific transcription, a sequential series of recombinase-based genetic circuits generates Activated Stem Cells (ASCs) that divide asymmetrically into two cell types: bud cells that terminally differentiate into Factory Cells (FCs) and mother cells that remain self-renewing ASCs. Time-lapse microscopy demonstrated 100% differentiation fidelity across 97 cell divisions. Phenotypic and genotypic analyses showed that stem cell populations could be converted to over 95% FCs within 24 generations. By converting FCs into leucine auxotrophs, we inhibited FC proliferation while allowing continued ASC division, demonstrating complete uncoupling of cell growth from product synthesis. Because they continuously generate healthy new FCs, MiSTY cultures maintain high levels of productivity even under conditions that severely impair the growth and biosynthetic capacity of metabolically exhausted factory cells.
    DOI:  https://doi.org/10.64898/2025.12.04.692473
  3. ACS Synth Biol. 2025 Dec 15.
    Eukaryotic-like Synthetic Cells with Chemically Controlled Protein Localization.
    Keita Tsutsui, Tomoaki Matsuura, Shinya Tsukiji.
      Compartmentalization by organelles and the dynamic control of protein localization within these compartmentalized spaces are key mechanisms for regulating biological processes in eukaryotic cells. Here, we present a bottom-up approach for constructing cell-sized liposomes (giant unilamellar vesicles, GUVs) encapsulating an artificial organelle with chemically controlled protein localization. In this system, proteins fused to Escherichia coli dihydrofolate reductase are rapidly recruited on demand from the inner solution to the interior of a DNA-droplet-based ("nucleus"-like) organelle within GUVs upon addition of a synthetic, DNA-binding trimethoprim derivative to the external solution. By coupling this system with a sequence-specific protease, we constructed a synthetic cell platform that enables chemically induced, multistep cascade reactions─including protein relocalization, organelle-specific enzymatic activity, and product release from the organelle─that culminate in the control of synthetic-cell phenotypes, such as pore formation in the GUV membrane. This work provides a versatile platform for the bottom-up creation of eukaryotic-like synthetic cells with sophisticated and programmable functions.
    DOI:  https://doi.org/10.1021/acssynbio.5c00754
  4. Nat Commun. 2025 Dec 13.
    Hierarchically structuralized hydrogels with ligament-like mechanical performance.
    Diwei Shi, Donghwan Ji, Jinhye Bae.
      Mechanical properties of synthetic hydrogels remain inferior to those of load-bearing tissues such as ligaments, one of the strongest and stiffest natural hydrogels in the human body. Inspired by biological structures and their mechanisms conferring high mechanical properties, we report strong, stiff, and tough hydrogels composed of fiber-shaped elements that can be assembled into parallel bundles, closely resembling natural ligaments. These hydrogel fibers, readily fabricated with diameters of a few hundred micrometers, comprise polymer-particle hybrid agglomerates embedded in a continuous, interconnected polymer matrix. Strong polymer-particle interactions combined with spatial confinement within the agglomerates enable efficient load transfer, resulting in significant load-transfer lengths and substantial energy dissipation across the network. This design overcomes the conventional trade-offs between strength/stiffness and toughness/stretchability in polymer composites, thereby achieving tensile strength of 61 ± 8 MPa, elastic modulus of 131 ± 15 MPa, toughness 135 ± 11 MJ m-3, and stretchability exceeding 400%. When assembled into millimeter-scale hierarchical bundles, the hydrogels mimic the structural organization of ligaments, sustain loads of tens of kilograms, and function as strain sensors.
    DOI:  https://doi.org/10.1038/s41467-025-66536-8
  5. Small. 2025 Dec 19. e11039
    Living Hydrogel Bioreactors With Liquid Cavities Stabilize Microbial Consortia for Sustainable Algal Lipid Biomanufacturing.
    Zhipeng Huang, Lingfeng Yuan, Yihu Wang, Juan Li, Yujia Peng, Haixia Shen, Weiliang Dong, Ziyi Yu.
      Compartmentalized microbes and microbial consortia enable sustainable biomanufacturing, but the stability of these systems is frequently compromised by growth-rate mismatches and inhibitory metabolites. Here, we present living hydrogel bioreactors with liquid cavities that confine bacteria while permitting metabolite exchange with algae, thereby mitigating deleterious interactions and supporting lipid biosynthesis. A carbonate-bicarbonate buffer further stabilizes the culture environment. In a co-culture of Lactiplantibacillus plantarum and Chlorella vulgaris, hydrogel confinement alone improves algal viability and lipid yield, while further regulation with buffering increases lipid accumulation by over threefold relative to free co-culture. Integration into a continuous-flow photobioreactor sustains long-term symbiosis, maintains near-neutral pH, and achieves robust lipid productivity over extended operation. These results establish living hydrogel bioreactors as a platform for engineering stable, programmable microbial consortia in sustainable algal lipid biomanufacturing.
    Keywords:  bioreactors; continuous flow; hydrogels; microbial consortia
    DOI:  https://doi.org/10.1002/smll.202511039
  6. Nat Mater. 2025 Dec 16.
    Materials reach new levels of frustration.
    Aravind Devarakonda.
      
    DOI:  https://doi.org/10.1038/s41563-025-02442-0
  7. Sci Adv. 2025 Dec 19. 11(51): eadz2928
    Multimaterial 3D printed soft robots with embedded actuation and sensing.
    Zixiao Zhu, Dong Wang, Mengjie Zhang, Le Dong, Qinghua Yu, Chengru Jiang, Xiaoyang Zhu, Mei Chen, Kun Zhou, Guoying Gu.
      Soft robots require the seamless integration of actuation and sensing units to achieve autonomy and adaptability behaviors. This demands conformal, stretchable, and spatially distributed electronic components-an unmet challenge with conventional design and fabrication methods due to complex three-dimensional (3D) geometries, multimaterial integration, and mechanical-electrical mismatches between rigid electronics and soft bodies. Here, we present a design and fabrication framework for autonomous soft robots with embedded actuation and sensing. We develop an integrated digital light processing and direct ink writing 3D printing technology to fabricate soft robots with embedded and conformal 3D electronics in an automated manner. To ensure both electrical and mechanical stability under large deformation, we introduce a structural design strategy incorporating lattice metamaterials, wavy interconnects, and discretized printed circuit boards. By combining the fabrication and design methods, we demonstrate soft robots with multimodal actuation, real-time tactile sensing, wireless communication, tactile-to-visual feedback, and autonomous obstacle avoidance. Our approach paves the way for the development of electronics-integrated autonomous soft robots.
    DOI:  https://doi.org/10.1126/sciadv.adz2928
  8. Bioresour Technol. 2025 Dec 16. pii: S0960-8524(25)01773-0. [Epub ahead of print] 133806
    Engineering living bio-hybrid materials for sustainable l-threonine production.
    Shuqi Shi, Jinming Zhang, Shiya Zhu, Yu Sha, Qingguo Liu, Tianpeng Chen, Wenjun Sun, Wei Zhuang, Yong Chen, Hanjie Ying.
      Living materials integrating microorganisms and functional matrices have emerged as a promising platform for sustainable biomanufacturing and environmental applications. However, precise control of cell-material interactions remains challenging. Here, we developed an engineered Escherichia coli strain (THR007) displaying the lectin FimH, which specifically recognizes Mannose ligand on a mannose-functionalized composite carrier (CF-PEI-MM). This engineered living bio-hybrid material establishes directional and reversible adhesion via FimH-methyl-α-d-mannopyranoside recognition, enabling compact biofilm formation and selective, reusable cell-material assembly. During continuous l-threonine fermentation, this system increased production by 22.15 % and shortened the fermentation time by 5 h. This study provides a generalizable strategy for constructing programmable living materials that couple molecular recognition with microbial activity, paving the way for sustainable biomanufacturing and continuous fermentation.
    Keywords:  Engineering living bio-hybrid materials; Escherichia coli; Mannose-functionalized carrier; Sustainable biomanufacturing
    DOI:  https://doi.org/10.1016/j.biortech.2025.133806
  9. Soft Matter. 2025 Dec 19.
    Multiscale hierarchical design of tough hydrogels: from natural to biomimetic.
    Rui Xie, Yang Yang, Yixuan Zhang, Peng Lu.
      Many natural biological hydrogels, such as tendons, skin, cartilage, etc., are extremely tough, which is also a crucial merit for versatile applications of artificial hydrogels. Natural tough hydrogels serve as a vital source of inspiration for developing synthetic counterparts. This review begins with six representative examples of tough natural hydrogels. A thorough discussion of their unique structures and material compositions leads to the reasoning of toughness from the perspective of multiscale hierarchical design: based on the effective control of materials and structures at the molecular-nano-micro scales, as well as synergistic interactions between the different hierarchical scales. Following these design principles, we summarize the design strategies for biomimetic tough hydrogels, and the latest advanced applications of biomimetic tough hydrogels are further explored. Finally, it concludes by discussing the current challenges and prospects concerning the fabrication and application of biomimetic hydrogels.
    DOI:  https://doi.org/10.1039/d5sm00984g
  10. Nat Commun. 2025 Dec 15.
    A synthetic cell phage cycle.
    Antoine Levrier, Paul Soudier, David Garenne, Ziane Izri, Steven Bowden, Ariel B Lindner, Vincent Noireaux.
      Viral infection of living cells, exemplified by bacteriophage interaction with bacteria, is fundamental to biology and universal across living systems. Here, we establish an all-cell-free viral cycle where T7 phages infect synthetic cells, equipped with lipopolysaccharides on the outer leaflet of the lipid membrane, while encapsulating a cell-free gene expression system. We track each cycle step to demonstrate T7 phage-specific adsorption onto the liposomes, genome entry, replication, expression, and assembly of new infectious virions within the synthetic cells. We quantify key characteristics of the cycle, including the multiplicity of infection, replication efficiency, liposome size constraints, and phage rebinding dynamics. This work establishes a versatile, fully defined in vitro platform for reconstructing and investigating viral infections from individual molecular components.
    DOI:  https://doi.org/10.1038/s41467-025-67249-8
  11. ACS Appl Mater Interfaces. 2025 Dec 14.
    Solution-Processable, Elongated Liquid Metal Particles for Composites with Enhanced Thermal Management.
    Ren-Mian Chin, Lijun Zhou, Mohammad H Malakooti.
      The natural tendency of liquid metal (LM) droplets to minimize surface energy and form spherical shapes presents a fundamental challenge for synthesizing elongated LM particles in solution. Overcoming this limitation is critical for the development of anisotropic functional materials with potential applications in stretchable electronics and wearable devices. To address this challenge, a solution-based method is presented to synthesize stable, elongated particles of eutectic gallium-indium (EGaIn) by combining a high-intensity mixing process with particle surface modification. Various surface modification agents are investigated, and the elongated LM particles are incorporated into uncured elastomers. In particular, polyvinylpyrrolidone (PVP)-functionalized EGaIn particles retain their high aspect ratio after embedding in silicone elastomers. Furthermore, these elongated particles are aligned within the elastomer matrix via printing and doctor-blading techniques, producing composites with anisotropic internal microstructures. The resulting LM-elastomer composites exhibit enhanced heat dissipation and thermal conductivity compared with isotropic counterparts, with numerical simulations confirming the role of the elongated particle morphology. Beyond thermal management, the elongated, solution-processable LM particles serve as programmable liquid-state functional units compatible with diverse polymer matrices and fabrication methods.
    Keywords:  anisotropic composites; direct ink writing; high-aspect-ratio particles; liquid metals; surface functionalization; thermal management
    DOI:  https://doi.org/10.1021/acsami.5c17075
  12. ACS Macro Lett. 2025 Dec 19.
    Ultrasound-Triggered Self-Assembly of Discrete Oligourethanes into Supramolecular Gels: Importance of Stereocenter Sequence.
    Eduardo Castellanos, Wojciech Dudziak, Paweł Groch, Michał Szuwarzyński, Róża Szweda.
      Stereochemistry and the monomer sequence of biopolymers are key parameters that guide self assemblies and functions of biological systems. However, abiotic macromolecules are still behind in mimicking the selective interactions that drive the complexity of living matter. Herein, we report that synthetic, precise oligourethanes can form noncovalent assemblies leading to supramolecular gels. Notably, the process of supramolecular gelation occurs outside the aqueous environment and exhibits reversible adaptive behavior in response to external stimuli, including ultrasound and temperature. Gel formation and its properties are guided by the information encoded in the sequence and stereochemistry of their backbones and depend on the solvent environment. The performed spectroscopic studies reveal that the stereochemical control governing the oligourethane conformations, in turn, directs the higher-order assembly pathway. This work demonstrates the compelling property of abiotic oligourethanes that opens up opportunities to fine-tune self-assembly features using sequence control previously thought to be confined to biopolymers. Our findings open up new possibilities for designing synthetic polyurethane materials that can operate in nonphysiological environments while mimicking biopolymer features, thereby laying the foundation for applications in adaptive soft materials, organic-phase catalysis, and chemical sensing, utilizing ultrasonic-based technologies.
    DOI:  https://doi.org/10.1021/acsmacrolett.5c00650
  13. ACS Synth Biol. 2025 Dec 17.
    Force Transmission by Minimal Focal Adhesion Complexes Induces Synthetic Cell Deformation.
    Natalie Huhn, Chiao-Peng Hsu, Timon Nast-Kolb, Arsenii Hordeichyk, Andreas R Bausch.
      Cells sense and respond to mechanical cues through focal adhesions-dynamic, multiprotein assemblies linking the actin cytoskeleton to the extracellular matrix. These complexes are essential to processes from cell migration to tissue morphogenesis, yet the minimal physical requirements for their force-transmitting and mechanosensing functions remain unclear. Here, we reconstitute minimal focal adhesion-like complexes in giant unilamellar vesicles (GUVs) using kindlin-2, talin-1, FAK, paxillin, zyxin, and VASP anchored to membranes containing PIP2 and integrin β1 tails. These assemblies nucleate and anchor actin filaments into networks spanning the vesicle surface. Upon addition of nonmuscle myosin IIa, actomyosin contraction thickens filament bundles, aligns the complexes, and deforms the GUVs, while the assemblies remain stably membrane-bound. Our findings show that actin recruitment, force transmission, and structural stability under load can emerge from defined protein-membrane interactions alone. This minimal, three-dimensional platform offers a controllable synthetic biology system for probing mechanosensing and engineering force-responsive biomimetic systems.
    Keywords:  actin; actomyosin; contractile force transmission; focal adhesion; protein complex; reconstitution
    DOI:  https://doi.org/10.1021/acssynbio.5c00645
  14. Nat Methods. 2025 Dec 15.
    MultiCell: geometric learning in multicellular development.
    Haiqian Yang, George Roy, Anh Q Nguyen, Dapeng Bi, Tomer Stern, Markus J Buehler, Ming Guo.
      During developmental processes such as embryogenesis, how a group of cells self-organizes into specific structures is a central question in biology. However, it remains a major challenge to understand and predict the behavior of every cell within the living tissue over time during such intricate processes. Here we present MultiCell, a geometric deep learning method that can accurately capture the highly convoluted interactions among cells. We demonstrate that multicellular data can be represented with both granular and foam-like physical pictures through a unified graph data structure, considering both cellular interactions and cell junction networks. Using this method, we achieve interpretable four-dimensional morphological sequence alignment and predict single-cell behaviors before they occur at single-cell resolution during Drosophila embryogenesis. Furthermore, using neural activation map and model ablation studies, we demonstrate that cell geometry and cell junction networks are essential features for predicting cell behaviors during morphogenesis. This method sets the stage for data-driven quantitative studies of dynamic multicellular developmental processes at single-cell precision, offering a proof-of-concept pathway toward a unified morphodynamic atlas.
    DOI:  https://doi.org/10.1038/s41592-025-02983-x
  15. Small Sci. 2025 Dec;5(12): e202500278
    Embedded 3D Printing of Graphene Oxide-Containing, Chemically Crosslinkable Poly(Ethylene Glycol) Inks.
    Helena P Ferreira, Monize C Decarli, Duarte Moura, Rúben F Pereira, Andreia T Pereira, Lorenzo Moroni, Inês C Gonçalves.
      The incorporation of graphene-based materials into hydrogels enhances their mechanical, electroconductive, and antimicrobial properties, offering significant potential for biomedical applications. However, 3D printing graphene-containing inks may present challenges because of their unsuitable shape retention or the fact that the concentration of the graphene component can hinder photocrosslinking. This study explores embedded 3D printing to process a chemically crosslinkable poly(ethylene glycol) ink with a high (4% w/v) graphene oxide concentration (PEG/GO). Given the PEG/GO ink's insufficient shape retention and slow crosslinking, various support baths are screened, with the microparticulate bath of the crystal self-healing embedding bioprinting (CLADDING) method proving most effective. The interstitial solution of the CLADDING bath influences the mechanical properties of printed PEG/GO constructs. Multilayered PEG/GO cylindrical constructs with <500 μm filament width and up to 4.5 mm height (30 layers) are fabricated, presenting better tensile properties when printed within CLADDING in calcium chloride (vs. baths in crosslinking initiators). The surface of PEG/GO constructs is anti-adhesive toward human foreskin fibroblasts, and their extracts are cytocompatible. Hence, embedded 3D printing emerges as an innovative strategy to surpass limitations of shaping graphene-containing hydrogels into complex geometries, broadening the biomanufacturing possibilities for diverse biomedical applications requiring kPa-range mechanical properties.
    Keywords:  additive manufacturing; anti‐adhesiveness; graphene oxide; poly(ethylene glycol) hydrogels; shape retention; support baths
    DOI:  https://doi.org/10.1002/smsc.202500278
  16. bioRxiv. 2025 Dec 01. pii: 2025.11.26.690741. [Epub ahead of print]
    Modular Parallel Plate Flow Chamber with Tunable Substrate Mechanics and Defined Shear Stress.
    Bryan J Ferrick, Jason P Gleghorn.
      Cells integrate multiple mechanical cues simultaneously, yet most in vitro models examine extracellular matrix (ECM) stiffness and fluid shear stress (FSS) in isolation, limiting our understanding of mechanotransduction. We developed a parallel plate flow chamber with a polyacrylamide (PAA) substratum enabling independent, tunable control of substrate stiffness and FSS using readily available materials. We confirm that the PAA substratum has controllable mechanical properties that support the growth of Madin-Darby canine kidney epithelial cells across a range of stiffnesses. Furthermore, the flow chamber design accommodates the volumetric equilibrium swelling of the gel, maintaining a predictable fluid channel height that allows for the application of controlled fluid shear stress to cells within the device, confirmed through particle image velocimetry of perfused microspheres. Single flow chambers support the growth of sufficient cellular numbers for endpoint analyses, such as Western blots. Finally, quantitative analysis of F-actin organization revealed that substrate stiffness and FSS synergistically increase filament length with independent effects on filament width, demonstrating the ability and usefulness of this model as a tool for studying the effect of multiple concurrent forces on cell behavior.
    DOI:  https://doi.org/10.1101/2025.11.26.690741
  17. Science. 2025 Dec 18. eady7209
    Multistep genomics on single cells and live cultures in subnanoliter capsules.
    Ignas Mazelis, Haoxiang Sun, Arpita Kulkarni, Theresa L Torre, Allon M Klein.
      Single-cell sequencing methods uncover natural and induced variation between cells. Many functional genomic methods, however, require multiple steps that cannot yet be scaled to high throughput, including assays on living cells. Here we develop capsules with amphiphilic gel envelopes (CAGEs), which selectively retain cells and large analytes while being freely accessible to media, enzymes and reagents. Capsules enable high-throughput multistep assays combining live-cell culture with genome-wide readouts. We establish methods for barcoding CAGE DNA libraries, and apply them to measure persistence of gene expression programs in cells by capturing the transcriptomes of tens of thousands of expanding clones in CAGEs. The compatibility of CAGEs with diverse enzymatic reactions will facilitate the expansion of the current repertoire of single-cell, high-throughput measurements and their extension to live-cell assays.
    DOI:  https://doi.org/10.1126/science.ady7209
  18. Curr Opin Biotechnol. 2025 Dec 17. pii: S0958-1669(25)00160-0. [Epub ahead of print]97 103416
    Cell-free protein synthesis in microcompartments towards cell-cell communication.
    Joshua Ricouvier, Aurore Dupin, Matthaeus Schwarz-Schilling, Ferdinand Greiss, Shirley S Daube, Roy H Bar-Ziv.
      Recent efforts in bottom-up synthetic biology focus on fabricating programmable biological units that can be viewed as synthetic cells. Combining microfluidic techniques with cell-free protein expression systems defines the geometrical limits of the synthetic cell (e.g. microfluidic compartments, droplets, vesicles) and facilitates communication pathways to distribute functions over an assembly of synthetic cells. In this review, we describe and compare the different strategies implemented to reconstitute cell-cell communication among synthetic cells. We focus especially on various experimental setups of microcompartmentalization containing a cell-free expression system and genetic material. We highlight efforts to develop and engineer different modes of communication among the synthetic cells in different forms, varying by the degree of permeability, resource renewal, stability, and scalability, and how these influence the trade-off between programmability and biomimicry. We then summarize recent progress in the realization of different stages of communication (signaling, processing, and output generation) by genetic circuits, holding great promise for applications in synthetic biology and biotechnology.
    DOI:  https://doi.org/10.1016/j.copbio.2025.103416
  19. Cell Syst. 2025 Dec 17. pii: S2405-4712(25)00279-0. [Epub ahead of print]16(12): 101446
    Integrating synthetic biology to understand and engineer the heart, lung, blood, and sleep systems.
    Elliot L Chaikof, Jichao Chen, Martha U Gillette, Laurie A Boyer, Tara L Deans, Pulin Li, Isaac B Hilton, Kyle Daniels, Yogesh Goyal, Ying Mei, Changyang Linghu, Theresa B Loveless, David M Truong, Michael R Blatchley, Mingxia Gu, Caleb J Bashor, Jason H Yang, Ritu Raman, Akhilesh B Reddy, Krishanu Saha, Jennifer Davis, Kalpna Gupta, Xiaojing J Gao, Kate E Galloway.
      Synthetic biology offers control over cellular and tissue functions. As it moves beyond microbes into humans, synthetic biology enables precise control over gene expression, cell fate, and tissue organization across heart, lung, blood, and sleep systems. By integrating genome engineering, dynamic gene circuits, and high-dimensional biosensors, these advances support scalable, quantitative models of multicellular biology, expanding the need for systems-level models and integration. We highlight emerging systems such as tunable transcriptional regulators, synthetic organizers, and feedback circuits that bridge molecular control with functional outcomes. Furthermore, by combining omics data with artificial intelligence (AI)-guided circuit design, synthetic biology enables high-resolution cellular and tissue-scale models of development, cellular interactions, drug development, gene therapy, and therapeutic response. Key challenges remain-including delivery, transgene stability, and robust spatiotemporal control in physiologically relevant models. This perspective synthesizes field-spanning progress and defines shared priorities for engineering cells and tissues that function reliably across dynamic, multi-organ environments.
    DOI:  https://doi.org/10.1016/j.cels.2025.101446
  20. Small. 2025 Dec 15. e12282
    4D-Printable, Smart Lubricious Pickering Emulsion Gels Fabricated with Reversibly Assembled Nanogel Surfactants.
    Yu Zhang, Yujie Yang, Yunjing Wang, Wenlong Xu, Weiyan Yu, Lu Xu.
      Gels with high and convertible tribological performance are of great importance for constructing smart devices, sensors, and biomimetic soft matter systems. Of these materials, lubricious gels capable of being manufactured into objects with arbitrary, controllable shapes can exhibit superb adaptability to complex working environments and broader materials design freedoms, but still remain challenging for a number of oleogel and hydrogel systems. Herein, by exploiting a nanoparticle surfactant assembled using N-isopropylacrylamide-methacrylic acid copolymerized nanogel and diamine-terminated polydimethylsiloxane, which can yield near-zero oil/water interfacial tensions and high-strength interfacial films, as both an emulsifier and physical crosslinker, highly stable, viscoelastic, shear-thinning and thixotropic water-in-oil Pickering emulsion gels available for creating various high-resolution 3D-printing patterns and architectures with long-term structural stability and swelling resistance as well as providing favorable macroscale lubrication both in air and under water, can be fabricated. And their lubricious property can be maintained for at least 400 000 continuous reciprocating friction cycles. Further building on the temperature- and pH-controlled reversible assembly of the nanoparticle surfactant, effective shape reconfigurations of the printed gel macrostructures and multilevel switched frictional behavior of the gels can be achieved. Our study may provide new indications for developing novel, versatile, smart, and adaptive soft materials.
    Keywords:  4D printing; emulsion gels; nanoparticle surfactants; reversible assembly; switchable lubrication
    DOI:  https://doi.org/10.1002/smll.202512282
  21. Cell Chem Biol. 2025 Dec 18. pii: S2451-9456(25)00391-5. [Epub ahead of print]32(12): 1432-1435
    Peptide passports: Programmable import fuels novel protein building blocks.
    Linlin Wang, Sicong Yao, Yu-Hsuan Tsai.
      Proteins with noncanonical amino acids can serve as precision tools and therapeutics, but their creation is often inefficient. In a recent Nature publication, Iype et al.1 engineered bacteria to ferry designer amino acids as peptide cargos, overcoming a major uptake bottleneck and enabling robust, scalable incorporation under routine culture conditions.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.011
  22. Nat Electron. 2025 Feb;8(2): 127-134
    Soft electronics based on particle engulfment printing.
    Rongzhou Lin, Chengmei Jiang, Sippanat Achavananthadith, Xin Yang, Hashina Parveen Anwar Ali, Jianfeng Ping, Yuxin Liu, Xianmin Zhang, Benjamin C K Tee, Yong Lin Kong, John S Ho.
      Soft polymers programmed with functional particles can be used to create intrinsically stretchable electronics. However, current approaches to fabricating such materials require that the particles be first colloidally dispersed in a liquid monomer or polymer solution that have limited material compatibilities and necessitate precise control over the associated fluid mechanics during the printing process. Here we report the direct incorporation of functional particles in soft polymers using particle engulfment, a process in which particles are spontaneously subsumed by the polymer matrix via surface energy. The engulfment phenomenon occurs when the characteristic size of the particles is much smaller than the elastocapillary length of the polymer matrix, resulting in an energetically stable configuration where functional particles become deeply embedded into the polymer. We use the approach to fabricate multilayered, multimaterial and elastic devices with wireless sensing, communication and power transfer capabilities.
    DOI:  https://doi.org/10.1038/s41928-024-01291-0
  23. Nat Commun. 2025 Dec 15.
    Reconstituting transcription-translation-coupled DNA replication within complex in vitro biological systems.
    Xiao Zheng, Wenli Gao, Wan-Qiu Liu, Yufei Zhang, Shuhui Huang, Xiangyang Ji, Yicong Lu, Yifan Liu, Shengjie Ling, Jian Li.
      Reconstructing transcription-translation-coupled DNA replication (TTcDR) in artificial systems is crucial for creating synthetic life; however, existing approaches face limitations mainly due to their reliance on purified biological components. Here, we introduce LoopReX, a cell-free system that reconstitutes TTcDR using crude Escherichia coli extracts, offering a more complex native biological environment. LoopReX leverages a minimal machinery composed of phi29 DNA polymerase and T7 RNA polymerase, with the latter facilitating DNA replication initiation through the generation of primer RNAs. Using machine learning, we optimize LoopReX to enhance the efficiency of both DNA replication and protein expression, achieving scalable, sustainable genetic flow and high-yield protein production with robust iterative performance. Furthermore, artificial nucleoids, autonomously formed through CipB-based compartmentalization, improve DNA spatial organization and support multiple biological functions. This work advances the construction of artificial life by reconstituting TTcDR within a single, scalable, and functionalized system, opening exciting possibilities for synthetic biology, biotechnology, and bio-hybrid applications.
    DOI:  https://doi.org/10.1038/s41467-025-67411-2
  24. Nature. 2025 Dec 17.
    Transient hepatic reconstitution of trophic factors enhances aged immunity.
    Mirco J Friedrich, Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, Rhiannon K Macrae, Feng Zhang.
      Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy and vaccine failure1-3. Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility1,3-5. Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic mapping across central and peripheral niches in young and aged animals, leading to the identification of Notch and Fms-like tyrosine kinase 3 ligand (FLT3L) pathways, together with interleukin-7 (IL-7) signalling, as declining with age. Delivery of mRNAs encoding Delta-like ligand 1 (DLL1), FLT3L and IL-7 to hepatocytes expanded common lymphoid progenitors, boosted de novo thymopoiesis without affecting haematopoietic stem cell (HSC) composition, and replenished T cells while enhancing dendritic cell abundance and function. Treatment with these mRNAs improved peptide vaccine responses and restored antitumour immunity in aged mice by increasing tumour-specific CD8+ infiltration and clonal diversity and synergizing with immune checkpoint blockade. These effects were reversible after dosing ceased and did not breach self-tolerance, in contrast to the inflammatory and autoimmune liabilities of recombinant cytokine treatments6,7. These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.
    DOI:  https://doi.org/10.1038/s41586-025-09873-4
  25. Nat Methods. 2025 Dec 18.
    SpaceBar enables single-cell-resolution clone tracing with imaging-based spatial transcriptomics.
    Grant Kinsler, Caitlin Fagan, Haiyin Li, Jessica Kaster, Maggie Dunne, Robert J Vander Velde, Ryan H Boe, Sydney Shaffer, Meenhard Herlyn, Arjun Raj, Yael Heyman.
      Imaging-based spatial transcriptomics methods allow for the measurement of spatial determinants of cellular phenotypes but are incompatible with random barcode-based clone-tracing methods, preventing the simultaneous detection of clonal and spatial drivers. Here we report SpaceBar, which enables simultaneous clone tracing and spatial gene expression profiling with standard imaging-based spatial transcriptomics pipelines. Our approach uses a library of 96 synthetic barcode sequences that combinatorially labels each cell. Thus, SpaceBar can distinguish between clonal dynamics and environmentally driven transcriptional regulation in complex tissue contexts.
    DOI:  https://doi.org/10.1038/s41592-025-02968-w
  26. Small. 2025 Dec 17. e08236
    Filomicelle-Embedded Composite Hydrogels for Localized Gelation Within the Anterior Chamber of the Eye.
    Hyeohn Kim, Sofia Lara Ochoa, Swagat Sharma, Asmaa A Youssif, Benjamin R Thomson, Mark Johnson, Evan A Scott.
      Anterior segment diseases, including glaucoma and uveitis, affect millions of patients worldwide. Nanocarriers hold transformative potential for treating these conditions, yet corneal epithelium impermeability necessitates intraocular injection. Given the discomfort and infection risk, an injectable hydrogel-based depot offers a promising strategy for sustained delivery. However, because the aqueous humor is a large, fluid-filled environment, achieving spatially confined gelation remains a key challenge, as injected materials rapidly diffuse. Herein, a composite hydrogel (C-gel) is presented that enables localized in situ gelation and sustained nanocarrier release within the anterior chamber. This is achieved by embedding poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) filomicelles (FMs) within a crosslinked multi-arm PEG hydrogel. The FM structure facilitated the spatial confinement of DBCO- and azide-PEG crosslinking reactions, promoting efficient gel formation-the first use of FM morphology for enhanced localized gelation. As a result, 90% of the injected polymer is retained within the crosslinked matrix. Embedded FMs undergo oxidation-induced cylinder-to-sphere transitions, facilitating gradual release of micellar nanocarriers. The mechanical properties and release kinetics of C-gels can be specified by adjusting the formulation parameters. Sustained release of dye-loaded nanocarriers, used as a fluorescent model cargo, persisted for over a month under anterior chamber-mimicking conditions, underscoring the C-gel's potential as a long-acting depot for ocular drug delivery.
    Keywords:  PEG‐b‐PPS block copolymer; anterior segment eye diseases; composite hydrogel; filomicelle; localized gelation; sustained nanocarrier release
    DOI:  https://doi.org/10.1002/smll.202508236
  27. ACS Chem Biol. 2025 Dec 14.
    A Chemically Switchable Synthetic Condensate Platform for Reversible Protein Sequestration and Release.
    Yoko Fukaya, Masaru Yoshikawa, Kazuhiro Aoki, Helen Farrants, Kai Johnsson, Shinya Tsukiji.
      Creating artificial organelles that sequester and release specific proteins in response to a small molecule in mammalian cells is an attractive approach for regulating protein function. In this work, by combining phase-separated condensates formed by the tandem fusion of two oligomeric proteins with a trimethoprim (TMP)-responsive nanobody switch for GFP (GFPLAMA; ligand-modulated antibody fragment), we developed a synthetic condensate system that initially sequesters GFP-tagged proteins within condensates and rapidly releases them into the cytoplasm upon TMP treatment. The released proteins can then be resequestered by washing out the TMP. This system enabled user-defined, temporal, rapid, and reversible control of cellular processes, including membrane ruffling mediated by exogenously expressed GFP-Vav2 and modulation of the cellular localization of endogenous ERK2-GFP generated by genome knock-in. Our results highlight the utility of the GFPLAMA-based synthetic condensate platform as a novel, chemically switchable tool for regulating protein function through controlled protein sequestration and release in mammalian cells.
    DOI:  https://doi.org/10.1021/acschembio.5c00719
  28. Chem Rev. 2025 Dec 15.
    Thermodynamic and Molecular Origins of Crack Resistance in Polymer Networks.
    Zheqi Chen, Zhigang Suo.
      A material tears, peels, and breaks by growing a crack. In a zone around the crack front, atoms undergo an irreversible process of breaking─and possibly reforming─bonds. Trailing behind the crack front are two layers of scars. Outside the irreversible zone and scars, atoms undergo the reversible process of elasticity. The irreversible zone is considered localized if it is small relative to the body. The idealization of localized irreversibility leads to a thermodynamic framework centered on the energy release rate. This crack driving force is defined using an ideal body in which a crack is stationary and deformation is elastic, and is applied to a real body in which a crack grows by an irreversible process. The irreversible zone scales with a material length: the fractocohesive length. We review recent advances in the development of crack-resistant elastomers and hydrogels as well as polymer networks reinforced by hard particles, fibers, or fabrics, subject to monotonic, cyclic, and static loading. Emphasis is placed on how molecular features, such as strand length, entanglements, noncovalent bonds, and chemical reactions, govern crack resistance. Design principles are highlighted that reconcile high toughness with low hysteresis through stress deconcentration. This review traces crack resistance to molecular origins, providing a foundation for designing next-generation crack-resistant materials.
    DOI:  https://doi.org/10.1021/acs.chemrev.5c00663
  29. Soft Matter. 2025 Dec 16.
    Thermodynamics of microphase separation in a swollen, strain-stiffening polymer network.
    Carla Fernández-Rico, Robert W Style, Stefanie Heyden, Shichen Wang, Peter D Olmsted, Eric R Dufresne.
      Elastic MicroPhase separation (EMPS) provides a simple route to create soft materials with homogeneous microstructures by leveraging the supersaturation of crosslinked polymer networks with liquids. At low supersaturation, network elasticity stabilizes a uniform mixture, but beyond a critical threshold, metastable microphase-separated domains emerge. While previous theories have focused on describing qualitative features about the size and morphology of these domains, they do not make quantitative predictions about EMPS phase diagrams. In this work, we extend Flory-Huggins theory to quantitatively capture EMPS phase diagrams by incorporating strain-stiffening effects. This model requires no fitting parameters and relies solely on independently measured solubility parameters and large-deformation mechanical responses. Our results confirm that strain-stiffening enables metastable microphase separation within the swelling equilibrium state and reveal why the microstructures can range from discrete droplets to bicontinuous networks. This works highlights the critical role of nonlinear elasticity in controlling phase-separated morphologies in polymer gels.
    DOI:  https://doi.org/10.1039/d5sm00594a
  30. Sci Adv. 2025 Dec 19. 11(51): eaeb0879
    Programmable acoustofluidic engineering for creating gradient biomaterials.
    Yujing Lu, Ye He, Jianping Xia, Mingyuan Liu, Joseph Rich, Ke Jin, Ruoyu Zhong, Kaichun Yang, Jiao Qian, Ying Chen, Ke Li, Zhiteng Ma, Tony Jun Huang.
      Gradient biomaterials that exhibit spatially varying physical, chemical, or biological properties can be used in various applications such as tissue engineering, organoid development, mechanobiology, and spatially controlled drug delivery. However, current fabrication methods often suffer from limited gradient precision, restricted material compatibility, and poor reproducibility. Here, we introduced gradient regulation via acoustofluidic dynamic engineering (GRADE), a programmable system to generate high-fidelity gradient biomaterials across different material systems. By incorporating focused interdigital transducers with the pulsed surface acoustic wave actuation, GRADE can achieve tunable and directional acoustic streaming (0 to 22 millimeters per second), which allows accurate regulation of the gradient magnitude and length. Its open microchannel design enables nondestructive extraction of centimeter-scale gradients and supports device reuse, enhancing practicality and scalability. In contrast to magnetic or electrospinning techniques that are limited to specific material types, the GRADE approach supports composition-independent fluid manipulation of a diverse group of biomaterials and cross-linking methods, thus providing greater versatility and translational potential. Furthermore, we demonstrate stiffness-dependent mechanosensation in stem cells cultured on customized gradient substrates, which validates the platform's usability. The experimental results show that GRADE has the ability to uncover mechanobiological responses in physiologically relevant contexts. All these results establish GRADE as a powerful and versatile platform for gradient biomaterial fabrication. It shows broad potential to advance both fundamental research and translational biomedical applications.
    DOI:  https://doi.org/10.1126/sciadv.aeb0879
  31. ACS Synth Biol. 2025 Dec 18.
    Ribozyme-Enabled Tissue Specificity (RETS): A System for Precise Gene Expression without Specialized Promoters.
    Max M Combest, Josh Conlin, Vivia Van De Mark, Morgan Boisen, Hadley Colwell, Arjun Khakhar.
      Tissue- or cell-type-specific expression of transgenes is often essential for interrogation of the biological phenomenon or predictable engineering of multicellular organisms but can be stymied by cryptic enhancers that make identification of promoters that generate desired expression profiles challenging. In plants, the months-to-years long timeline associated with prototyping putative tissue-specific promoters in transgenic lines deepens this challenge. We have developed a novel strategy called Ribozyme-Enabled Tissue Specificity (RETS) that leverages the knowledge of where and when genes are expressed derived from transcriptomic studies to enable tissue-specific expression without needing characterized promoters. It uses a split self-splicing ribozyme based on a group I intron from Tetrahymena thermophila to enable the conditional reconstitution of a transgene mRNA in the presence of a secondary tissue-specific mRNA of choice. We elucidate the design features that enable flexible swapping of transgenes and targets, enhancing transgene expression, and circumventing host RNA interference responses. We then show that these innovations enable tissue-specific and dose-dependent expression of transgenes in Arabidopsis thaliana. Finally, we demonstrate the utility of RETS both for creating genetically encoded biosensors to study the spatiotemporal patterns of gene expression in planta and for engineering tissue-specific changes in organ size. RETS provides a novel avenue to study expression patterns of native loci with nondestructive imaging, complementing the weakness of existing approaches. Additionally, the spatiotemporal control of transgene expression afforded by RETS enables precision engineering of plant phenotypes, which will facilitate enhancing crops without the trade-offs associated with constitutive expression.
    Keywords:  expression biosensor; plant development; plant synthetic biology; ribozymes; tissue-specific expression
    DOI:  https://doi.org/10.1021/acssynbio.5c00712
  32. RSC Adv. 2025 Dec 12. 15(58): 49714-49727
    Development of biobased dynamic thiol-acrylate photopolymers: 3D-printed self-healing and shape memory materials.
    Viranchika Bijalwan, Sandra Schlögl, Sravendra Rana.
      Dynamic covalent bonds have revolutionized polymer science by imparting advanced properties to the polymer networks, such as autonomous repair, reprocessability, adaptability, and shape recovery. The use of biobased precursors, such as plant-derived oils and natural monomers, further enhances the sustainability and environmental compatibility of these materials. By pairing dynamic covalent bonds with biobased precursors, 3D printing technologies can produce functional materials with both high performance and reduced environmental impact. In this study, we develop biobased thiol-acrylate vitrimers tailored for 3D printing applications, specifically targeting soft active devices with self-healing and shape-memory capabilities. Utilizing a digital light processing 3D printing technique, the resin formulation contains AESBO (an acrylated epoxidized soybean oil), a glycerol-derived reactive diluent, and a thiol crosslinker to attain tunable viscoelastic properties and dynamic bond exchange reactions within the printed object. The presence of hydroxyl-ester bonds in the thiol-acrylate network enables efficiently catalysed transesterification at elevated temperature in the presence of a tin-based catalyst Sn(Oct)2. Notably, Sn(Oct)2 functions not only as an efficient transesterification catalyst but also as a stabilizing additive that prevents premature gelation, ensuring resin shelf-stability for over two months. Experimental analysis such as dynamic mechanical analysis (DMA), reveals the significant impact of AESBO content on glass transition temperature (T g), mechanical performance, and network adaptability. The findings from stress relaxation experiments indicate that the printed material is capable of dissipating 63% of its initial stresses within 3.6 minutes at a temperature of 200 °C, thereby facilitating self-healing and shape reformation. The materials showed promising healing, shape memory, degradability, and reprocessing capabilities, highlighting its potential for use in soft active devices and soft robotics application.
    DOI:  https://doi.org/10.1039/d5ra07879b
  33. Nat Nanotechnol. 2025 Dec 15.
    DNA nanodevice for analysis of force-activated protein extension and interactions.
    Kun Zhou, Minhwan Chung, Shankar Pandey, Jing Cheng, John T Powell, Qi Yan, Jun Liu, Yong Xiong, Martin A Schwartz, Chenxiang Lin.
      Force-induced changes in protein structure and function mediate cellular responses to mechanical stresses that are important in human development, physiology and diseases. However, existing methods to study proteins under mechanical force are generally single-molecule techniques unsuitable for biochemical and structural analysis. Taking advantage of DNA nanotechnology, including the well-defined geometry of DNA origami and the programmable mechanics of DNA hairpins, we built a nanodevice to apply controlled forces to proteins. This device was used to study the R1-R2 segment of the talin1 rod domain as a model protein. R1-R2 consists of two α-helical bundles that reversibly unfold under tension to expose binding sites for the cytoskeletal protein vinculin. Electron microscopy confirmed tension-dependent protein extension, and biochemical analysis demonstrated enhanced vinculin binding under tension. Using the device in pull-down assays with cell lysates, we identified filamins as novel tension-dependent talin binders. The DNA nanodevice thus provides a valuable molecular tool for studying mechanosensitive proteins on a biochemical scale.
    DOI:  https://doi.org/10.1038/s41565-025-02086-w
  34. bioRxiv. 2025 Dec 08. pii: 2025.12.04.692348. [Epub ahead of print]
    Low-Cost, Rapid Fabrication of Customizable Polyethylene Glycol-Based Cell Culture Devices.
    Emily L Pallack, Maxwell W Oulundsen, Hannah R Goldberg, Yan Kolpakov, Aneth J Fernandez, Noah D Teaney, Faith E Y Moran, Nisha R Iyer.
      Biological research groups may face a high barrier to entry when constructing custom 3D cell culture devices to investigate multi-tissue interactions in vitro . Standard fabrication methods such as lithography, etching, or molding are expensive and require specialized equipment and expertise. To address this, we developed an accessible approach for producing polyethylene glycol (PEG)-based cell culture devices using stereolithography (SLA) 3D printing with a polydimethylsiloxane (PDMS) intermediate mold. Both the intermediate molding steps and the sterilized final device show low cytotoxicity, the final device swells to predictable dimensions and retains its shape for at least 10 days. We used this approach to develop a human pluripotent stem cell (hPSC)-derived neural spheroid outgrowth model that supports directed neurite extension over 14 days. Together, this method provides a highly customizable, affordable platform for rapid fabrication of PEG-based microphysiological systems (MPS) for diverse tissue engineering applications.
    Impact: As biomedical labs work to complement animal models with tissue-engineered MPSs, there is a growing need for low-cost, rapid, and iterative fabrication workflows. We developed a pipeline combining 3D printing, a PDMS intermediate mold, and PEG casting, avoiding the need for specialized photolithography. The resulting devices support stable, nutrient-permissive cell culture while allowing control over device dimensions and customizable channel or compartment configurations. We demonstrate its utility with reprogrammed hPSC-derived neurons, which remain challenging to support sustained neurite outgrowth in engineered models. This workflow expands access to cell culture device fabrication for MPSs across a broader range of biological laboratories.
    DOI:  https://doi.org/10.64898/2025.12.04.692348
  35. bioRxiv. 2025 Dec 13. pii: 2025.12.10.693598. [Epub ahead of print]
    MechanoMR microparticle (M 3 ) sensors reveal dynamic stress loading as a driver of epithelial-mesenchymal transition.
    Minji An, Ri Yu, Annie Lin, Jinho Jang, Jiyeon Ohk, Young-Joo Kim, Hosung Jung, Minsuk Kwak, Young-Wook Jun, Jinwoo Cheon.
      The dynamic mechanical response of tissues underlies their physiological function, yet direct, quantitative measurement of tissue stress in vivo has remained a major challenge. Here, we introduce the m echano M R m icroparticle (M 3 , "M-cube") sensor, a hybrid soft-matter/nanoparticle probe that integrates directly into tissue mechanical networks while transducing local stress into quantitative magnetic resonance (MR) readouts with single-particle resolution. We demonstrate the utility of this platform across diverse model systems, including tumor spheroids, Xenopus embryos, and mouse xenografts, where the M 3 sensor enables noninvasive, spatiotemporally resolved mapping of tissue stress dynamics during cancer development. Using this approach, we reveal that epithelial-mesenchymal transition (EMT) is accompanied by distinctive stress-remodeling patterns observable in vivo . Strikingly, we find that abrupt stress increases, rather than cumulative or peak stress magnitude, are the key determinants of EMT induction in cancer cells within the tumor microenvironment. Transcriptomic profiling under controlled stress-loading dynamics shows that sustained yet gradual stress escalation activates cytoprotective antioxidation pathways (e.g., FOXO/AMPK) that reinforce epithelial stability, whereas acute stress surges overwhelm these defense mechanisms, predisposing cells toward mesenchymal reprogramming. These findings establish the M 3 sensor as a broadly applicable technology for linking dynamic mechanical cues to cell-state transitions in development, homeostasis, and disease.
    DOI:  https://doi.org/10.64898/2025.12.10.693598
  36. Chem Commun (Camb). 2025 Dec 15.
    Functionalized nanopipettes for pH-gated single cell DNA delivery.
    Shi-Yu Zheng, Man-Sha Wu, Shi-Yi Zhang, Meng-Qi Zhao, Xin-Yue Liu, Bin-Bin Chen, Da-Wei Li, Ruo-Can Qian, Jian Lv.
      Here, we present i-motif-functionalized glass nanopipettes that enable pH-triggered DNA release into single living cells. Acid-induced folding of the i-motif drives complementary strand dissociation through the ∼80 nm tip with minimal invasiveness. This pH-gated nanopipette enables reversible, on-demand single cell DNA delivery via rectification changes, establishing a potential platform for intracellular manipulation.
    DOI:  https://doi.org/10.1039/d5cc05685c
  37. ACS Appl Polym Mater. 2025 Nov 14. 7(21): 14781-14792
    Photodegradable Hydrogels Formed by Thiol-Norbornene Photopolymerization of Poly(ethylene glycol)-Norbornene-Carboxylate.
    Nathan H Dimmitt, Jonathan B Bryan, Chien-Chi Lin.
      Orthogonally cross-linked thiol-norbornene hydrogels are a versatile biomaterial platform for tissue engineering applications. Multiarm poly-(ethylene glycol)-norbornene (PEGNB) is the original macromer for thiol-norbornene hydrogel cross-linking, but a lengthy reaction and the use of nauseous 5-norbornene-2-carboxylic acid burdened its synthesis. Recently, a PEGNB variant, PEG-amide-norbornene-carboxylate (PEGaNBCA), was prepared by reacting PEG-amine with odorless carbic anhydride (CA) under ambient aqueous conditions. In this work, we employed a microwave reactor for the aqueous synthesis of PEGaNBCA, significantly reducing the synthesis time from 48 h to ∼22.5 min while increasing the degree of norbornene substitution to over 93%. Furthermore, we discovered that the thioether bonds formed after photo-cross-linking of PEGaNBCA with a thiol-bearing cross-linker were hydrolytically stable but susceptible to radical-mediated photodegradation. Macromer functionality and formulation were evaluated to achieve full photodegradation of the photo-cross-linked hydrogels. Furthermore, light intensities, wavelengths, and photoinitiator concentrations were tested to achieve tunable photodegradation kinetics. Temporal control of photodegradation was demonstrated, and the hydrogels remained stable postdegradation. Lastly, spatial control of photodegradation was achieved by patterning complex geometries onto 3D-printed PEGaNBCA hydrogels. Taken together, this work presents a facile synthesis route to prepare PEGaNBCA, which can be readily photo-cross-linked into modular and photodegradable hydrogels without the need for a special photolabile motif.
    Keywords:  3D printing; hydrogels; microwave-assisted synthesis; photodegradation; photopolymerization; thiol-norbornene photoclick reaction
    DOI:  https://doi.org/10.1021/acsapm.5c03090
  38. bioRxiv. 2025 Dec 11. pii: 2025.12.08.693064. [Epub ahead of print]
    Building dynamical models of multi-step state transitions from single cell gene expression trajectories.
    Yukai You, Cristian Caranica, Mingyang Lu.
      Multi-step cell state transitions often occur in biological processes, such as cell differentiation and disease progression, yet the regulatory mechanisms governing these transitions remain unclear. Here, we introduce NetDes, a computational method that integrates top-down and bottom-up systems biology to infer core transcription factor regulatory networks and build ODE-based dynamical models from single-cell gene expression trajectories. We demonstrate that NetDes predicts regulatory interactions and reproduces gene expression dynamics through benchmarking using in-silico time trajectories with decoys, tests on gene circuit simulations of embryonic phenotypic switching, and application to time-series scRNA-seq data from human iPSC differentiation. Compared to existing approaches, NetDes has the advantage of capturing sequential state transitions within a single dynamical model. Network simulations and coarse-graining further elucidate the regulatory roles of genes and their combinations in driving these transitions. Our approach provides a generalizable framework for mechanistic modeling of gene regulation in complex cell state transitions.
    DOI:  https://doi.org/10.64898/2025.12.08.693064
  39. Cell Syst. 2025 Dec 17. pii: S2405-4712(25)00257-1. [Epub ahead of print]16(12): 101424
    Engineering mammalian protein secretion: Toward the convergence of high-throughput biology and computational methods.
    Jacopo Gabrielli, Nathan E Lewis, Cleo Kontoravdi, Francesca Ceroni.
      Protein secretion in mammalian cells is the active transport of proteins from the cytoplasm to the extracellular space. It plays a fundamental role in mammalian physiology and signaling, as well as biotherapeutics production and cell and gene therapies. The efficacy of protein secretion, however, is impacted by features of the secreted protein itself, and the host-cell machinery that supports each step of the secretion process. High-throughput techniques such as microfluidics, cell display, and cell encapsulation assays for the study and engineering of secreted proteins are transforming biomedical knowledge and our ability to modulate protein secretion. In addition, computational advances, including signal peptide modeling, whole-protein machine learning models, and genome-scale simulations, are opening new pathways for rational design of protein secretion. Here, we highlight recent developments in secretion engineering that are leading to the convergence of high-throughput experimentation and machine learning methods and can help address current challenges in bioproduction and support future efforts in cell and gene therapy while enabling new modalities.
    Keywords:  bioproduction; biotherapeutics; cell encapsulation; computational protein design; high throughput; microfluidics; protein engineering; protein secretion; synthetic biology; systems biology
    DOI:  https://doi.org/10.1016/j.cels.2025.101424
  40. Metab Eng. 2025 Dec 11. pii: S1096-7176(25)00192-2. [Epub ahead of print]94 192-201
    Machine learning-driven optimization of metabolic balance for β-carotene production.
    Weiming Tu, Jiabao Xu, Yongshuo Ma, Constantinos Katsimpouras, Gregory Stephanopoulos.
      Balancing metabolic pathways is critical for engineering microbial platforms to efficiently and robustly synthesize value-added bioproducts. In the oleaginous yeast Yarrowia lipolytica engineered for β-carotene production, lipid synthesis supports carotenoid storage but also competes with carotenoid synthesis for cellular resources, necessitating precise regulation for optimal resource allocation. In this study, we establish a machine learning framework that captures the complex interactions among three key metabolic modules for β-carotene synthesis: the mevalonate pathway (precursor supply for β-carotene), lipid synthesis (storage capacity), and the β-carotene synthetic cluster (product formation). This computational framework enables the prediction of β-carotene output based on gene combinations and guides iterative gene integration strategies across these interconnected pathways to optimize production. Using this approach, the best-performing strain YLT226 achieved a 7-fold increase in β-carotene titer compared to the initial strain YLT001 through nine rounds of guided gene integration. This work provides a promising strategy for understanding and engineering metabolic flux distributions.
    DOI:  https://doi.org/10.1016/j.ymben.2025.12.002
  41. bioRxiv. 2025 Nov 28. pii: 2025.11.26.690796. [Epub ahead of print]
    LARIS enables accurate and efficient ligand and receptor interaction analysis in spatial transcriptomics.
    Min Dai, Tivadar Török, Dawei Sun, Vallari Shende, Grace Wang, Yuesang Lin, Sherry Jingjing Wu, Alyssa Rukshin, Gord Fishell, Fei Chen.
      Advances in spatially resolved transcriptomics provide unprecedented opportunities to characterise intercellular communication pathways. However, robust and computationally efficient incorporation of spatial information into intercellular communication inference remains challenging. Here, we present LARIS ( L igand A nd R eceptor Interaction analysis in S patial transcriptomics), an accurate and scalable method that identifies cell type-specific and spatially restricted ligand-receptor (LR) interactions at single-cell or bead resolution. LARIS is compatible with all spatial transcriptomic technologies and quantifies specificity, infers sender-receiver directionality, and detects how differential interactions vary across time and space. To compare LARIS with existing methods, we established a simulation framework to generate ground truth of LR interactions with defined tissue architecture and gene expression patterns. LARIS demonstrates superior performances over other methods in accuracy and scalability. We further applied LARIS to human tonsil and developing mouse cortex spatial transcriptomics datasets collected from various spatial techniques. This uncovered the signalling mechanisms shaping tissue organisation and their changes over time. LARIS reveals cell type-, niche-, and condition-specific signalling and scales to hundreds of thousands of cells in minutes. This provides an efficient and direct method for discovering the molecular interplay between apposed cells across development.
    DOI:  https://doi.org/10.1101/2025.11.26.690796
  42. Nat Biotechnol. 2025 Dec 16.
    Antibody-lectin chimeras for glyco-immune checkpoint blockade.
    Jessica C Stark, Melissa A Gray, Itziar Ibarlucea-Benitez, Marta Lustig, Annalise Bond, Brian Cho, Ishika Govil, Tran Luu, Megan J Priestley, Tim S Veth, Wesley J Errington, Bence Bruncsics, Mikaela K Ribi, Leo A Williams, Casim A Sarkar, Simon Wisnovsky, Nicholas M Riley, Meghan A Morrissey, Thomas Valerius, Jeffrey V Ravetch, Carolyn R Bertozzi.
      Despite the curative potential of checkpoint blockade immunotherapy, many patients remain unresponsive to existing treatments. Glyco-immune checkpoints, which involve interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors, have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular system for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin 'decoy receptor' domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate cancer cell destruction by primary human immune cells in vitro and reduce tumour burden in a humanized, immunocompetent mouse model, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumours and immune cell subsets as well as glyco-immune checkpoints, thus representing a potential modality for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41587-025-02884-6
  43. Commun Biol. 2025 Dec 14.
    A chemically inducible, leakless Cre recombinase by split-protein-based efficient and enhanced degradation (SPEED).
    Dewen Cai, Fuun Kawano, Takahiro Otabe, Koji Hashimoto, Moritoshi Sato.
      Chemically inducible DNA recombination systems are a very attractive tool for implementing potent genetic applications. However, conventional systems still suffer from leaky properties in the absence of chemicals. Here we describe a chemically inducible, leakless destabilized Cre recombinase (SPEED-Cre) based on a new approach, split-protein-based efficient and enhanced degradation (SPEED), that consists of a self-assembling split-Cre tagged with a destabilizing domain (DD) mutant from the Escherichia coli dihydrofolate reductase that is stabilized by the antibiotic ligand trimethoprim (TMP). We demonstrate that SPEED-Cre has no significant leak activity of background DNA recombination in the absence of TMP; nevertheless, it enables full induction of TMP-dependent Cre-loxP recombination in human cells and living mice. We also demonstrate the general applicability of the SPEED approach, which can be widely applied to other proteins, by showing high TMP-dependent recombination performances of destabilized Flp, VCre and Dre recombinases based on the SPEED approach. This robust platform technology will greatly enhance chemogenetic applications for genome engineering in living systems.
    DOI:  https://doi.org/10.1038/s42003-025-09359-z
  44. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1353. [Epub ahead of print]53(22):
    Nascent RNA profiling reveals genome-wide productive reiterative initiation regulating gene transcription in bacteria.
    Zhe Sun, Guozhong Huang, Yuqiong Zhang, Shuang Wang, Mikhail Kashlev.
      Productive reiterative initiation at promoters is an alternative transcription mechanism characterized by RNA slippage relative to the template DNA and RNA polymerase, resulting in the incorporation of extra nucleotides into transcripts. A comprehensive understanding of the mechanisms underlying productive reiterative initiation, and its functional implications has been hindered due to the complexity of heterogeneous slippage transcripts. Here, we develop and employ 5' Terminal Native Elongating Transcript Sequencing (5'TNET-seq) to identify and quantify productive reiterative initiation events in Escherichia coli. Using this method, we reveal that more than half of promoters exhibit productive reiterative initiation. The conserved promoter -10 region, an appropriate spacer between the -10 region and the TSS, and the transcription initiation region associated with weak RNA-DNA hybrid stability, particularly "AAA" and "TTT" trinucleotide tracts, contribute to high productive reiterative initiation. In addition, up to four consecutive nucleotides can be added in a single cycle of productive reiterative initiation. A smaller transcription bubble is observed during productive reiterative initiation, which may stabilize the transcription initiation complex to stimulate gene transcription. Our results suggest that productive reiterative initiation emerges as an inherent transcription process regulating biological processes independent of protein regulators.
    DOI:  https://doi.org/10.1093/nar/gkaf1353
  45. Rep Prog Phys. 2025 Dec 15.
    Decoding the architecture of living systems.
    Manlio De Domenico.
      The possibility that evolutionary forces -- together with a few fundamental factors such as thermodynamic constraints, specific computational features enabling information processing, and ecological processes -- might constrain the logic of living systems is tantalizing. However, it is often overlooked that any practical implementation of such a logic requires complementary circuitry that, in biological systems, happens through complex networks of genetic regulation, metabolic reactions, cellular signalling, communication, social and eusocial non-trivial organization. Here, we review and discuss how circuitries are not merely passive structures, but active agents of change that, by means of hierarchical and modular organization, are able to enhance and catalyze the evolution of evolvability. By analyzing the role of non-trivial topologies in major evolutionary transitions under the lens of statistical physics and nonlinear dynamics, we show that biological innovations are strictly related to circuitry and its deviation from trivial structures and (thermo)dynamic equilibria. &#xD;&#xD;We argue that sparse heterogeneous networks such as hierarchical modular, which are ubiquitously observed in nature, are favored in terms of the trade-off between energetic costs for redundancy, error-correction and mantainance. We identify three main features -- namely, interconnectivity, plasticity and interdependency -- pointing towards a unifying framework for modeling the phenomenology, discussing them in terms of dynamical systems theory, non-equilibrium thermodynamics and evolutionary dynamics. Within this unified picture, we also show that "slow" evolutionary dynamics is an emergent phenomenon governed by the replicator-mutator equation as the direct consequence of a constrained variational nonequilibrium process. Overall, this work highlights how dynamical systems theory and nonequilibrium thermodynamics provide powerful analytical techniques to study biological complexity.
    Keywords:  biological networks; complex networks; complex systems; evolution; nonequilibrium processes; nonlinear dynamical systems; statistical physics
    DOI:  https://doi.org/10.1088/1361-6633/ae2ca2
  46. Nanoscale. 2025 Dec 18.
    On-surface polymerization of natural amino acids: substrate engineering and monomer design.
    Yinuo Zhu, Miao Zhou, Tianchao Niu.
      Poly(amino acids), protein analogues with amide backbones, have garnered wide attention due to their biodegradability and tunable physicochemical properties. However, the absence of an efficient polymerization strategy that combines simplified procedures with kinetic control for synthesizing poly(amino acids) remains a critical technical bottleneck, hindering their practical applications in advanced materials science. On-surface synthesis under ultra-high vacuum (UHV) conditions emerges as a promising avenue to overcome these challenges. In this review, we systematically review the design of monomers, synthetic methodologies, and network structures of surface-confined polyamides, emphasizing the pivotal roles of substrate engineering and monomer design in governing polymerization outcomes. We first elucidate the formation of surface-confined amide bonds and polyamide chains on noble metal substrates, involving acyl chloride-amine coupling for constructing one-dimensional linear polyamides and two-dimensional (2D) porous polyamide networks, and direct dehydration condensation of carboxyl and amino species. Additionally, we explore oligomerization pathways of natural amino acids, exemplified by the nickel-catalyzed formation of oligoprolines on the Au(111) surface. Looking forward, we propose that 2D materials, featuring tunable phase structures and versatile electronic properties, offer a transformative alternative to conventional metal substrates with limited modifiability. Meanwhile, natural amino acids, endowed with diverse functional side groups, present unique opportunities for synthesizing structurally complex polymer networks. By synergistically optimizing substrate properties and monomer structures, and harnessing advanced surface synthesis techniques, we aim to establish robust strategies for the substrate-confined catalytic precision synthesis of poly(amino acids). These advances are anticipated to unlock innovative applications in molecular electronics, nanoscale templating, and bio-inspired functional materials.
    DOI:  https://doi.org/10.1039/d5nr04579g
  47. Small. 2025 Dec 15. e10178
    Reversibly Damping Protein Fibers with High Strength and Self-Recovery Capacity Enabled by Dual Dynamic Bonding Networks.
    Mengyao Wang, Huaxia Zhu, Dawen Qin, Peng Zhang, Juanjuan Su, Fan Wang, Hongjie Zhang, Kai Liu, Jingjing Li.
      Spider silk exhibits a unique combination of high strength and self-recoil capability through supercontraction, crucial for cyclic loading applications. However, reproducing these properties in synthetic polymer or recombinant protein fibers remains challenging, primarily due to their rigid molecular structures or monotonous cross-linking networks that limit molecular mobility and hinder structural recovery. Here, reversibly damping protein fibers are engineered by developing a dual-dynamic network fiber chemistry (DNFC) strategy. The resulting fibers integrate high-density hydrogen bonds and dynamic imine cross-links with entropy-driven elasticity, overcoming the limitations of static networks. The DNF exhibits high mechanical strength and up to 88.95% damping efficiency during cyclic loading, the latter surpassing that of regenerated silk and polymer fibers. This reversible energy dissipation arises from a unique humidity-responsive structural recovery mechanism. The process involves hydration-triggered chain recoil and reversible β-sheet rezipping through inter-domain hydrogen bond rearrangement, followed by dehydration-driven imine bond reformation. The approach establishes a versatile platform for engineering dynamically adaptive materials, pioneering an innovative paradigm in biomimetic protein fiber technology through modular chemical cross-linking strategies.
    Keywords:  humidity response; modular engineering; protein fibers; reversible damping capacity
    DOI:  https://doi.org/10.1002/smll.202510178
  48. bioRxiv. 2025 Nov 25. pii: 2025.11.23.690051. [Epub ahead of print]
    RAPMS 2.0 Improves Specificity and Throughput for Proteomic Identification of RNA Binding Proteins.
    D Honson, W Deng, M Blanco, J Sha, K Plath, J A Wohlschlegl, M Guttman, D Majumdar.
      RNA-protein complexes are critical factors in development, homeostasis, and disease. RNA proteomics methods are essential for characterizing these complexes but suffer from high levels of background, which hinders identification of ribonucleoprotein (RNP) components. Here, we present RNA Antisense Purification followed by Mass Spectrometry 2.0 (RAP-MS 2.0), an updated version our original RAP-MS protocol with innovations in bead preparation, RNA capture, and peptide purification. RAP-MS 2.0 has lower background than our original protocol, and allows lysate to be reused to capture multiple RNAs. We demonstrate that RAP-MS 2.0 recapitulates known RNPs for 7SL, 7SK, RMRP, U1, U2, U6, U7, and Xist. Additionally, we use RAP-MS 2.0 to identify novel RNA-protein interactions between Xist and TREX components and U1 with FET family transcriptional regulators.
    DOI:  https://doi.org/10.1101/2025.11.23.690051
  49. Adv Mater. 2025 Dec 16. e15350
    Moth-Wing-Inspired Multifunctional Metamaterials.
    Haoran Pei, Hang Yang, Ning Zhang, Tian Li, Xinxin Wang, Miao Zhao, Shuwei Ding, Xin Wang, Qinniu Lv, Zijie Xu, Yinghong Chen, Xinwei Li, Wei Zhai.
      To evade ultrasonic predation by bats, moths have evolved wing scale architectures capable of absorbing and scattering high-frequency acoustic signals. Drawing inspiration from this natural defense strategy, a bioinspired multifunctional metamaterial is presented that integrates broadband sound absorption, thermal insulation, and mechanical energy dissipation within a unified structural framework. Inspired by the graded pore architecture of moth scales, acoustic performance is first optimized via genetic algorithm-driven pore design and the structures using 3D printing. The resulting metamaterial exhibits broadband acoustic absorption with an average coefficient of 0.742 across the 1000-6000 Hz frequency range. When implemented in helmet-based noise reduction systems, the proposed metamaterial outperforms conventional commercial foams in suppressing environmental noise. In addition, the metamaterial retains a negative Poisson's ratio under large deformation, which enhances its mechanical energy dissipation and impact resilience. Furthermore, the alternating architecture of polymer layers and internal air cavities reduces the effective thermal conductivity to 30.2 mW m-1 K-1, ensuring excellent thermal insulation. This work demonstrates that leveraging biological architectures enables the simultaneous integration of acoustic, mechanical, and thermal functionalities in lightweight metamaterials, offering a new paradigm for multifunctional design.
    Keywords:  bioinspired design; broadband sound absorption; mechanical energy dissipation; multifunctional metamaterial; thermal insulation
    DOI:  https://doi.org/10.1002/adma.202515350
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