bims-enlima Biomed News
on Engineered living materials
Issue of 2025–06–15
sixty-one papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. Tuning viscoelasticity and fine structure of living materials via synthetic adhesion logic and rheological perturbations.
  2. The Challenge of the Yuck Factor in Public Acceptance of Engineered Living Materials.
  3. Rapid model-guided design of organ-scale synthetic vasculature for biomanufacturing.
  4. Mechanics control the proliferation of diatoms entrapped in hydrogels.
  5. Engineered transcription factor-binding arrays for DNA-based gene expression control in mammalian cells.
  6. Living dynamic polymeric materials.
  7. Mechanical Comparison of Escherichia coli Biofilms with Altered Matrix Composition: A Study Combining Shear-Rheology and Microindentation.
  8. Materials Evolution by Programmed Twisting: a DNA-Inspired Ultrastrong Supercoiled Conformational Fiber for Energy-Storage and Buffering.
  9. Generating forces in confinement via polymerization.
  10. Motile and Chemotactic Minicells and Minicell-Driven Biohybrids Engineered for Active Cargo Delivery.
  11. Extracellular-Matrix-Mimetic Hydrogels by Using Nanomaterials.
  12. Engineering controllable alteration of malonyl-CoA levels to enhance polyketide production.
  13. DNA-programmed responsive microorganism assembly with controlled patterns and behaviors.
  14. In Vivo Multicellular Feedback Control in Synthetic Microbial Consortia.
  15. Equilibrium-gated pattern formation: How molecular dissociation thermodynamics drive emergent behavior in dissipative polymeric systems.
  16. Magnetically Actuated Cell Culture Platform for Controlling High-Throughput Cyclic Strain.
  17. De Novo Design of Integrin α5β1 Modulating Proteins to Enhance Biomaterial Properties.
  18. Computer processors built from 2D materials.
  19. Bioengineered Human Cardiac Ventricular Model with Transmural Helical Remodeling.
  20. Polyacrylamide Hydrogels with Reversibly Photocontrolled Stiffness for 2D Mechanobiology.
  21. Motor-driven microtubule diffusion in a photobleached dynamical coordinate system.
  22. 3D Printing of Deformable Multicolor Alternating-Current Electroluminescent Devices Through Rational Design of Functional Inks.
  23. Digitally constructed mask brings a damaged painting back to life.
  24. Designing the Self-Assembly of Disordered Materials Via Color Frustration.
  25. Mechanistic Insights for Glucose-Driven Coacervation of a Supramolecular Peptide and Therapeutic Protein.
  26. Graphene inks for printing based on thermoresponsive ABC triblock terpolymer gels.
  27. High-Throughput Analysis of Protein Adsorption to a Large Library of Polymers Using Liquid Extraction Surface Analysis-Tandem Mass Spectrometry (LESA-MS/MS).
  28. Instant assembly of collagen for tissue engineering and bioprinting.
  29. Multifunctional nanoparticle platform for targeted delivery and vaccines.
  30. Functional Nanoparticle-Enhanced Silk Hydrogels for Tissue Engineering Biomaterials.
  31. Deterministic control of nanomagnetic spiral trajectories using an electric field.
  32. Bioprinting of hepatic tissue model using photocrosslinkable dECM-containing composite hydrogel.
  33. Engineering tough, energy-dissipating soft materials via sacrificial chemical bonds.
  34. A discovery platform for identification of host-induced bacterial biosensors from diverse sources.
  35. Cell cycle regulation in Escherichia coli: from governing principles, checkpoints, and control variables to molecular mechanisms.
  36. Additive Manufacturing of Energy Materials Using Self-Assembled Graphene Oxide and Printable Resin.
  37. Direct Laser Writing of Selectively Degradable Polypeptide Hydrogel Microstructures by Proteolytic Enzymes.
  38. Limitations of cell embedding metrics assessed using drifting islands.
  39. Materials Horizons Emerging Investigator Series: Dr Jung-Yao Chen, National Cheng Kung University.
  40. Living Kombucha Electronics with Proteinoids.
  41. Principles and functional consequences of plasmid chromatinization in mammalian cells.
  42. Passive nanorheological tool to characterise hydrogels.
  43. The design, manufacture and LNP formulation of mRNA for research use.
  44. Hybrid hydrogel-extracellular matrix scaffolds identify biochemical and mechanical signatures of cardiac ageing.
  45. From Physical Cross-Linking to Tailored Phosphorylation: Unlocking High-Performance and Biocompatible Xanthan-Konjac Hydrogels for Zinc-Ion Batteries.
  46. Smart Materials and Devices for Enhanced Delivery of Extracellular Vesicles.
  47. Trade-off between resistance and persistence in high cell density cultures.
  48. Author Correction: Boosting hydrogel conductivity via water-dispersible conducting polymers for injectable bioelectronics.
  49. Light-activated decellularized extracellular matrix-based bioinks for enhanced mechanical integrity.
  50. Discovery of FoTO1 and Taxol genes enables biosynthesis of baccatin III.
  51. Bioactive DNA hydrogel interfacing with living cells and extracellular vesicles.
  52. Orthogonal replication with optogenetic selection evolves yeast JEN1 into a mevalonate transporter.
  53. VesicleVoyager: In vivo selection of surface displayed proteins that direct extracellular vesicles to tissue-specific targets.
  54. Tissue-like compression stiffening in biopolymer networks induced by aggregated and irregularly shaped inclusions.
  55. Modulating Hydrogel Stiffness Through Light-Based 3D Printing to Mimic Cardiac Fibrosis and Cardiomyocyte Dysfunction Using hiPSC-Derived Cells.
  56. Engineering Sustained-Release Broadly Neutralizing Antibody Formulations.
  57. Harnessing Microbial Tools: Escherichia coli as a Vehicle for Neuropeptide Functional Analysis in Caenorhabditis elegans.
  58. Uncovering the principles coordinating systems-level organelle biogenesis with cellular growth.
  59. Complex interplay between gene deletions and the environment uncovers cellular roles for genes of unknown function in Escherichia coli.
  60. Fungal bioconversion of lignin-derived aromatics: Pathways, enzymes, and biotechnological potential.
  61. Giant activity-induced elasticity in entangled polymer solutions.
  1. bioRxiv. 2025 Jun 04. pii: 2025.06.04.657808. [Epub ahead of print]
    Tuning viscoelasticity and fine structure of living materials via synthetic adhesion logic and rheological perturbations.
    Stefana A Costan, Kira Hallerbach, Samuel Y Kim, Chris Camp, Minkyu Kim, Ingmar H Riedel-Kruse.
      Engineered living materials (ELMs) at the multicelluar level represent an innovation that promises programmable properties for biomedical, environmental, and consumer applications. However, the rational tuning of the mechanical properties of such ELMs from first principles remains a challenge. Here we use synthetic cell-cell adhesins to systematically characterize how rheological and viscoelastic properties of multicellular materials made from living bacteria can be tuned via adhesin strength, cell size and shape, and adhesion logic. We confirmed that the previous results obtained for non-living materials also apply to bacterial ELMs. Additionally, the incorporation of synthetic adhesins, combined with the adaptability of bacterial cells in modifying various cellular parameters, now enables novel and precise control over material properties. Furthermore, we demonstrate that rheology is a powerful tool for actively shaping the microscopic structure of ELMs, enabling control over cell aggregation and particle rearrangement, a key feature for complex material design. These results deepen our understanding of tuning the viscoelastic properties and fine structure of ELMs for applications like bioprinting and microbial consortia design including natural systems.
    DOI:  https://doi.org/10.1101/2025.06.04.657808
  2. Glob Chall. 2025 Jun;9(6): 2400384
    The Challenge of the Yuck Factor in Public Acceptance of Engineered Living Materials.
    Kristen K Intemann, Hannah R Lavoie, Kirke D A Elsass, Brandon G Scott, Robin Gerlach.
      Engineered Living Materials (or ELMs) are an emerging class of materials that utilize microorganisms that can either generate their own structure (such as biofilms) or that can be incorporated into synthetic matrices using technologies (such as 3D printing). ELMs can be designed to have multiple functions, such as biosensing, self-repair, or bioremediation. Such materials have the potential to address a variety of problems related to sustainability, including water security, energy, and health. One major challenge to widescale social acceptance and adoption of these materials is the so-called yuck factor, or the propensity these materials may have to elicit disgust reactions. This Perspective provides an overview of social science research directed at the yuck factor to identify the drivers and demographics of disgust experiences and to examine how each of these are likely to arise in relation to ELMs. Strategies for overcoming these challenges are also addressed. Finally, areas where future empirical research is needed to better understand disgust toward ELMs, or particular ELM applications, are identified.
    Keywords:  disgust; living materials; social acceptance of materials; yuck factor
    DOI:  https://doi.org/10.1002/gch2.202400384
  3. Science. 2025 Jun 12. 388(6752): 1198-1204
    Rapid model-guided design of organ-scale synthetic vasculature for biomanufacturing.
    Zachary A Sexton, Dominic Rütsche, Jessica E Herrmann, Andrew R Hudson, Soham Sinha, Jianyi Du, Daniel J Shiwarski, Anastasiia Masaltseva, Fredrik Samdal Solberg, Jonathan Pham, Jason M Szafron, Sean M Wu, Adam W Feinberg, Mark A Skylar-Scott, Alison L Marsden.
      Our ability to produce human-scale biomanufactured organs is limited by inadequate vascularization and perfusion. For arbitrarily complex geometries, designing and printing vasculature capable of adequate perfusion poses a major hurdle. We introduce a model-driven design platform that demonstrates rapid synthetic vascular model generation alongside multifidelity computational fluid dynamics simulations and three-dimensional bioprinting. Key algorithmic advances accelerate vascular generation 230-fold and enable application to arbitrarily complex shapes. We demonstrate that organ-scale vascular network models can be generated and used to computationally vascularize >200 engineered and anatomic models. Synthetic vascular perfusion improves cell viability in fabricated living-tissue constructs. This platform enables the rapid, scalable vascular model generation and fluid physics analysis for biomanufactured tissues that are necessary for future scale-up and production.
    DOI:  https://doi.org/10.1126/science.adj6152
  4. Soft Matter. 2025 Jun 11.
    Mechanics control the proliferation of diatoms entrapped in hydrogels.
    Rani Boons, Dominic Gerber, Robert W Style, Anouk Droux, Tanja Zimmermann, Gustav Nyström, Gilberto Siqueira, André R Studart.
      The proliferation of microorganisms in hydrogels is crucial for the design of engineered living materials and biotechnological processes, and may provide insights into cellular growth in aquatic environments. While the mechanical properties of the gel have been shown to affect the division of entrapped cells, research is still needed to understand the impact and the origin of mechanical forces controlling the growth of microorganisms inside hydrogels. Using diatoms as model microorganisms, we investigate the viability, time to division and growth dynamics of cells entrapped in agar hydrogels with tuneable mechanical properties. Cell culture experiments, confocal optical microscopy and particle tracking velocimetry are performed to uncover the role of stress relaxation and residual stresses in the gel and how these affect diatom proliferation. Our experiments reveal that the interplay between the internal pressure of the dividing cell and the mechanical response of the hydrogel control the proliferation behaviour of the entrapped diatoms. By providing quantitative guidelines for the selection of hydrogels for the entrapment and growth of microorganisms, this study offers new insights on the design of living materials for established and emerging biotechnologies.
    DOI:  https://doi.org/10.1039/d5sm00391a
  5. Trends Biotechnol. 2025 Jun 09. pii: S0167-7799(25)00172-6. [Epub ahead of print]
    Engineered transcription factor-binding arrays for DNA-based gene expression control in mammalian cells.
    Annalise Zouein, Brittany Lende-Dorn, Kate E Galloway, Tom Ellis, Francesca Ceroni.
      Tools that manipulate gene expression in mammalian cells without any additional expression are critical for cell engineering applications. Here, we demonstrate the use of arrays of transcription factor (TF) recognition elements (REs) as DNA tools for controlling gene expression. We first demonstrate that TetR-based RE arrays can alter synthetic gene circuit performance. We then open the approach to any TF with a known binding site by developing a new technique called Cloning Troublesome Repeats in Loops (CTRL), which can assemble plasmids with up to 256 RE repeats. Transfection of custom RE array plasmids assembled by CTRL into mammalian cells modifies host cell gene regulation by sequestration of TFs of interest and can sequester both synthetic and native TFs, offering applications in the control of gene circuits and for directing cell fate. This work advances our ability to assemble repetitive DNA arrays and shows how TF-binding RE arrays expand possibilities in mammalian cell engineering.
    Keywords:  gene expression regulation; mammalian cells; synthetic biology; transcription factor; transcription factor decoy
    DOI:  https://doi.org/10.1016/j.tibtech.2025.05.006
  6. Mater Horiz. 2025 Jun 09.
    Living dynamic polymeric materials.
    Jiahui Liu, Marek W Urban.
      Many materials exhibit static and functional properties. This article elaborates on how the last few decades of material research have demonstrated the apparent similarities between the equilibrium thermodynamics of static materials and the biological world utilizing non-equilibria biological processes. Dynamic polymer networks involving covalent and non-covalent multi-stimulus materials at nano-, micro-, and macro-scales and their biological counterparts at molecular, cellular, and species levels are addressed in the context of opportunities and challenges governing their development involving non-equilibria processes.
    DOI:  https://doi.org/10.1039/d5mh00710k
  7. ACS Biomater Sci Eng. 2025 Jun 12.
    Mechanical Comparison of Escherichia coli Biofilms with Altered Matrix Composition: A Study Combining Shear-Rheology and Microindentation.
    Macarena Siri, Adrien Sarlet, Ricardo Ziege, Laura Zorzetto, Carolina Sotelo Guzman, Shahrouz Amini, Regine Hengge, Kerstin G Blank, Cécile M Bidan.
      The mechanical properties of bacterial biofilms depend on the composition and microstructure of their extracellular matrix (ECM), which constitutes a network of extracellular proteins and polysaccharide fibers. In particular, Escherichia coli macrocolony biofilms were suggested to present tissue-like elasticity due to a dense fiber network consisting of amyloid curli and phosphoethanolamine-modified cellulose (pEtN-cellulose). To understand the contribution of these two main ECM components to the emergent mechanical properties of E. coli biofilms, we performed shear-rheology and microindentation experiments on biofilms grown from E. coli strains that produce different ECM. We measured that biofilms containing curli fibers are stiffer in compression than curli-deficient biofilms. We further quantitatively demonstrate the crucial contribution of pEtN-cellulose, and especially of the pEtN modification, to the stiffness and structural stability of biofilms when associated with curli fibers. To compare the differences observed between the two methods, we also investigated how the structure and mechanical properties of biofilms with different ECM compositions are affected by the sample preparation method used for shear-rheology. We found that biofilm homogenization, used prior to shear-rheology, destroys the macroscale structure of the biofilm while the microscopic ECM architecture may remain intact. The resulting changes in biofilm mechanical properties highlight the respective advantages and limitations of the two complementary mechanical characterization techniques in the context of biofilm research. As such, our work does not only describe the role of the ECM on the mechanical properties of E. coli biofilms. It also informs the biofilm community on considering sample preparation when interpreting mechanical data of biofilm-based materials.
    Keywords:  E. coli; biofilm; extracellular matrix; mechanical properties
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00261
  8. Adv Mater. 2025 Jun 12. e2503330
    Materials Evolution by Programmed Twisting: a DNA-Inspired Ultrastrong Supercoiled Conformational Fiber for Energy-Storage and Buffering.
    Ziyu Zhao, Jiarui Yang, Wenrui Cai, Guojiang Wen, Zhiwei Zhu, Zhengying Liu, Xuewei Fu, Zhiqiang Cao, Zunfeng Liu, Wei Yang, Yu Wang.
      The conformational folding/unfolding behaviors of DNA supercoils serve as a fundamental mechanism governing ultradense bio-information storage and precise genetic transcription. Mimicking those nanoscale dynamic conformational behaviors for macroscopic materials to achieve unusual functionalities will be of great interest but remains unexplored. Herein, a DNA-inspired materials evolution paradigm is presented to create multifunctional supercoiled conformational fibers (SCFs) by programmed twisting controlled self-buckling. Through the programmed twist-stress modulation, a low-density polyethylene strip is transformed into high-performance DNA-like SCF through a unique multiscale microstructure evolution process. This DNA-like SCF exhibits five hallmark characteristics unattainable before, including ultra-large elastic deformability (900 ± 50%), metal-level mechanical strength (330 ± 30 MPa), unprecedented torsional energy-storage density (16.1 ± 0.6 kJ kg-1), torsional energy release upon appropriate stimulations, and impact buffering through conformation-mediated energy-dissipation. Characterization reveals that these unexpected energy-related properties mainly are contributed by the multiscale twisting-reinforced microstructures and conformation mechanics. Potential applications of the SCFs are demonstrated finally by harvest-and-storage of wind energy and soft-landing. The DNA-like SCFs indicate a general platform for materials evolution with extraordinary mechanics and functions.
    Keywords:  DNA‐mimetic conformation materials; bioinspired micro‐engine; energy absorption and impact buffering; polymeric energy materials; torsional energy storage
    DOI:  https://doi.org/10.1002/adma.202503330
  9. Soft Matter. 2025 Jun 09.
    Generating forces in confinement via polymerization.
    Dino Osmanović, Elisa Franco.
      Understanding how to produce forces using biomolecular building blocks is essential for the development of adaptive synthetic cells and living materials. Here we ask whether a dynamic polymer system can generate deformation forces in soft shells by pure self-assembly, motivated by the fact that biological polymer networks like the cytoskeleton can exert forces, move objects, and deform membranes by simply growing, even in the absence of molecular motors. We address this question by investigating polymer force generation by varying the release rate, the structure, and the interactions of self-assembling monomers. First, we develop a toy computational model of polymerization in a soft elastic shell that reveals the emergence of spontaneous bundling which enhances shell deformation. We then extend our model to account more explicitly for monomer binding dynamics. We find that the rate at which monomers are released into the interior of the shell is a crucial parameter for achieving deformation through polymer growth. Finally, we demonstrate that the introduction of multivalent particles that can join polymers can either improve or impede polymer performance, depending on the amount and on the structure of the multivalent particles. Our results provide guidance for the experimental realization of polymer systems that can perform work at the nanoscale, for example through rationally designed self-assembling proteins or nucleic acids.
    DOI:  https://doi.org/10.1039/d4sm01339e
  10. ACS Appl Mater Interfaces. 2025 Jun 12.
    Motile and Chemotactic Minicells and Minicell-Driven Biohybrids Engineered for Active Cargo Delivery.
    Irina Kalita, Remy Colin, Sarah Hoch, Saadet Fatma Baltaci, Metin Sitti, Victor Sourjik.
      Bacterial minicells are submicrometer-sized spherical compartments produced by bacteria as a result of aberrant cell division. Minicells have a similar cellular composition to the parental bacteria but lack chromosomal DNA and are thus unable to proliferate. Due to that, minicells have attracted attention as potential means of effector delivery in bioengineering and biomedical applications. However, until now, the efficiency of delivery by minicells has been limited by passive collisions with their targets. To develop minicell-based active delivery, here we engineer Escherichia coli strains generating motile minicells with enhanced swimming properties by introducing genetic modifications specifically targeting flagella number, length, and rotation speed. The engineered minicells preserve motility over an extended period of time and, in contrast to parental E. coli cells, increase their swimming speed for the intermediate viscosity of the medium. Despite their small size, minicells show an efficient chemotactic response and utilize the same chemotactic strategy as parental E. coli cells. Moreover, we develop a procedure for conjugating minicells with cargo particles and demonstrate that such minicell-driven biohybrid swimmers are chemotactic and thus capable of actively accumulating at the source of an attractant. These engineered chemotactic minicells and minicell-based biohybrids can serve as cargo delivery platforms with active targeting, thus overcoming the challenges posed by nontargeted therapies.
    Keywords:  active biohybrids; bacterial minicells; chemotaxis; drug delivery; microswimmers; motility
    DOI:  https://doi.org/10.1021/acsami.5c04638
  11. Int J Mol Sci. 2025 May 22. pii: 4987. [Epub ahead of print]26(11):
    Extracellular-Matrix-Mimetic Hydrogels by Using Nanomaterials.
    Do Gyun Kim, Gi Doo Cha.
      Matrigel, a tumor-derived basement membrane extract, has been commercially used in the field of cell culture and tissue engineering due to its extracellular-matrix-mimetic (ECM-mimetic) properties. However, its batch-to-batch variability and limited mechanical tunability hinder reproducibility and clinical translation. To overcome these issues, synthetic ECM-mimetic hydrogels have been developed to improve reproducibility and biocompatibility. While they are effective in mimicking ECMs, these materials must go beyond passive replication by implementing the complex functionalities of the ECM. The integration of nanomaterials with hydrogel could address this need by reinforcing mechanical properties, enabling various functionalities, and featuring dynamic responsiveness. In this review, we present the evolution from Matrigel to ECM-mimetic hydrogels and ECM-mimetic hydrogel nanocomposites, exploring their key advancements and challenges. We will discuss the advantages and disadvantages of the transition from Matrigel to ECM-mimetic hydrogels and ECM-mimetic hydrogel nanocomposites, along with cases that have addressed Matrigel's limitations and added new functionalities. Furthermore, we discuss future directions for the design of the ECM-mimetic hydrogels, emphasizing how nanotechnology strategies can drive innovation in tissue engineering and regenerative medicine.
    Keywords:  3D cell culture; ECM-mimetic hydrogel; extracellular matrix; nanomaterial; synthetic ECM-mimetic hydrogel; tissue engineering
    DOI:  https://doi.org/10.3390/ijms26114987
  12. Nat Chem Biol. 2025 Jun 11.
    Engineering controllable alteration of malonyl-CoA levels to enhance polyketide production.
    Sarah H Klass, Mia Wesselkamper, Aidan E Cowan, Namil Lee, Nathan Lanclos, Seokjung Cheong, Zilong Wang, Yan Chen, Jennifer W Gin, Christopher J Petzold, Jay D Keasling.
      Heterologous expression of polyketide synthase (PKS) genes in Escherichia coli has enabled the production of various valuable natural and synthetic products. However, the limited availability of malonyl-CoA (M-CoA) in E. coli remains a substantial impediment to high-titer polyketide production. Here we address this limitation by disrupting the native M-CoA biosynthetic pathway and introducing an orthogonal pathway comprising a malonate transporter and M-CoA ligase, enabling efficient M-CoA biosynthesis under malonate supplementation. This approach substantially increases M-CoA levels, enhancing fatty acid and polyketide titers while reducing the promiscuous activity of PKSs toward undesired acyl-CoA substrates. Subsequent adaptive laboratory evolution of these strains provides insights into M-CoA regulation and identifies mutations that further boost M-CoA and polyketide production. This strategy improves E. coli as a host for polyketide biosynthesis and advances understanding of M-CoA metabolism in microbial systems.
    DOI:  https://doi.org/10.1038/s41589-025-01911-6
  13. Sci Adv. 2025 Jun 13. 11(24): eads8651
    DNA-programmed responsive microorganism assembly with controlled patterns and behaviors.
    Yuhan Kong, Qi Du, Dan Zhao, Yujian Wen, Tianqing Zhang, Zhiwang Geng, Maben Ying, Bryan Wei, Tong Si, Ye Tian, Feng Li, Zhou Nie, Hang Xing.
      Programming microorganism adhesions to engineer multicellular microbial communities holds promise for synthetic biology and medicine. Current chemical and genetic engineering approaches often lack specificity or require engineered bacteria, making the design of responsive interactions challenging. Here, we demonstrate the use of functional DNA as programmable surface receptors to regulate the patterns and behaviors of microbial communities. Using metabolic labeling and hydrophobic insertion, we modified various microorganisms with DNA, including Gram-positive and Gram-negative bacteria, and dormant spores. By incorporating distinct sequences, we achieved precise spatial control of bi- and tricomponent microbial assemblies, forming diverse morphologies like core-shell and selective clusters. Stimuli-responsive clustering was successfully realized using aptamers, strand displacement, and reverse-Hoogsteen base pairing, with oligonucleotides or small molecules as exogenous cues. This work extends the use of functional DNA to control microbial interactions, enabling living communities with dynamic biofunctions, such as biofilm formation, antibiotic sensitivity, and quorum sensing, in response to biological triggers.
    DOI:  https://doi.org/10.1126/sciadv.ads8651
  14. ACS Synth Biol. 2025 Jun 11.
    In Vivo Multicellular Feedback Control in Synthetic Microbial Consortia.
    Davide Salzano, Barbara Shannon, Claire Grierson, Lucia Marucci, Nigel J Savery, Mario di Bernardo.
      In this paper, we present a biomolecular control architecture able to guarantee stable and precise regulation of gene expression. Specifically, we engineer a microbial consortium comprising a cellular population, named controllers, that is tasked to regulate the expression of a gene in a second population, termed targets. Traditional biomolecular control strategies, while effective, are predominantly confined to single-cell applications, limiting their complexity and adaptability due to factors such as competition for limited cell resources and incompatible chemical reactions. Our approach overcomes these limitations by employing a distributed multicellular feedback loop between two strains of Escherichia coli, allowing for division of labor across the consortium. In vivo experiments demonstrate that this control system maintains precise and robust gene expression in the target population, even amid variations in consortium composition. Our study fills a critical gap in synthetic biology and paves the way for more complex and reliable applications in the field.
    Keywords:  Escherichia coli; control engineering; cybergenetics; gene regulation; modularity; multicellular control; synthetic biology; synthetic microbial consortia
    DOI:  https://doi.org/10.1021/acssynbio.4c00862
  15. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2503176122
    Equilibrium-gated pattern formation: How molecular dissociation thermodynamics drive emergent behavior in dissipative polymeric systems.
    Donald Bistri, Anna Cramblitt, Ignacio Arretche, Conan Zhang, Reid B Cope, Michael Zakoworotny, Mya G Mills, Luis E Rodriguez Koett, Lauren Chua, Rafael Gómez-Bombarelli, Sameh H Tawfick, Nancy R Sottos, Jeffrey S Moore, Philippe H Geubelle.
      Emergent patterns in biological systems arise through dissipative processes that balance reaction and transport phenomena, producing highly functional properties from self-regulating mechanisms. Synthetic fabrication, by contrast, often relies on user-controlled, multistep methods that lack the self-organizing capabilities of natural systems. Inspired by nature, we sought chemical systems that integrate strongly coupled reaction and transport phenomena, identifying frontal ring-opening metathesis polymerization (FROMP) as a method capable of creating diverse forms and functions through reactive processing. By employing discrete molecular initiators, FROMP allows precise control of key reaction steps-inhibition, initiation, and propagation. Using an integrated computational and experimental framework, we uncover how near-equilibrium inhibition dynamics, coupled with far-from-equilibrium reaction kinetics, drive pattern formation in frontally polymerized synthetic materials. We propose the concept of equilibrium-gated pattern formation, demonstrating how initiator chemistry can be tuned to achieve programmable macroscale properties. Our study reveals a surprising insight: Emergent behavior in FROMP systems arises from the inhibition-dominated regime of resin composition, expanding prior observations that such behavior is confined to a narrow compositional space near the boundary between front quenching and uniform front propagation. We identify a broader compositional window, far from the quenching regime, where emergent behavior reliably manifests. This expanded design space significantly enhances the operational flexibility of reactive systems and their capacity for self-organization. These insights provide a roadmap for designing bioinspired materials with self-organizing capabilities, unlocking possibilities in synthetic manufacturing.
    Keywords:  architected polymers; frontal polymerization; spontaneous patterning; thermochemistry
    DOI:  https://doi.org/10.1073/pnas.2503176122
  16. Macromol Biosci. 2025 Jun 10. e00466
    Magnetically Actuated Cell Culture Platform for Controlling High-Throughput Cyclic Strain.
    Bryce J Stottlemire, Aparna R Chakravarti, Cory J Berkland.
      Cells efficiently manage various mechanical inputs, converting them into biochemical outputs to regulate function. Mechanobiologists aim to harness this capacity by developing platforms that mimic physiological mechanical environments. Current commercial and research-based dynamic cell culture platforms rely on external force generators to control substrate deformation or translation. However, this tends to make the systems bulky, and can sacrifice throughput and adaptability. Thus, this work presents the advancement of magnetic-polydimethylsiloxane (PDMS) cell culture systems to precisely control the mechanical strain environment of 2D and 3D cell cultures with multiple high-throughput embodiments. First, an indirect 3D fabrication technique is utilized to develop high-fidelity, deformable microporous magnetic composite material for high-throughput cyclic straining of a 3D hydrogel. Second, a magnetic PDMS membrane is developed for 2D cell culture to mimic the complex and nonhomogeneous mechanical environment cells experience in vivo. The proposed advancements can significantly shift cell culture technologies by leveraging magnetic responsive materials to develop dynamic bioreactor systems with diverse interfaces and high throughput capabilities, enabling precise control over cellular environments with diverse strain profiles and gradients for more sophisticated cell behavior and differentiation studies.
    Keywords:  3D printing; cell stretching; magnetic materials; remote control; soft actuators; tissue engineering
    DOI:  https://doi.org/10.1002/mabi.202400466
  17. Adv Mater. 2025 Jun 09. e2500872
    De Novo Design of Integrin α5β1 Modulating Proteins to Enhance Biomaterial Properties.
    Xinru Wang, Jordi Guillem-Marti, Saurav Kumar, David S Lee, Daniel Cabrerizo-Aguado, Rachel Werther, Kevin Alexander Estrada Alamo, Yan Ting Zhao, Adam Nguyen, Irina Kopyeva, Buwei Huang, Jing Li, Yuxin Hao, Xinting Li, Aritza Brizuela-Velasco, Analisa Murray, Stacey Gerben, Anindya Roy, Cole A DeForest, Timothy Springer, Hannele Ruohola-Baker, Jonathan A Cooper, Melody G Campbell, Jose Maria Manero, Maria-Pau Ginebra, David Baker.
      Integrin α5β1 is crucial for cell attachment and migration in development and tissue regeneration, and α5β1 binding proteins can have considerable utility in regenerative medicine and next-generation therapeutics. We use computational protein design to create de novo α5β1-specific modulating miniprotein binders, called NeoNectins, that bind to and stabilize the open state of α5β1. When immobilized onto titanium surfaces and throughout 3D hydrogels, the NeoNectins outperform native fibronectin (FN) and RGD peptides in enhancing cell attachment and spreading, and NeoNectin-grafted titanium implants outperformed FN- and RGD-grafted implants in animal models in promoting tissue integration and bone growth. NeoNectins should be broadly applicable for tissue engineering and biomedicine.
    Keywords:  RGD; biomaterial; de novo protein design; hydrogel; integrin α5β1; regenerative medicine; titanium
    DOI:  https://doi.org/10.1002/adma.202500872
  18. Nature. 2025 Jun;642(8067): 312-313
    Computer processors built from 2D materials.
    Michael Waltl, Tibor Grasser.
      
    Keywords:  Materials science; Nanoscience and technology
    DOI:  https://doi.org/10.1038/d41586-025-01453-w
  19. Adv Healthc Mater. 2025 Jun 12. e2502005
    Bioengineered Human Cardiac Ventricular Model with Transmural Helical Remodeling.
    Nisa P Williams, Kevin M Beussman, John R Foster, Marcus Rhodehamel, Charles A Williams, Jonathan H Tsui, Alec S T Smith, Paulos Y Mengsteab, Hyeon-Cheol Park, David L Mack, Charles E Murry, Nathan J Sniadecki, Deok-Ho Kim.
      The heart's helical myocardial architecture enables efficient contraction by generating a twisting motion to eject blood. However, few existing approaches can replicate the complex structure-function relationships that govern cardiac performance at the macroscopic organ level. Here, we present a human 3D ventricular model with helical transmural architecture, engineered using multilayered, patterned cardiac sheets assembled on a 3D-printed conical mold. Tissue-engineered ventricles with cardiomyocytes pre-aligned parallel or perpendicular to the long axis exhibited enhanced contractile pressures and maximum capture rates compared to tissue constructs with angled or randomly oriented cells. Notably, the inner layers of perpendicular sheets underwent spontaneous realignment over 4 days, adopting a parallel orientation and forming a physiologically relevant helical transmural structure, whereas minimal remodeling was observed in parallel or angled sheets. Finite element analysis of engineered ventricles revealed that circumferential alignment induces the highest perpendicular shear stress at the inner layer, while longitudinal alignment generates the highest parallel stress, suggesting that cells remodel to reduce local shear stress. By enabling dynamic remodeling of organized cardiac sheets within a physiologically relevant 3D geometry, our platform demonstrates how mechanical cues guide transmural reorientation and tissue remodeling, and elucidates the mechanobiology underlying myocardial structure-function relationships.
    Keywords:  contractile pressure; induced pluripotent stem cells; structure‐function relationship; tissue engineering; ventricular remodeling
    DOI:  https://doi.org/10.1002/adhm.202502005
  20. ACS Appl Mater Interfaces. 2025 Jun 06.
    Polyacrylamide Hydrogels with Reversibly Photocontrolled Stiffness for 2D Mechanobiology.
    Eric C Abenojar, Ekta Minocha, Emmanuel A Garcia Villatoro, Viraj C Kirinda, Ashwani Kumar Gupta, Boyeong Kang, Ik Sung Cho, Vivian Zhang, Jae-Won Shin, Jason A Wertheim, Julia A Kalow.
      We report the development of polyacrylamide hydrogels with photoswitchable stiffness using solely visible light and their application to cell culture. We have previously shown that azobenzenes can control the binding constants of dynamic covalent boronic ester bonds (Chem. Sci. 2018, 9, 5987; J. Am. Chem. Soc. 2020, 142, 19969). Here we show that these photoswitchable dynamic bonds can be incorporated into polyacrylamide hydrogels that are stable for at least 10 days in buffer without changes in stiffness or photoresponse. Reversible stiffening and softening are achieved with green and blue irradiation, respectively. We prepared soft (877 ± 79 Pa) and stiff (8.4 ± 0.3 kPa) hydrogels that undergo rapid, photoreversible changes in modulus over at least 3 light irradiation cycles. In vitro studies show that the hydrogels are nontoxic to HepG2 cells. The cells undergo the expected changes in morphology, actin stress fiber formation, and Yes-associated protein (YAP) subcellular localization upon stiffening and softening the hydrogel substrate with visible light. These results validate the suitability of our visible-light-controlled hydrogel as a versatile platform for cellular mechanotransduction studies.
    Keywords:  cell culture; dynamic covalent chemistry; hydrogels; mechanobiology; photoresponsive materials; photoswitch; polyacrylamide; stimuli-responsive materials
    DOI:  https://doi.org/10.1021/acsami.5c02909
  21. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2417020122
    Motor-driven microtubule diffusion in a photobleached dynamical coordinate system.
    Soichi Hirokawa, Heun Jin Lee, Rachel A Banks, Ana I Duarte, Bibi Najma, Matt Thomson, Rob Phillips.
      A hallmark feature of active matter systems is the ability of individual elements to interact and organize over length scales exceeding that of the constituent molecular players. However, the nature of internal redistribution that occurs in the bulk of the collective is less clear. Using light-dimerizable kinesin motors to spatially control the formation and contraction of a microtubule network, we deliberately photobleach a grid pattern onto the filament network serving as a transient and dynamic coordinate system to observe the deformation and translation of the remaining fluorescent squares of microtubules. We find that the network contracts at a rate set by motor speed but is accompanied by a diffusive-like spread throughout the bulk of the contracting network with effective diffusion constant two orders of magnitude lower than that for freely diffusing microtubules. We further find that on micron scales, the diffusive timescale is only a factor of ≈3 slower than that of advection regardless of conditions, showing that the global contraction and long-time relaxation from this diffusive behavior are both motor-driven but exhibit local competition within the network bulk.
    Keywords:  active matter; cytoskeleton; photobleaching
    DOI:  https://doi.org/10.1073/pnas.2417020122
  22. Small. 2025 Jun 12. e2502435
    3D Printing of Deformable Multicolor Alternating-Current Electroluminescent Devices Through Rational Design of Functional Inks.
    Jeongbin Park, Shakti Singh, Jinhwan Yoon.
      The development of flexible and customizable electroluminescent devices represents a significant challenge in advanced manufacturing. This paper introduces a novel approach for fabricating highly deformable, fully 3D-printed alternating-current electroluminescent devices through the rational design of UV-curable functional inks. The devices feature a unique multilayer structure including a UV-curable thiol-ene crosslinked emission layer (ZBS-t-SE) and temperature-responsive ionic hydrogel electrodes (FFP). The ZBS-t-SE demonstrates exceptional mechanical properties, with a strain of 259% at 727 kPa, whereas the FFP electrodes exhibit excellent printability through controlled micelle formation, high ionic conductivity (2.5 × 10⁻2 S cm-1), and stable performance under repeated deformation (>3000 cycles at 200% strain). The optimized devices maintain stable operation under various deformation modes, including stretching, bending, and twisting, achieving a maximum luminance of 267.4 cd m- 2 at 200% strain. Furthermore, the 3D printing approach enables the fabrication of complex 3D structures with multi-color emission through precise spatial control of functional materials, presenting a transformative strategy for next-generation flexible electronics and display technologies.
    Keywords:  3D printing; alternating‐current electroluminescent devices; ionic hydrogels; stretchable electronics; thiol‐ene click chemistry
    DOI:  https://doi.org/10.1002/smll.202502435
  23. Nature. 2025 Jun;642(8067): 305-306
    Digitally constructed mask brings a damaged painting back to life.
    Hartmut Kutzke.
      
    Keywords:  Arts; Culture; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-01582-2
  24. Adv Mater. 2025 Jun 10. e2502136
    Designing the Self-Assembly of Disordered Materials Via Color Frustration.
    Andreas Neophytou, Francesco Sciortino, John Russo.
      The ability to control self-assembly with atomic-level precision has led to remarkable advances in the rational design of crystalline materials. However, similar design strategies have yet to be developed for amorphous materials. Here, a strategy is devised for programming the self-assembly of amorphous structures by encoding frustration into the building block design. The building blocks are tailored to locally favor the formation of five-member rings and yield a network of face-sharing dodecahedral cages whose icosahedral symmetry prevents long-range order. Surprisingly, unlike geometrically frustrated glasses that form through kinetic arrest, the network nucleates spontaneously from the liquid phase, representing a novel type of thermodynamically stable disordered phase. The stabilization of this frustrated phase via programmable interactions paves the way for a new generation of disordered materials.
    Keywords:  amorphous materials; glass; material design; patchy particles; phase transition; programmed self‐assembly
    DOI:  https://doi.org/10.1002/adma.202502136
  25. ACS Appl Mater Interfaces. 2025 Jun 11.
    Mechanistic Insights for Glucose-Driven Coacervation of a Supramolecular Peptide and Therapeutic Protein.
    Pradeep Kadu, Bernice Webber, Weike Chen, Evgenii L Kovrigin, Matthew J Webber.
      Biological systems leverage spontaneous and transient liquid-liquid phase separation (LLPS) of proteins and biomolecules to achieve remarkable functionality. In particular, the LLPS of intrinsically disordered proteins underpins the formation of membraneless compartments in living cells, inspiring synthetic designs based on polymers and polypeptides. While these bioinspired materials have garnered significant interest, LLPS driven by ordered supramolecular assemblies of low-molecular-weight building blocks remains less explored. The current report further investigates a glucose-triggered coacervation arising from a net-cationic supramolecular peptide amphiphile (PA) incorporating a glucose-binding motif upon its interaction with glucose at physiologically relevant concentrations in the presence of a net-anionic therapeutic protein. The phase regime for LLPS is established by varying the concentrations of each component of the system, while a systematic investigation of electrostatic, hydrophobic, and hydrogen bonding interactions performed through the use of disruptive stimuli along with structural changes to PA design reveals key molecular-scale determinants governing phase behavior. Specifically, LLPS arises through cohesive hydrogen bonding and hydrophobic interactions, with electrostatic contributions via screening from oppositely charged components and ambient salt. Interesting temperature-dependent behaviors furthermore align with established theories of complex coacervation that emphasize both enthalpic and entropic contributions. The preparation of materials that undergo LLPS through a balance of intermolecular forces enables new opportunities to design physiologically adaptive drug delivery platforms.
    Keywords:  droplets; drug delivery; self-assembly; supramolecular chemistry; transient biomaterials
    DOI:  https://doi.org/10.1021/acsami.5c07167
  26. RSC Appl Polym. 2025 Jun 02.
    Graphene inks for printing based on thermoresponsive ABC triblock terpolymer gels.
    Xu Liu, Bailin Feng, Stefano Tagliaferri, Anna P Constantinou, Alexandra E Porter, Cecilia Mattevi, Theoni K Georgiou.
      Additive manufacturing has revolutionized the fabrication of complex 3D materials. Hydrogels are commonly used as "inks" in 3D printing and offer easy mixing and processing of many materials. Here, the synthesis and characterization of a new library of thermoresponsive ABC triblock copolymers based on oligo(ethylene glycol) methyl ether methacrylate (OEGMA, Molar Mass, MM = 300 g mol-1, A block), 2-phenylethyl methacrylate (PhEMA, B block) and di(ethylene glycol) methyl ether methacrylate (DEGMA, C block) is reported. Polymers of different comonomer compositions were fabricated and investigated in terms of their aqueous solution properties and their ability to form thermogels. The most promising polymer was then used to fabricate a graphene-containing ink, and graphene constructs were successfully printed and characterized in terms of the electrical conductivity properties.
    DOI:  https://doi.org/10.1039/d5lp00071h
  27. Anal Chem. 2025 Jun 10.
    High-Throughput Analysis of Protein Adsorption to a Large Library of Polymers Using Liquid Extraction Surface Analysis-Tandem Mass Spectrometry (LESA-MS/MS).
    Joris Meurs, Aishah Nasir, Grazziela P Figueredo, Laurence Burroughs, Salah A Abdelrazig, Chris Denning, David A Winkler, David A Barrett, Dong-Hyun Kim, Morgan R Alexander.
      Biomaterials play an important role in medicine from contact lenses to joint replacements. High-throughput screening coupled with machine learning has identified synthetic polymers that prevent bacterial biofilm formation, prevent fungal cell attachment, control immune cell attachment and phenotype, or direct stem cell fate. In-vitro preadsorption of proteins from culture medium plays a pivotal role in controlling cell response. However, there is a paucity of studies on the screening of protein adsorption into material libraries. Here, we show how quantitative analysis of protein adsorption on a 208-member polymer microarray can be achieved using liquid extraction surface analysis, combined with an adaptation of the droplet microarray (DMA) approach and tandem mass spectrometry (LESA-MS/MS) for protein identification. This study uses a fully defined cell culture medium containing only four proteins (Essential 8) to demonstrate the feasibility of the analysis approach. Our findings show that we can generate quantitative and predictive machine learning models of protein adsorption that elucidate key polymer features that describe the relationship between surface chemistry and protein adsorption. This information is of use for the rational design of new materials with bespoke protein attachment properties for biomaterials, medical devices, or in vitro compound screening.
    DOI:  https://doi.org/10.1021/acs.analchem.5c01636
  28. Nat Mater. 2025 Jun 06.
    Instant assembly of collagen for tissue engineering and bioprinting.
    Xiangyu Gong, Zhang Wen, Zixie Liang, Hugh Xiao, Sein Lee, Alejandro Rossello-Martinez, Qinzhe Xing, Thomas Wright, Ryan Y Nguyen, Michael Mak.
      Engineering functional cellular tissue components holds great promise in regenerative medicine. Collagen I, a key scaffolding material in bodily tissues, presents challenges in controlling its assembly kinetics in a biocompatible manner in vitro, restricting its use as a primary scaffold or adhesive in cellular biofabrication. Here we report a collagen fabrication method termed as tunable rapid assembly of collagenous elements that leverages macromolecular crowding to achieve the instant assembly of unmodified collagen. By applying an inert crowder to accelerate the liquid-gel transition of collagen, our method enables the high-throughput creation of physiological collagen constructs across length scales-from micro to macro-and facilitates cell self-assembly and morphogenesis through the generation of tunable multiscale architectural cues. With high biocompatibility and rapid gelation kinetics, the tunable rapid assembly of collagenous elements method also offers a versatile bioprinting approach for collagen over a wide concentration range, enabling the direct printing of cellular tissues using pH-neutral, bioactive collagen bioinks and achieving both structural complexity and biofunctionality. This work broadens the scope of controllable multiscale biofabrication for tissues across various organ systems using unmodified collagen.
    DOI:  https://doi.org/10.1038/s41563-025-02241-7
  29. iScience. 2025 Jun 20. 28(6): 112599
    Multifunctional nanoparticle platform for targeted delivery and vaccines.
    Anja S Redecker, Medea Neek, Philip E J Smith, James R Swartz.
      We describe a versatile, targeted delivery platform based on the Hepatitis B core protein virus-like particle (VLP). Multiple protein mutations were combined with cell-free protein synthesis and anaerobic processing to enable reliable production of nanoparticles (NPs) loaded with single or multiple cargoes (typically with concentration factors >10ˆ4) and functionalized with single or multiple surface adducts. Our design supports multiple functional requirements while also enabling flexible and reliable production. Process yields are about 6 x 1013 NPs per mL of cell-free reaction; approximately 100-fold higher than current adeno-associated virus (AAV) yields and 8 times previously reported HBc VLP yields. We demonstrate platform feasibility and versatility by the surface display of a challenging-to-fold dengue fever antigen and by pharmacokinetic studies using whole-body mouse imaging. The platform supports rapid, parallel production of multiple product candidates to increase success rates for targeted therapeutics, gene therapies, imaging agents, and vaccines.
    Keywords:  Biochemistry; Biomaterials; Drug delivery system; Nanoparticles; Therapeutics
    DOI:  https://doi.org/10.1016/j.isci.2025.112599
  30. J Biomed Mater Res A. 2025 Jun;113(6): e37945
    Functional Nanoparticle-Enhanced Silk Hydrogels for Tissue Engineering Biomaterials.
    Olivia K Foster, Derek Hiscox, Sawnaz Shaidani, Jean Park, Ella Canas, Charlotte Jacobus, Riley Patten, David L Kaplan.
      Hydrogels prepared from natural polymers, such as silk fibroin, are useful in the field of tissue engineering due to their biocompatibility, biodegradability, and biological performance. However, poor mechanical properties can limit their broader utility. This study investigated reinforcing enzymatically crosslinked silk hydrogels with 130 nm silk nanoparticles (SNPs) to generate silk-silk composite materials with tunable strength and stiffness. The strength of the materials was dependent on SNP concentration, and hydrogels with Young's moduli of 14, 34, and 67 kPa were fabricated by adding no SNPs, 2 mg/mL SNPs, and 4 mg/mL SNPs, respectively. These methods were applied to silk bioinks using Freeform Reversible Embedding of Suspended Hydrogels (FRESH) 3D printing to fabricate complex 3D structures with control of elasticity and modulus. Cylinders with Young's moduli of 17, 35, and 58 kPa were obtained with no SNPs, 2 mg/mL SNPs, and 4 mg/mL SNPs, respectively. SNPs were also preloaded with epidermal growth factor (EGF), relevant for tissue development and wound healing, and sustained release was achieved for over 15 days when embedded in hydrogels. Pilot studies of dermal fibroblast encapsulation in SNP-reinforced silk hydrogels demonstrated cytocompatibility. Tunable silk hydrogels reinforced with SNPs provide application-specific scaffolding for a variety of biomaterial and tissue engineering applications.
    Keywords:  FRESH 3D printing; hydrogels; self‐reinforcing; silk fibroin; silk nanoparticles
    DOI:  https://doi.org/10.1002/jbm.a.37945
  31. Nat Commun. 2025 Jun 06. 16(1): 5269
    Deterministic control of nanomagnetic spiral trajectories using an electric field.
    Samuel H Moody, Matthew T Littlehales, Daniel A Mayoh, Geetha Balakrishnan, Diego Alba Venero, Peter D Hatton, Jonathan S White.
      The intertwined nature of magnetic and electric degrees of freedom in magnetoelectric (ME) materials is well described by ME-coupling theory. When an external electric field is applied to a ME material, the ME coupling induces unique and intriguing magnetic responses. Such responses underpin the utilisation of ME materials across diverse applications, ranging from electromagnetic sensing to low-energy digital memory technologies. Here, we use small angle neutron scattering and discover a novel magnetic response within an archetypal chiral ME material, Cu2OSeO3. We find that the propagation direction of an incommensurate magnetic spiral is deterministically actuated and deflected along controllable trajectories. Furthermore, we predict the emergence of distinct non-linear regimes of spiral-deflection behaviour with external electric and magnetic fields, unlocking innovative devices that leverage controlled and customisable variations in macroscopic polarisation and magnetisation.
    DOI:  https://doi.org/10.1038/s41467-025-60288-1
  32. Mater Today Bio. 2025 Jun;32 101824
    Bioprinting of hepatic tissue model using photocrosslinkable dECM-containing composite hydrogel.
    Nima Tabatabaei Rezaei, Hitendra Kumar, Hongqun Liu, Ashna Rajeev, Giovanniantonio Natale, Samuel S Lee, Simon S Park, Keekyoung Kim.
      The liver, as one of the vital organs in the body, plays a crucial role in various bodily functions. Numerous factors can cause liver damage, that the sole remedy for severe liver conditions is transplantation of healthy liver tissue. In response to the transplantation challenges, innovative approaches involving hydrogel-based technologies have emerged, leading to the creation of highly functionalized tissues. The development of three-dimensional printing and patterning of cell-laden biomaterial matrices offers promising advances for creating tissue-specific structures in tissue engineering and bioprinting. However, the matrix materials currently used in bioprinting liver microtissue often fail to capture the complexity of the natural extracellular matrix (ECM), hindering their ability to restore innate cellular shapes and functions. Liver ECM-based hydrogels are increasingly recognized for their potential as biomimetic three-dimensional (3D) cell culture systems that facilitate the exploration of liver disease, metabolism, and toxicity mechanisms. Yet, the conventional production of these hydrogels relies on slow thermal gelation processes, which restrict the manipulation of their mechanical characteristics. In this research, we introduce a novel approach with a functionalized photocrosslinkable liver decellularized extracellular matrix (dECM). By combining liver dECM methacrylate (LdMA) with gelatin methacrylate (GelMA), we achieved accelerated crosslinking under visible light irradiation and the ability to tune the mechanical, rheological, and physiological properties of the material. We encapsulated human hepatocellular carcinoma cells within an optimal concentration of the GelMA-LdMA hybrid hydrogel and examined cell proliferation and function over an extended period. The results demonstrated that the GelMA-LdMA hybrid hydrogel effectively sustains cell viability over an extended period while promoting enhanced liver cell proliferation, suggesting its potential for drug screening applications and liver cancer metastasis research. Notably, albumin secretion in the dECM-based hydrogel was approximately 40 % higher compared to the control GelMA sample. Furthermore, when evaluating acetaminophen-induced hepatotoxicity, the hybrid hydrogel showed a promising drug response, with significant upregulation of the drug metabolism-related gene cytochrome P450-1A2 (CYP1A2). Overall, the dECM-based hepatic tissue model demonstrated excellent biofunctionality and responsiveness to drug treatment, making it a promising candidate for in vitro toxicological studies.
    Keywords:  Bioprinting; Drug screening; Liver decellularized extracellular matrix; Liver functionality; Visible light photo crosslinking
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101824
  33. Nanoscale. 2025 Jun 09.
    Engineering tough, energy-dissipating soft materials via sacrificial chemical bonds.
    Parbhat Kumar, Abhishek Roy, Benjamin E Partridge.
      Impact-resistant materials such as Kevlar provide impact protection but lack flexibility and processability due to their highly crystalline, rigid structures. In contrast, the natural world is replete with examples of soft materials that can resist applied load. For example, sea cucumbers and other echinoderms modulate the stiffness of their outer skin in response to predators. This dynamic change in mechanical properties is regulated by transient, non-covalent interactions between the collagenic protein fibers that comprise the dermis. Upon the application of force, these transient interactions break, thereby acting as sacrificial bonds and providing a means of energy dissipation without damaging the protein fibers. This mechanism has been mimicked in synthetic materials, typically based on covalent polymers augmented with non-covalent bonding motifs. In this review, we survey the current state-of-the-art in the field of energy-dissipating soft materials. Specifically, we present recent (post-2017) highlights from the primary literature, organized by the chemical nature of the weak sacrificial bonds to outline the chemical toolkit available for programming material properties. We conclude by highlighting some opportunities to advance the development of soft yet tough energy-dissipating materials that harness the sacrificial bond.
    DOI:  https://doi.org/10.1039/d5nr00018a
  34. Mol Syst Biol. 2025 Jun 09.
    A discovery platform for identification of host-induced bacterial biosensors from diverse sources.
    Clare M Robinson, David Carreño, Tim Weber, Yangyumeng Chen, David T Riglar.
      Synthetic biology approaches such as whole-cell biosensing and 'sense-and-respond' therapeutics aim to enlist the vast sensing repertoire of gut microbes to drive cutting-edge clinical and research applications. However, well-characterised circuit components that sense health- and disease-relevant conditions within the gut remain limited. Here, we extend the flexibility and power of a biosensor screening platform using bacterial memory circuits. We construct libraries of sensory components sourced from diverse gut bacteria using a bespoke two-component system identification and cloning pipeline. Tagging unique strains using a hypervariable DNA barcode enables parallel tracking of thousands of unique clones, corresponding to ~150 putative biosensors, in a single experiment. Evaluating sensor activity and performance heterogeneity across various in vitro and in vivo conditions using mouse models, we identify several biosensors of interest. Validated hits include biosensors with relevance for autonomous control of synthetic functions within the mammalian gut and for non-invasive monitoring of inflammatory disease using faecal sampling. This approach will promote rapid biosensor engineering to advance the development of synthetic biology tools for deployment within complex environments.
    Keywords:  Bacterial Biosensor; Gut Microbiome; Inflammation; Synthetic Biology
    DOI:  https://doi.org/10.1038/s44320-025-00123-3
  35. Curr Opin Microbiol. 2025 Jun 07. pii: S1369-5274(25)00038-4. [Epub ahead of print]86 102616
    Cell cycle regulation in Escherichia coli: from governing principles, checkpoints, and control variables to molecular mechanisms.
    Alix Meunier, Sander K Govers.
      All cells share the basic challenge of integrating the various processes that ensure their faithful replication. In most bacteria, this occurs without the dedicated regulatory machinery and additional layers of internal organization seen in eukaryotic cells. Despite this apparent reduction in complexity, bacterial replication is remarkably faithful and can be exceptionally fast. While spatiotemporal regulation of cell cycle processes is crucial for such efficient and reliable proliferation, many aspects of this currently remain elusive in bacteria. In this review, we focus on the cell cycle regulation of Escherichia coli, one of the best-studied bacterial models. We highlight how large-scale quantitative phenomenological studies have leveraged cellular variability to identify governing principles of cell cycle control in recent years. We discuss how these principles constrain the ongoing search for molecular mechanisms, examine the limitations of various approaches, and compare contradicting models and proposed molecular mechanisms.
    DOI:  https://doi.org/10.1016/j.mib.2025.102616
  36. Small. 2025 Jun 11. e2503438
    Additive Manufacturing of Energy Materials Using Self-Assembled Graphene Oxide and Printable Resin.
    Han Wei Lee, Artemii Ivanov, Sergey Grebenchuk, Mo Lin, Siyu Chen, Qian Wang, Benjamin Rui Peng Yip, Guillermo C Bazan, Maxim Trubyanov, Kostya S Novoselov, Daria V Andreeva.
      A strategy is reported for fabricating 3D-printed electrodes using self-assembled graphene oxide (GO) core-shell microspheres as tunable microreactors. This approach enables control over microsphere size and shell thickness via pH adjustment and sonication parameters, yielding either individual conductive particles or interconnected networks suitable for Direct Ink Writing. Following pyrolysis, the resulting hierarchically porous, rigid constructs exhibit surface area of 1000 m2 g-1 and compressive strengths up to 9.5 MPa - outperforming most 3D-printed carbon supercapacitor structures in mechanical robustness. Electrochemically, the optimized architecture delivers 125 F g-1, 1.4 F and 4.7 F cm-3 in 1 m H2SO4, and maintains >95% of its capacity after 30 000 cycles while preserving structural integrity. This method combines bottom-up GO self-assembly with top-down additive manufacturing to produce mechanically resilient, high-performance supercapacitor electrodes - bridging nanoscale material design with macroscale energy storage systems engineering.
    Keywords:  additive manufacturing; energy storage; graphene oxide; microspheres
    DOI:  https://doi.org/10.1002/smll.202503438
  37. ACS Appl Mater Interfaces. 2025 Jun 10.
    Direct Laser Writing of Selectively Degradable Polypeptide Hydrogel Microstructures by Proteolytic Enzymes.
    Yekaterina Tskhe, Viviane Chiaradia, Brian J Rodriguez, Larisa Florea, Colm Delaney, Robert D Murphy.
      The discovery of materials with on-demand, tunable degradability is of significant utility for (micro)structures generated through additive manufacturing techniques. Disclosed here are a series of star polypeptide cross-linkers comprising either l-lysine alone or l-lysine and l-alanine residues for use in direct laser writing of hydrogel microstructures, which are selectively degradable via intrinsic amino acid affinities to different proteolytic enzymes. Through multimaterial printing, direct laser writing permitted the formation of microstructural topographies through free radical polymerization of formulated polypeptide cross-linkers and commercial photoresists, whereby sections of the microstructures could undergo selective degradation in the presence of target proteases, thermolysin, and trypsin.
    Keywords:  direct laser writing; enzyme degradation; hydrogels; polypeptides; two-photon polymerization
    DOI:  https://doi.org/10.1021/acsami.5c02960
  38. Nat Biotechnol. 2025 Jun 11.
    Limitations of cell embedding metrics assessed using drifting islands.
    Hanchen Wang, Jure Leskovec, Aviv Regev.
      Biological studies rely on embeddings of single-cell profiles but assessing the quality of these embeddings is challenging. Here we show that current evaluation metrics are incomplete by training a three-layer perceptron, Islander. Islander outperforms all leading embedding methods on a diverse set of cell atlases but it distorts biological structures, limiting its use for biological discovery. We then present a new metric, scGraph, to help flag such distortions.
    DOI:  https://doi.org/10.1038/s41587-025-02702-z
  39. Mater Horiz. 2025 Jun 13.
    Materials Horizons Emerging Investigator Series: Dr Jung-Yao Chen, National Cheng Kung University.
      Our Emerging Investigator Series features exceptional work by early-career researchers working in the field of materials science.
    DOI:  https://doi.org/10.1039/d5mh90064f
  40. ACS Omega. 2025 Jun 03. 10(21): 21128-21146
    Living Kombucha Electronics with Proteinoids.
    Anna Nikolaidou, Panagiotis Mougkogiannis, Andrew Adamatzky.
      The work introduces a composite material that combines Kombucha cellulose mats with synthetic thermal proteinoids to create electroactive biofilms, capable of sensing and computation. The synthesis of proteinoids involves heating amino acid mixtures, which leads to the formation of proto-cell structures capable of biological electrical signaling. We demonstrate that these hybrid biofilms exhibit adjustable memristive and memfractance properties, which can be utilized for unconventional computing tasks. The potential applications of living biofilms extend beyond neural interfaces, encompassing bioinspired robotics, smart wearables, adaptive biorobotic systems, and other technologies that rely on dynamic bioelectronic materials. The composite films offer a wide range of options for synthesis and performance customization. Current research is dedicated to customizing the composition, nanostructure, and integration of proteinoids in hybrid circuits to achieve specific electronic functionalities. Overall, these cross-kingdom biofilms are an intriguing category of materials that combine the unique properties of biological organisms and smart polymers. The Kombucha-proteinoid composites are a significant step forward in the development of future technologies that bridge the gap between living and artificial life systems. These composites have the remarkable ability to support cellular systems and demonstrate adaptive bioelectronic behavior.
    DOI:  https://doi.org/10.1021/acsomega.4c09743
  41. bioRxiv. 2025 May 30. pii: 2025.05.27.656122. [Epub ahead of print]
    Principles and functional consequences of plasmid chromatinization in mammalian cells.
    Benjamin J Mallory, Thomas W Tullius, Carina G Biar, Jonas A Gustafson, Stephanie C Bohaczuk, Danilo Dubocanin, Lea M Starita, Andrew B Stergachis.
      Plasmids have fundamentally transformed how we resolve regulatory grammar across the tree of life. However, although chromatin plays an integral role in regulating the function of regulatory elements along the nuclear genome, our understanding of how, or whether, similar chromatin structures form on plasmids transfected into mammalian cells remains limited. We demonstrate that plasmid single-molecule chromatin fiber sequencing (plasmid Fiber-seq) can accurately map chromatin architectures along individual, full-length transfected plasmid molecules at near single-nucleotide resolution. Application of plasmid Fiber-seq to diverse plasmids and cell lines demonstrates that plasmids are chromatinized in a sequence-dependent organized manner and adopt a heterogeneous and incomplete chromatin architecture relative to nuclear-encoded chromatin fibers. We show that the focal occupancy of nucleosomes and transcription factors along transfected plasmids is central to their transcriptional activity within mammalian cells, and demonstrate that plasmids indeed are capable of recapitulating nuclear genome-encoded chromatin architectures, although not always. Finally, we demonstrate that combining plasmid Fiber-seq with high-throughput reporter assays can establish the molecular mechanisms underlying pathogenic non-coding variants, including disentangling the effects of transcriptional activators and repressors with near-single-nucleotide resolution. Overall, our findings reveal the principles by which plasmid-based assays can be used for accurate fine-scale mapping of chromatin-dependent regulatory grammar.
    DOI:  https://doi.org/10.1101/2025.05.27.656122
  42. Nanoscale. 2025 Jun 11.
    Passive nanorheological tool to characterise hydrogels.
    Moira Lorenzo Lopez, Victoria R Kearns, Eann A Patterson, Judith M Curran.
      Hydrogels are highly versatile, multi-phase materials with a wide variety of applications, due to their complex structures and tuneable features at the micron and sub-micron scale. Physical and chemical properties within the local environments contribute to the overall properties of a hydrogel. Current quantitative techniques used to characterise the properties of a hydrogel usually focus on bulk properties and are limited to identifying macroscopic properties, providing little information about local variations and heterogeneity, or fail to provide insight into real-time dynamic responses to external stimuli. These issues are especially challenging when characterising soft hydrogels due to their high-water content, which induces weak signals and noisy data. Here, we present a passive nanorheological tool that indirectly enables the characterisation of soft hydrogels at the micro/nanoscale by tracking nanoprobes with a label-free optical microscopy technique, making this an inexpensive, time-efficient, and user-friendly tool. This tool allows effective mapping of the properties in local micro/nano environments in heterogeneous soft materials thus permitting the identification of real-time sol-gel phase transition in thermosensitive hydrogels. Hence, this novel nanorheological characterisation tool has great potential for use in soft material design, manufacturing and quality control processes.
    DOI:  https://doi.org/10.1039/d5nr00875a
  43. Nat Protoc. 2025 Jun 10.
    The design, manufacture and LNP formulation of mRNA for research use.
    Laura J Leighton, Natasha Chaudhary, Hannah T Tompkins, Abhishek Kulkarni, Nissa L Carrodus, Magdalena A Budzinska, Sneha Lakshman Das, Seth W Cheetham, Tim R Mercer.
      The delivery of mRNA provides a versatile platform to achieve rapid and robust protein expression within cells. mRNA delivery has therefore been widely adopted in research, and mRNA medicines are now being developed to treat a range of diseases. However, high-quality mRNA must be produced to ensure the safety, performance and effectiveness of these medicines. Here, we provide a validated, end-to-end protocol describing the production of mRNA for research and preclinical use. This protocol includes primary sequence design, DNA template production, mRNA synthesis by in vitro transcription, formulation into lipid nanoparticles and transfection into cultured cells. Each step is supported by a range of quality control tests to analyze mRNA integrity and purity and is illustrated with example results to provide information about expected performance. The protocol prioritizes simple production steps that are suitable for small-scale mRNA manufacture, such as PCR preparation of the DNA template, and that can be performed within a laboratory and avoid specialized equipment. The protocol produces high-quality mRNA that can be used for in vitro and in vivo preclinical studies, including for vaccine, protein and gene- and cell-therapy applications. Together, this provides a fast and reliable protocol to produce high-quality mRNA suitable for laboratory research and preclinical development.
    DOI:  https://doi.org/10.1038/s41596-025-01174-4
  44. Nat Mater. 2025 Jun 12.
    Hybrid hydrogel-extracellular matrix scaffolds identify biochemical and mechanical signatures of cardiac ageing.
    Avery Rui Sun, Md Faris H Ramli, Xingyu Shen, Karthikbabu Kannivadi Ramakanth, Dixiao Chen, Yang Hu, Prasanna Vidyasekar, Roger S Foo, Yuchen Long, Jin Zhu, Matthew Ackers-Johnson, Jennifer L Young.
      Extracellular matrix remodelling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Such remodelling is multifaceted including changes to the biochemical composition, architecture and mechanics, clouding our understanding of how and which extracellular matrix properties contribute to a dysfunctional state. Here we describe a decellularized extracellular matrix-synthetic hydrogel hybrid scaffold that independently confers two distinct matrix properties-ligand presentation and stiffness-to cultured cells in vitro, allowing for the identification of their specific roles in cardiac ageing. The hybrid scaffold maintains native matrix composition and organization of young or aged murine cardiac tissue, whereas its mechanical properties can be independently tuned to mimic young or aged tissue stiffness. Seeding these scaffolds with murine primary cardiac fibroblasts, we identify distinct age- and matrix-dependent mechanisms of cardiac fibroblast activation, matrix remodelling and senescence. Importantly, we show that the ligand presentation of a young extracellular matrix can outweigh the profibrotic stiffness cues typically present in an aged extracellular matrix in maintaining or driving cardiac fibroblast quiescence. Ultimately, these tunable scaffolds can enable the discovery of specific extracellular targets to prevent ageing dysfunction and promote rejuvenation.
    DOI:  https://doi.org/10.1038/s41563-025-02234-6
  45. Adv Mater. 2025 Jun 11. e2505132
    From Physical Cross-Linking to Tailored Phosphorylation: Unlocking High-Performance and Biocompatible Xanthan-Konjac Hydrogels for Zinc-Ion Batteries.
    Lei Gou, Lin Zhu, Wei Wang, Zheqi Yang, Si-Yao Wang, Dong-Lin Li, Xiao-Bing Bao, Qiao-Mei Luo, Hui Li, Zi-Zhuo Zhang, Xiao-Yong Fan.
      Natural polymer-based hydrogel electrolytes, though biocompatible and cost-effective, often exhibit poor mechanical strength and ionic conductivity, limiting their use in high-performance energy storage. Phos-XK, a novel hydrogel electrolyte derived from xanthan gum (XG) and konjac glucomannan (KGM), has been developed via physical cross-linking and targeted phosphorylation. Specifically, physical cross-linking forms a robust 3D network that provides a stable structural foundation. Building on this, the phosphorylation process introduces phosphate monoesters (MPE) and diesters (DPE) in a precisely controlled ratio. MPE groups enhance ionic conductivity by facilitating Zn2+ desolvation and ion migration, while DPE strengthens mechanical integrity through enhanced cross-linking. These distinct roles of MPE and DPE are confirmed through both theoretical calculations and experimental results. Optimizing the phosphorylation ratio achieves a balance between mechanical strength (2.524 MPa) and ionic conductivity (20.72 mS cm-1), resulting in remarkable electrochemical performance, including an extended cycle life exceeding 3000 h and a high Coulombic efficiency of 99.45% in Zn//Cu batteries. Moreover, Phos-XK is biocompatible and biodegradable, ideal for sustainable energy storage. This work highlights the potential of bio-based materials to overcome the limitations of traditional hydrogel electrolytes and stresses the importance of molecular engineering in achieving high-performance, eco-friendly energy storage.
    Keywords:  aqueous zinc‐ion batteries; biodegradability; hydrogel electrolytes; ionic conductivity; mechanical strength
    DOI:  https://doi.org/10.1002/adma.202505132
  46. Adv Mater. 2025 Jun 11. e2501081
    Smart Materials and Devices for Enhanced Delivery of Extracellular Vesicles.
    Yang You, Mengrui Liu, Na Yan, Dashuai Zhu, Xiao Cheng, Yilan Hu, Yuan Li, Zhen Qin, Zhixin Zhu, Ke Cheng.
      Extracellular vesicles (EVs) are vesicle-like structures secreted by various cell types, playing a crucial role in cell communication. As an efficient and safe therapeutic carrier, EVs offer new insights and methods for disease treatment and drug development due to high stability, low immunogenicity, and broad resources. However, current applications on EV-based delivery systems are still challenging, and additional strategies are needed to achieve precise and targeted delivery, enhance stability and safety, and avoid unnecessary immune reactions or side effects. This review summarizes the latest progress in using smart materials or devices to enhance EV delivery, aiming to provide a reference for designing novel and efficient EV-based targeted delivery strategies.
    Keywords:  exosomes; extracellular vesicles; smart materials; targeted delivery; therapeutics
    DOI:  https://doi.org/10.1002/adma.202501081
  47. mSystems. 2025 Jun 13. e0032325
    Trade-off between resistance and persistence in high cell density cultures.
    F Beulig, J Bafna-Rührer, P E Jensen, S H Kim, A Patel, V Kandasamy, C Steffen, K Decker, D Zielinski, L Yang, E Özdemir, S Sudarsan, B Palsson.
      Bacterial growth to high cell densities is commonly observed in infections, microbiomes, and biomanufacturing, yet there is limited understanding of how transcriptional regulation changes to balance between growth and survival under associated stresses. Here, we utilized well-controlled culturing systems to grow wild-type and metabolically engineered Escherichia coli strains into high cell densities (50-80 gcell dry weight L-1) and determine the associated transcriptional dynamics. Knowledge-enriched, machine-learning-based data analytics reveal distinct stress-related gene expression patterns that are consistent with a fundamental trade-off between resistance and persistence. We suggest that this trade-off explains observed growth arrests in high-density cultures and that it results from the disruption of cellular homeostasis, due to re-allocation of limited cellular resources from resistance functions toward increased maintenance requirements. This study deepens our understanding of high-density physiology, illustrates a common link between biomanufacturing and infection, and suggests that persistence phenotypes are programmed as hidden transcriptional states in E. coli.IMPORTANCEThis study presents the first systems-level characterization of Escherichia coli high-cell-density physiology, using an integrated experimental and computational approach. Knowledge-enriched, machine-learning-based analysis of the >470 transcriptomic samples reveals distinct stress-related gene expression patterns that allow the first functional and quantitative description of associated stimulons. The identified stimulons reveal a hitherto undiscovered trade-off between resistance- and persistence-like functions. Our findings have fundamental implications for genome editing of strains optimized for resilience toward stresses of cell-dense environments, particularly those encountered in biomanufacturing.
    Keywords:  Escherichia coli; high cell density physiology; persistence; resistance; stimulons
    DOI:  https://doi.org/10.1128/msystems.00323-25
  48. Nat Commun. 2025 Jun 12. 16(1): 5308
    Author Correction: Boosting hydrogel conductivity via water-dispersible conducting polymers for injectable bioelectronics.
    Hossein Montazerian, Elham Davoodi, Canran Wang, Farnaz Lorestani, Jiahong Li, Reihaneh Haghniaz, Rohan R Sampath, Neda Mohaghegh, Safoora Khosravi, Fatemeh Zehtabi, Yichao Zhao, Negar Hosseinzadeh, Tianhan Liu, Tzung K Hsiai, Alireza Hassani Najafabadi, Robert Langer, Daniel G Anderson, Paul S Weiss, Ali Khademhosseini, Wei Gao.
      
    DOI:  https://doi.org/10.1038/s41467-025-60718-0
  49. Mater Today Bio. 2025 Jun;32 101859
    Light-activated decellularized extracellular matrix-based bioinks for enhanced mechanical integrity.
    Minji Kim, Dayoon Kang, Hohyeon Han, Jinah Jang.
      Decellularized extracellular matrix (dECM)-based bioinks have emerged as key materials in tissue engineering and 3D bioprinting technologies due to their ability to closely mimic the biochemical composition and structural organization of native extracellular matrices. These bioinks facilitate critical cellular behaviors, such as adhesion, proliferation, and lineage-specific differentiation, which makes them invaluable for constructing tissue analogs for applications in regenerative medicine, organ transplantation, and disease modeling. Despite their transformative promise, dECM bioinks face persistent challenges, including limited mechanical robustness, delayed gelation kinetics, and suboptimal printability, all of which constrain their translational utility. The advent of photocrosslinking technologies marks a paradigm shift, with light-activated functional groups such as methacrylates, thiol-enes, and phenols substantially improving the gelation efficiency, mechanical properties, and spatial fidelity of the printed constructs. The present review critically examines the state-of-the-art advancements in light-mediated dECM-based bioink crosslinking strategies, with a focus on innovations in bioink and photoinitiator design along with optimized crosslinking kinetics to address inherent limitations such as cytotoxicity and structural variability. Further, the review highlights the necessity of standardized dECM processing protocols and scalable biofabrication techniques to ensure reproducibility and clinical translation. By overcoming these challenges, dECM-based bioinks can enable the production of high-resolution, volumetric tissue constructs, thereby paving the way for transformative advances in regenerative medicine and translational biomedical applications.
    Keywords:  3D bioprinting technology; Bioinks; Decellularized extracellular matrix (dECM); Photocrosslinking; Tissue engineering
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101859
  50. Nature. 2025 Jun 11.
    Discovery of FoTO1 and Taxol genes enables biosynthesis of baccatin III.
    Conor James McClune, Jack Chun-Ting Liu, Chloe Wick, Ricardo De La Peña, Bernd Markus Lange, Polly M Fordyce, Elizabeth S Sattely.
      Plants make complex and potent therapeutic molecules1,2, but sourcing these molecules from natural producers or through chemical synthesis is difficult, which limits their use in the clinic. A prominent example is the anti-cancer therapeutic paclitaxel (sold under the brand name Taxol), which is derived from yew trees (Taxus species)3. Identifying the full paclitaxel biosynthetic pathway would enable heterologous production of the drug, but this has yet to be achieved despite half a century of research4. Within Taxus' large, enzyme-rich genome5, we suspected that the paclitaxel pathway would be difficult to resolve using conventional RNA-sequencing and co-expression analyses. Here, to improve the resolution of transcriptional analysis for pathway identification, we developed a strategy we term multiplexed perturbation × single nuclei (mpXsn) to transcriptionally profile cell states spanning tissues, cell types, developmental stages and elicitation conditions. Our data show that paclitaxel biosynthetic genes segregate into distinct expression modules that suggest consecutive subpathways. These modules resolved seven new genes, allowing a de novo 17-gene biosynthesis and isolation of baccatin III, the industrial precursor to Taxol, in Nicotiana benthamiana leaves, at levels comparable with the natural abundance in Taxus needles. Notably, we found that a nuclear transport factor 2 (NTF2)-like protein, FoTO1, is crucial for promoting the formation of the desired product during the first oxidation, resolving a long-standing bottleneck in paclitaxel pathway reconstitution. Together with a new β-phenylalanine-CoA ligase, the eight genes discovered here enable the de novo biosynthesis of 3'-N-debenzoyl-2'-deoxypaclitaxel. More broadly, we establish a generalizable approach to efficiently scale the power of co-expression analysis to match the complexity of large, uncharacterized genomes, facilitating the discovery of high-value gene sets.
    DOI:  https://doi.org/10.1038/s41586-025-09090-z
  51. Biomater Sci. 2025 Jun 11.
    Bioactive DNA hydrogel interfacing with living cells and extracellular vesicles.
    Rui Zhang, Mingxing Liu, Hongjin Li, Yan Huang, Coo Yee Nah, Chi Yao, Dayong Yang.
      Biological vesicles, such as living cells and extracellular vesicles (EVs) in biological systems, are important agents and regulators of life functions and play an irreplaceable role in physiological processes and disease progression. The maintenance of high bioactivity and structural integrity as well as selective isolation of target biological vesicles from complex biological systems are of great significance for downstream applications, such as early diagnosis, treatment and prognostic monitoring of major diseases. Bioactive hydrogel is a material made of hydrogel containing bioactive molecules that simulate living systems in vitro. By exploiting the unique molecular recognition and sequence programmability of deoxyribonucleic acid (DNA), DNA containing multifunctional modules serves as the material chemistry basis. Through molecular design and functional unit incorporation, these strategies enable the construction of DNA hydrogels capable of targeted vesicle recognition. This review discusses interactions between DNA hydrogels and biological vesicles, focuses on controllable release mechanisms of vesicles, and highlights recent advances in biomedical applications boosted by bioactive DNA hydrogels, including cell and EV isolation, cell engineering and three-dimensional (3D) culture, disease detection, and disease treatments. First, the interaction and controllable release mechanisms of bioactive DNA hydrogels are summarized, and relevant research based on these mechanisms is reviewed. Second, pioneering work in biomaterial applications is summarized. Finally, it is concluded with the challenges faced by DNA hydrogels and the future prospects of bioactive DNA hydrogels.
    DOI:  https://doi.org/10.1039/d5bm00690b
  52. Mol Syst Biol. 2025 Jun 11.
    Orthogonal replication with optogenetic selection evolves yeast JEN1 into a mevalonate transporter.
    Scott A Wegner, Virginia Jiang, Jeremy D Cortez, José L Avalos.
      The in vivo continuous evolution system OrthoRep (orthogonal replication) is a powerful strategy for rapid enzyme evolution in Saccharomyces cerevisiae that diversifies genes at a rate exceeding the endogenous genome mutagenesis rate by several orders of magnitude. However, it is difficult to neofunctionalize genes using OrthoRep partly because of the way selection pressures are applied. Here we combine OrthoRep with optogenetics in a selection strategy we call OptoRep, which allows fine-tuning of selection pressure with light. With this capability, we evolved a truncated form of the endogenous monocarboxylate transporter JEN1 (JEN1t) into a de novo mevalonate importer. We demonstrate the functionality of the evolved JEN1t (JEN1tY180C/G) in the production of farnesene, a renewable aviation biofuel, from mevalonate fed to fermentation media or produced by microbial consortia. This study shows that the light-induced complementation of OptoRep may improve the ability to evolve functions not currently accessible for selection, while its fine tunability of selection pressure may allow the continuous evolution of genes whose desired function has a restrictive range between providing effective selection and cellular viability.
    Keywords:   JEN1 ; Continuous Evolution; Mevalonate Transporter Evolution; Optogenetics; OrthoRep
    DOI:  https://doi.org/10.1038/s44320-025-00113-5
  53. bioRxiv. 2025 Jun 07. pii: 2025.06.04.657858. [Epub ahead of print]
    VesicleVoyager: In vivo selection of surface displayed proteins that direct extracellular vesicles to tissue-specific targets.
    Yuki Kawai-Harada, Mehrsa Mardikoraem, Ashley V Makela, Katherine Lauro, Jeannie Lam, Christopher H Contag, Daniel Woldring, Masako Harada.
      The development of technologies for screening proteins that bind to specific tissues in vivo and facilitate delivery of large cargos remains challenging, with most approaches limited to cell culture systems that often yield clinically irrelevant hits. To overcome this limitation, we developed a novel molecular screening platform using an extracellular vesicle (EV) display library. EVs are natural molecular carriers capable of delivering diverse cargos, which can be engineered to enhance specificity and targeting through surface modifications. We constructed an EV-display library presenting monobody repertoires on EV surfaces, with genetic cargo inside the EVs corresponding to the displayed proteins. These libraries were screened for tissue specific delivery through serial passage in mice via sequential intravenous administration in and recovery of tissue-selected EVs and amplification of their encapsulated monobody genes at each passage. Our results demonstrated successful selection of tissue-specific targeting proteins, as revealed by fluorescence and bioluminescence imaging followed by DNA sequencing. To understand the stochastic relationship between displayed proteins and packaged genes, we developed a Markov chain model that quantified selection dynamics and predicted enrichment patterns despite the imperfect correlation between phenotype and genotype. This EV-based monobody screening approach, combined with mathematical modeling, is a significant advancement in targeted drug delivery by leveraging the natural capabilities of EVs with the selection of targeting proteins in a physiologically relevant environment.
    DOI:  https://doi.org/10.1101/2025.06.04.657858
  54. bioRxiv. 2025 Jun 06. pii: 2025.06.02.657447. [Epub ahead of print]
    Tissue-like compression stiffening in biopolymer networks induced by aggregated and irregularly shaped inclusions.
    Xuechen Shi, Jordan L Shivers, Fred C MacKintosh, Paul A Janmey.
      Biological tissues experience mechanical compression under various physiological and pathological conditions and often exhibit compression stiffening, in which their stiffness increases during compression, a phenomenon that plays a crucial role in regulating cell behavior and maintaining mechanical homeostasis. However, most isolated biopolymer networks, such as fibrin and collagen hydrogels that form the extracellular matrix and actin network that forms the internal cytoskeleton, undergo compression softening, raising questions about how tissues achieve compression stiffening despite the softening properties of their extracellular and intracellular matrix components. Previous studies have shown that spherical inclusions at large volume fractions can induce compression stiffening in biopolymer networks, but they do not account for the effects of aggregation and irregular morphologies of cellular assemblies or other components in tissues. Here, we demonstrate a novel mode of compression stiffening induced by aggregated or irregularly shaped inclusions that occurs at significantly lower volume fractions. Using carbonyl iron particles and coffee ground particles, we find that the morphological diversity of inclusions enables tissue-like compression stiffening at a low volume fraction of inclusions. Through a set of experiments and computational analyses, we demonstrate that these particles can percolate at low volume fractions. We further show that the percolation of stiff inclusions creates a stress-supporting network and enables tension-dominated stress propagation in fibrin fibers, both of which drive macroscopic stiffening during compression. These findings provide insights into the regulation of tissue stiffness and have implications for designing biomaterials with physiologically relevant mechanical properties for biomedical applications.
    Significance Statement: Biological tissues experience a variety of mechanical forces. Many tissues, such as brain, liver, fat, and blood clots, become stiffer under physiological compressive loads, a property known as compression stiffening. In contrast, most biopolymer networks, which are the primary structural components for tissues, soften under compression. Here, we show that incorporating a small amount of aggregated or irregularly shaped particles into biopolymer gels induces robust compression stiffening. These inclusions percolate through the gel and rearrange non-affinely under compression, stretching surrounding fibers and contributing to mechanical reinforcement. Together, these effects reproduce tissue-like compression stiffening. Our findings not only provide new physical models for understanding tissue mechanics but also offer insights for designing biomaterials to achieve physiologically relevant mechanical responses.
    DOI:  https://doi.org/10.1101/2025.06.02.657447
  55. bioRxiv. 2025 May 26. pii: 2025.05.20.655137. [Epub ahead of print]
    Modulating Hydrogel Stiffness Through Light-Based 3D Printing to Mimic Cardiac Fibrosis and Cardiomyocyte Dysfunction Using hiPSC-Derived Cells.
    Sogu Sohn, Nima Momtahan, Lynn M Stevens, Jiwan Han, Yutong Liu, Meghan T Kiker, Elizabeth A Recker, Zachariah A Page, Janet Zoldan.
      The human heart's limited regenerative capacity is a significant barrier to addressing cardiovascular disease (CVD). This is particularly true for cardiac fibrosis, a form of CVD wherein the wound healing process has gone awry. In cardiac fibrosis, excessive scar tissue formation due to dysregulated remodeling of the heart's extracellular matrix (ECM) results in increased stiffness that reduces cardiac output and can lead to heart failure. This dysregulated ECM deposition is driven by activated cardiac fibroblasts, where cell substrate stiffness is known to play a role in cardiac fibroblast activation. New preclinical models that accurately recapitulate the behavior of activated cardiac fibroblasts are needed to better understand and treat cardiac fibrosis. To this end, we describe a model wherein human induced pluripotent stem cell (hiPSC)-derived cardiac fibroblasts (HCFs) are cultured on 3D printed hydrogels of tunable stiffness, fabricated using dosage controlled digital light processing (DLP). We demonstrate that our model can induce HCF activation in the absence of TGFβ, a key mediator of fibroblast activation, surpassing the activation levels seen with HCFs activated with TGFβ on protein-coated tissue culture plates. Furthermore, combining stiffer hydrogels with TGFβ recapitulates fibroblast activation similar to what is observed in native cardiac tissue. Lastly, by indirectly coculturing HCFs seeded and activated on these stiff hydrogels with hiPSC-derived cardiomyocytes, we demonstrate that the activated HCFs in our cardiac fibrosis model can impair cardiomyocyte function, mimicking the deleterious effects of cardiac fibrosis.
    DOI:  https://doi.org/10.1101/2025.05.20.655137
  56. bioRxiv. 2025 Jun 01. pii: 2025.05.27.656504. [Epub ahead of print]
    Engineering Sustained-Release Broadly Neutralizing Antibody Formulations.
    Carolyn K Jons, Catherine M Kasse, Bryan T Mayer, Ollivier Hyrien, Samya Sen, Emily L Meany, Andrea I d'Aquino, Priya Ganesh, Noah Eckman, Changxin Dong, Jerry Yan, Leslee T Nguyen, Vanessa M Doulames, Ye Eun Song, Olivia M Saouaf, Christian M Williams, Shoshana C Williams, Jesus Paredes, Rajeev Raghavan, Martina Palomares, Michael Alpert, Nicole L Yates, Georgia D Tomaras, Michael S Seaman, Michael Farzan, Eric A Appel.
      Sustained serum levels of broadly neutralizing antibodies (bnAbs) are crucial for effective passive immunization against infectious diseases as protection persists only while these bnAbs remain at adequate concentrations within the body. Current obstacles, such as poor pharmacokinetics (PK) and burdensome administration, must be overcome to make bnAbs a viable option for pre- and post-exposure prophylaxis. In this work, we explore how a polymer-nanoparticle (PNP) hydrogel depot technology can be engineered to prolong protein delivery. In-vivo studies in mice and rats demonstrate prolonged protein release, and modeling efforts predict the impact of both the elimination half-life of the active pharmaceutical ingredient and hydrogel depot volume on overall pharmacokinetics. Moreover, flow cytometry characterization reveals that immune cell infiltration into the hydrogel depot can result in faster-than-expected release of antibody cargo on account of active transport via cellular uptake. We then demonstrate that co-formulation of antibodies with an anti-inflammatory agent reduces cellular infiltration and resulting active transport, further extending delivery and pharmacokinetics. Finally, multicompartmental modeling predicts the human PK profiles of clinically relevant HIV bnAbs delivered via subcutaneous hydrogel injection. These findings aid in the development of next generation hydrogel materials that stabilize and slowly release bnAbs for long-term pre-exposure immunoprophylaxis.
    DOI:  https://doi.org/10.1101/2025.05.27.656504
  57. bioRxiv. 2025 May 28. pii: 2025.03.03.641308. [Epub ahead of print]
    Harnessing Microbial Tools: Escherichia coli as a Vehicle for Neuropeptide Functional Analysis in Caenorhabditis elegans.
    Elizabeth M DiLoreto, Shruti Shastry, Emily J Leptich, Douglas K Reilly, Rachel N Arey, Jagan Srinivasan.
      Animals respond to changes in their environment and internal states via neuromodulation. Neuropeptides modulate neural circuits with flexibility because one gene can produce either multiple copies of the same neuropeptide or different neuropeptides. However, with this architectural complexity, the function of discrete and active neuropeptides is muddled. Here, we design a genetic tool that facilitates functional analysis of individual peptides. We engineered Escherichia coli bacteria to express active peptides, fed loss-of-function Caenorhabditis elegans , and rescued the activity of genes with varying lengths and functions: pdf-1, flp-3, ins-6 , and ins-22 . Some peptides were functionally redundant, while others exhibit unique and previously uncharacterized functions. We postulate our rescue-by-feeding approach can elucidate the functional landscape of neuropeptides, identifying the circuits and complex peptidergic pathways that regulate different behavioral and physiological processes.
    Article summary: Studying individual neuropeptides opens new avenues for exploring neuromodulation at a finer resolution. The researchers developed a method to create DNA vectors that encode an endogenous peptide sequence flanked by sequences containing dibasic endopeptidase cleavage sites in Caenorhabditis elegans . The researchers transformed these vectors into bacteria and fed them to C. elegans , which restored wildtype behavior in neuropeptide loss-of-function mutants. The researchers also discovered that neuropeptides from the same gene perform distinct functions, a research area more ready to explore using the presented technology.
    DOI:  https://doi.org/10.1101/2025.03.03.641308
  58. Cell Syst. 2025 Jun 03. pii: S2405-4712(25)00100-0. [Epub ahead of print] 101267
    Uncovering the principles coordinating systems-level organelle biogenesis with cellular growth.
    Shixing Wang, Deepthi Kailash, Shankar Mukherji.
      A complete framework of eukaryotic cellular growth control must include the growth of its defining hallmarks: organelles. Organelle coordination with cellular growth is opaque without measuring multiple organelles in the same cell with adequate statistics to test theoretical frameworks. Here, we map out the correlation structure of systems-level organelle biogenesis with cellular growth using "rainbow yeast," simultaneously visualizing 6 major metabolically active organelles. Hyperspectral imaging of thousands of rainbow yeast cells revealed that systems-level organelle biogenesis is organized into collective organelle modes activated by changes in nutrient availability. Chemical biological dissection suggests that sensed growth rate and cell size specifically activate these organelle modes. Mathematical modeling and synthetic control of cytoplasmic availability suggest that the organelle mode structure allows growth homeostasis in constant environments and responsiveness to environmental change. This regulatory architecture may underlie how compartmentalization allows cell size and growth rate flexibility to satisfy otherwise incompatible environmental and developmental constraints.
    Keywords:  cellular growth; hyperspectral imaging; mathematical modeling; organelle biogenesis; systems cell biology
    DOI:  https://doi.org/10.1016/j.cels.2025.101267
  59. mSystems. 2025 Jun 10. e0020625
    Complex interplay between gene deletions and the environment uncovers cellular roles for genes of unknown function in Escherichia coli.
    Kaat Sondervorst, Kristina Nesporova, Matthew Herdman, Bart Steemans, Joëlle Rosseels, Sander K Govers.
      Phenotypic outcomes can be heavily affected by environmental factors. In this study, we exploited the previously observed nutrient dependency of cell biological phenotypic features captured by a cross-condition image-based profiling assay of Escherichia coli deletion strains to examine this in more detail. We identified several general principles, including the existence of a spectrum of deviating phenotypes across nutrient conditions (i.e., from nutrient- or feature-specific to pleiotropic phenotypic deviations), limited conservation of phenotypic deviations across nutrient conditions (i.e., limited phenotypic robustness), and a subset of nutrient-independent phenotypic deviations (indicative of consistent genetic determinants of specific phenotypic features). In a subsequent step, we used this cross-condition data set to identify five genes of unknown function (yibN, yaaY, yfaQ, ybiJ, and yijD), of which the deletion displayed either nutrient-independent phenotypic deviations or phenotypic similarities to genes of known function. These genes showed different levels of phylogenetic conservation, ranging from conserved across the tree of life (yibN) to only present in some genera of the Enterobacterales (yaaY). Analysis of the structural properties of the proteins encoded by these y-genes, identification of structural similarities to other proteins, and the examination of their subcellular localization yielded new insights into their contribution to E. coli cell morphogenesis, cell cycle progression, and cell growth. Together, our approach showcases how bacterial image-based profiling assays and data sets can serve as a gateway to reveal the function of uncharacterized proteins.
    IMPORTANCE: Despite unprecedented access to genomic information, predicting phenotypes based on genotypes remains notoriously difficult. One major confounding factor is the environment and its ability to modulate phenotypic outcomes. Another fact is that a large fraction of protein-coding genes in bacterial genomes remain uncharacterized and have no known function. In this work, we use a large-scale cross-condition image-based profiling dataset to characterize nutrient-dependent phenotypic variability of Escherichia coli deletion strains and exploit it to provide insight into the cellular role of genes of unknown function. Through our analysis, we identified five genes of unknown function that we subsequently further characterized by examining their phylogenetic conservation, predicted structural properties and similarities, and their intracellular localization. Combined, this approach highlights the potential of cross-condition image-based profiling, which extracts many cell biological phenotypic readouts across multiple conditions, to better understand nutrient-dependent phenotypic variability and uncover protein function.
    Keywords:  Escherichia coli; cell biology; cell cycle; fluorescent image analysis; phylogenetic analysis; protein structure predictions; y-genes
    DOI:  https://doi.org/10.1128/msystems.00206-25
  60. Biotechnol Adv. 2025 Jun 10. pii: S0734-9750(25)00110-7. [Epub ahead of print] 108624
    Fungal bioconversion of lignin-derived aromatics: Pathways, enzymes, and biotechnological potential.
    Jinyang Li, Changyu Pi, Jintong Zhang, Fangting Jiang, Tongtong Bao, Le Gao, Xin Wu.
      Lignin, the most abundant aromatic biopolymer on Earth, holds immense potential as a renewable feedstock for the production of high-value bioproducts. However, its structural complexity and recalcitrance pose significant challenges for efficient valorization. Fungal biodegradation offers a sustainable strategy for lignin conversion by employing extracellular oxidative enzymes and specialized metabolic pathways to transform lignin-derived aromatic compounds into central metabolites or valuable end products. Despite extensive research on fungal ligninolytic systems, a systematic integration of aromatic catabolic pathways remains fragmented. This review consolidates recent advances in fungal metabolism of key lignin-derived aromatics, including cinnamic acid, gallic acid, ferulic acid and vanillin, with a focus on their assimilation into central metabolic networks and the enzymatic machinery involved. We highlight the critical role of fungal transporter systems in mediating aromatic compound uptake and efflux. Furthermore, we discuss future research directions, emphasizing the integration of synthetic biology, computational modeling, and systems biology to engineer robust fungal chassis for lignin valorization. Addressing these knowledge gaps will advance the development of fungal-based platforms for sustainable production of renewable aromatics, thereby contributing to the circular bioeconomy and green biomanufacturing.
    Keywords:  Aromatic metabolism; Catabolic pathways; Fungal conversion; Lignin valorization; Ligninolytic enzymes
    DOI:  https://doi.org/10.1016/j.biotechadv.2025.108624
  61. Nat Commun. 2025 Jun 12. 16(1): 5305
    Giant activity-induced elasticity in entangled polymer solutions.
    Davide Breoni, Christina Kurzthaler, Benno Liebchen, Hartmut Löwen, Suvendu Mandal.
      One of the key achievements of equilibrium polymer physics is the prediction of scaling laws governing the viscoelastic properties of entangled polymer systems, validated in both natural polymers, such as DNA, and synthetic polymers, including polyethylene, which form materials like plastics. Recently, focus has shifted to active polymers systems composed of motile units driven far from equilibrium, such as California blackworms, self-propelled biopolymers, and soft robotic grippers. Despite their growing importance, we do not yet understand their viscoelastic properties and universal scaling laws. Here, we use Brownian dynamics simulations to investigate the viscoelastic properties of highly-entangled, flexible self-propelled polymers. Our results demonstrate that activity enhances the elasticity by orders of magnitude due to the emergence of grip forces at entanglement points, leading to its scaling with polymer length ∼ L. Furthermore, activity fluidizes the suspension, with the long-time viscosity scaling as ∼ L2, compared to ∼ L3 in passive systems. These insights open new avenues for designing activity-responsive polymeric materials.
    DOI:  https://doi.org/10.1038/s41467-025-60210-9
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