bims-enlima Biomed News
on Engineered living materials
Issue of 2025–09–21
fifty-four papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. 3D Printing of Poly(methyl methacrylate) by Interfacial Photopolymerization.
  2. Tuning the mechanical properties and printability of viscoelastic skin-derived hydrogels for 3D cell culture.
  3. Bespoke 3D printing adapted to features mapped using computer vision.
  4. BIOPRINTING OF MICRODISSECTED TUMOR "CUBOIDS" IN HYDROGELS.
  5. Engineered prime editors with minimal genomic errors.
  6. Hybrid Biofabrication of Multilayered, Self-Supporting Tracheal Constructs Using Functionalized dECM Hydrogels.
  7. Design of Orthogonal Far-Red, Orange and Green Fluorophore-binding Proteins for Multiplex Imaging.
  8. Leaflet-specific phospholipid imaging using genetically encoded proximity sensors.
  9. Split NeissLock with Spy-Acceleration Arms Mammalian Proteins for Anhydride-Mediated Cell Ligation.
  10. A Modular Approach for the Optogenetic Control of Small GTPase Activity in Living Cells.
  11. Tunable Low-Rate Genomic Recombination with Cre-lox in Escherichia coli : A Versatile Tool for Environmental Biosensing and Synthetic Biology.
  12. Manufacturing mRNA-Loaded Lipid Nanoparticles with Precise Size and Morphology Control.
  13. Broad-Host-Range Synthetic Biology: Rethinking Microbial Chassis as a Design Variable.
  14. PyCLM: programming-free, closed-loop microscopy for real-time measurement, segmentation, and optogenetic stimulation.
  15. Nano-Confined Hydrogel Microspheres with Programmable Mechanics and Molecular Lubricity.
  16. Bioelectronic implants built from rolled-up stretchy circuits.
  17. Parametrically guided design of beta barrels and transmembrane nanopores using deep learning.
  18. Reprogrammable sequencing for physically intelligent underactuated robots.
  19. The density of Braun's Lipoprotein determines vesicle production in E. coli.
  20. Circular RNA lipid nanoparticle vaccine against SARS-CoV-2.
  21. Cell Behavior and Complex Mechanical Properties of 3D Printed Cell-Laden Alginate-Gelatin Macroporous Mesostructures.
  22. Polyphenol-Mediated Engineering of Lipid Nanoparticles With Crystalline Mesophases.
  23. Designers join scientists to make living architecture a reality.
  24. High-density soft bioelectronic fibres for multimodal sensing and stimulation.
  25. Programmable Continuous Electrowetting of Liquid Metal for Reconfigurable Electronics.
  26. Balancing Cell Growth and Product Synthesis for Efficient Microbial Cell Factories.
  27. Mutation-induced filaments of folded proteins are inert and non-toxic in a cellular system.
  28. Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines.
  29. Cancer subclone detection based on DNA copy number in single-cell and spatial omic sequencing data.
  30. A programmable genetic platform for engineering noninvasive biosensors.
  31. Force-Induced Selective Carbon-Carbon Bond Cleavage in Mechanoresponsive Topochemical Polymers.
  32. Genetically Encoded Control of In Vitro Transcription-Translation Coupled DNA Replication.
  33. Matrix-Engineered Self-Assembly of Fluorophores Based on Acidic Annealing for Robust Cellular Imaging.
  34. Collagen-Fibronectin Crosstalk in Engineered Matrices: Synergistic Assembly Orchestrates Fibrillar Morphogenesis and Cell Adhesion-Migration Dynamics.
  35. Aspiration-assisted bioprinting of spheroids.
  36. Monolithic three-dimensional neural probes from deterministic rolling of soft electronics.
  37. Multifunctional Physical and Chemical Stimuli Detection in Single-Module Device for Health Monitoring.
  38. Kinetic organization of the genome revealed by ultraresolution multiscale live imaging.
  39. Engineered histones reshape chromatin in human cells.
  40. De novo design of semisynthetic protein nanopores.
  41. A multifunctional living hydrogel for the synergistic management of infected diabetic wounds.
  42. Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2.
  43. Development of Reversible Color-Changing Three-Dimensional Structures Using a Thermochromic Resin in Digital Light Processing-Based Vat Photopolymerization.
  44. Covariation MS uncovers a protein that controls cysteine catabolism.
  45. In vivo pathway optimization in yeast via loxpsym-mediated shuffling of upstream activating sequences.
  46. STARNet enables spatially resolved inference of gene regulatory networks from spatial multi-omics data.
  47. Randomness with constraints: constructing minimal models for high-dimensional biology.
  48. Ultraviolet and Visible Light-Responsive RNA Photofluids.
  49. Cell Contractile Forces Drive Spatiotemporal Morphogenesis in 4D Bioprinted Living Constructs.
  50. 3D-Printed Nitrogen-Doped Carbon Interlayers for Spatially Modulating Lithium-Sulfur Reactions.
  51. Sono-uncaging for Spatiotemporal Control of Chemical Reactivity.
  52. Lipid-Inspired Low Melting Ionic Liquids via Synergistic Cyclopropanation and Branching of Terpenoids.
  53. RNA modification systems as therapeutic targets.
  54. NeKo: A tool for automatic network construction from prior knowledge.
  1. ACS Appl Mater Interfaces. 2025 Sep 16.
    3D Printing of Poly(methyl methacrylate) by Interfacial Photopolymerization.
    Prajwal Tumkur Mahesh, Cécile A C Chazot, Richard B Church, Michael N Durso, Carl J Thrasher, Megan A Creighton, A John Hart.
      Established light-based additive manufacturing (AM) processes, such as vat polymerization, utilize nonrecyclable thermoset polymers, posing sustainability concerns. This work presents a method for circular photopolymerization three-dimensional (3D) printing of thermoplastic parts, addressing the demand for low-waste production of complex, high-resolution polymer parts. This is achieved through interfacial photopolymerization (IPP), where linear polymer chains form layerwise into entangled networks at the interface between the immiscible organic and aqueous phases. IPP has previously been demonstrated, but with limited chemistries and without 3D structural control. We demonstrate herein a chemistry to form poly(methyl methacrylate) (PMMA) by IPP and a process for multilayer fabrication in a modified commercial projector-based 3D printer. Layer resolution and stability are enhanced using light-absorbing dye and a water-soluble polyethylene glycol (PEG) binder. Postprocessing with controlled air drying and thermal treatment with PEG infiltration preserves geometry and reduces cracking. The resulting composite comprises 75% PEG and 25% PMMA with mechanical properties akin to those of polymer foams. Circularity of the IPP-PMMA process is demonstrated by recycling and reincorporating printed objects across several cycles without significant degradation of properties. Although enhancements in geometric fidelity and mechanical properties are necessary, IPP 3D printing enables, for the first time, digital light processing of recyclable thermoplastic PMMA and PEG-based parts.
    Keywords:  digital light processing; interfacial polymerization; poly(methyl methacrylate); polymer; recycling; sustainable 3D printing; thermoplastic
    DOI:  https://doi.org/10.1021/acsami.5c11228
  2. Biomater Sci. 2025 Sep 16.
    Tuning the mechanical properties and printability of viscoelastic skin-derived hydrogels for 3D cell culture.
    Estelle Palierse, Alexia Maria Mihailescu, Ira Bergquist, Cecilia Persson, Morteza Aramesh.
      In vitro investigations or tissue engineering require the creation of hierarchical and acellularized 3D structures mimicking the native environment of cells in vivo. Bioprinting provides a powerful approach to fabricating 3D architectures with precision and control. However, developing a bioink suitable for 3D cell culture remains challenging, particularly in achieving optimal rheological properties, printability and bioactivity necessary for cellular viability, functionality and growth. Here, we developed tissue-derived hydrogels with tunable gelation kinetics and rheological properties. By precisely adjusting the bioink's physical characteristics, we optimized its printability for extrusion-based bioprinting, enabling fast fabrication of structurally stable constructs that support the formation of 3D cellular structures. A robust decellularization protocol was developed to consistently obtain porcine skin-derived dECM (decellularized extracellular matrix) hydrogels with minimal batch-to-batch variation. The influence of dECM concentration (1-5 mg mL-1) on the ink's viscoelastic properties, printability, gelation kinetics, and cellular response was investigated. Gelation kinetics varied between 7 minutes to several hours, while the storage modulus ranged between 10 to 1000 Pa. Additionally, more concentrated hydrogels led to more homogeneous prints due to their higher viscosity. Fibroblast cells infiltrated the 3D matrix of the softer hydrogels (1 and 2.5 mg mL-1), forming an interconnected network. In contrast, migration was significantly restricted in the denser hydrogels (5 mg mL-1). Our findings demonstrate the potential of tissue-derived hydrogels with tunable properties for 3D bioprinting applications, enabling fast and reproducible fabrication of dECM environments for cellular studies and tissue engineering, while highlighting the critical balance between mechanical and biological properties in bioink formulation.
    DOI:  https://doi.org/10.1039/d5bm00403a
  3. Nature. 2025 Sep 17.
    Bespoke 3D printing adapted to features mapped using computer vision.
      
    Keywords:  Biomaterials; Engineering
    DOI:  https://doi.org/10.1038/d41586-025-02956-2
  4. bioRxiv. 2025 Sep 10. pii: 2025.09.05.671932. [Epub ahead of print]
    BIOPRINTING OF MICRODISSECTED TUMOR "CUBOIDS" IN HYDROGELS.
    Anjul M Bansal, Lisa F Horowitz, Marcus Yeung, Taranjit S Gujral, Albert Folch.
      Microscale tumor models made from microdissected tumors that retain much of the original human tumor microenvironment (TME) are emerging as an alternative to preclinical animal models. We have introduced a drug testing approach that utilizes regularly-cut, cuboidal-shaped microdissected tissues, or "cuboids," as a way to maximize creation of microtissues from scarce biopsy materials. However, microtissues (e.g., cuboids, organoids, spheroids, etc.) can be difficult to place in precise locations, especially in applications that require their culture in hydrogels. Here, using cuboids from mouse tumor models, we demonstrate a simple bioprinting strategy for precise placement and immobilization of cuboids in hydrogel. We use a commercial bioprinter to bioprint-containing hydrogel into arrays of small hydrogel dots containing cuboids, or "cuboid dots," either onto a Transwell insert or into traps on a microplate. The hydrogel serves to immobilize the cuboids in place and provides a matrix to support cuboid viability. We demonstrate proof-of-concept applications for cancer drug testing and for protein profiling analysis. This approach will enable interface of cuboids with other devices, such as on top of a sensor or in a microfluidic platform. Furthermore, this automated process of dispensing and localizing cuboids (or other microtissue formats such as spheroids or organoids) could further their application to drug discovery and personalized medicine.
    TOC Graphic:
    DOI:  https://doi.org/10.1101/2025.09.05.671932
  5. Nature. 2025 Sep 17.
    Engineered prime editors with minimal genomic errors.
    Vikash P Chauhan, Phillip A Sharp, Robert Langer.
      Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3' ends1. These edited 3' new strands must displace competing 5' strands to install edits, yet a bias towards retaining the competing 5' strands hinders efficiency and can cause indel errors2. Here we discover that nicked end degradation, consistent with competing 5' strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1.
    DOI:  https://doi.org/10.1038/s41586-025-09537-3
  6. ACS Appl Bio Mater. 2025 Sep 16.
    Hybrid Biofabrication of Multilayered, Self-Supporting Tracheal Constructs Using Functionalized dECM Hydrogels.
    Meenu Ts, Shyama Sasikumar, Shibu Chameettachal, Falguni Pati.
      The trachea plays a vital role in maintaining airway patency and facilitating gas exchange. However, severe tracheal defects result from trauma, infection, congenital abnormalities, or malignancies. There are significant challenges with current treatments, such as synthetic implants, allografts, and autografts, suffering from immune rejection, donor shortages, poor mechanical integration, and inadequate long-term functionality. Existing tissue-engineered tracheal grafts often fail to replicate the native multilayered heterogeneous tissue structure and biomechanical properties, limiting their clinical success. To address this, we propose a multilayered heterogeneous tracheal construct using decellularized extracellular matrix (dECM) hydrogels by a hybrid approach of integrating digital light processing printing and gel casting, designed to mimic the native tracheal architecture and enhance cellular functionality. By this approach, we developed a self-standing multilayered tracheal construct by sequentially assembling cartilage, submucosa, and muscle layers using the dECM hydrogels functionalized with cells to replicate the native tracheal architecture. Structural integrity, ECM remodeling, and contractility were achieved within each layer. The developed multilayered tracheal construct demonstrated structural integrity and mechanical properties nearly comparable to native tracheal tissue, where it withstands airway dynamics along with cell viability, proliferation, and integration within each layer. Our hybrid approach of developing a multilayered tracheal construct presents a promising solution for tracheal reconstruction and regeneration, revolutionizing tracheal repair and improving treatment modalities.
    Keywords:  DLP bioprinting; biofabrication; biomaterials; decellularization; tracheal tissue regeneration
    DOI:  https://doi.org/10.1021/acsabm.5c01026
  7. bioRxiv. 2025 Sep 03. pii: 2025.08.03.668343. [Epub ahead of print]
    Design of Orthogonal Far-Red, Orange and Green Fluorophore-binding Proteins for Multiplex Imaging.
    Long Tran, Shajesh Sharma, Steffen Klein, David Jurgens, Justin Decarreau, Bingxu Liu, Yujia Wang, Asim K Bera, Alex Kang, Jon Woods, Emily Joyce, Dionne K Vafeados, Nicole Roullier, Wei Chen, Gyu Rie Lee, Julia Mahamid, Luke D Lavis, Linna An, David Baker.
      Fluorescent proteins and small molecule dyes have complementary strengths for biological imaging: the former are genetically manipulatable enabling tagging of specific proteins and detection of protein interactions, while the latter have greater photostability and brightness but are difficult to target. To combine these strengths, we used de novo protein design to generate binders to three bright, stable, cell-permeable dyes spanning the visible spectrum: JF657 (far red), JF596 (orange-red) and JF494 (green). For each dye, we obtain nanomolar binders with weak or no binding to the other two dyes; the accuracy of the design approach is confirmed by a crystal structure of one binder which is very close to the design model. Fusion of the JF567, JF596 and JF494 binders to three different targets followed by staining with the three dyes simultaneously enables multiplex imaging. We further expand functionality by incorporating an active site carrying out nucleophilic aromatic substitution to form a covalent linkage with the dye, and developing split versions which reconstitute fluorescence at subcellular locations where both halves are present, enabling both protein-protein interaction detection and chemically induced dimerization with fluorescence reporting. Our designs combine the advantages of fluorescent proteins and small molecule dyes and should be broadly useful for cellular imaging.
    DOI:  https://doi.org/10.1101/2025.08.03.668343
  8. Nat Chem Biol. 2025 Sep 15.
    Leaflet-specific phospholipid imaging using genetically encoded proximity sensors.
    William M Moore, Roberto J Brea, Caroline H Knittel, Ellen Wrightsman, Brandon Hui, Jinchao Lou, Christelle F Ancajas, Michael D Best, Christopher J Obara, Neal K Devaraj, Itay Budin.
      The lipid composition of cells varies widely across organelles and between individual membrane leaflets. Transport proteins are thought to generate this heterogeneity, but measuring their functions in vivo has been hampered by limited tools for imaging lipids at relevant spatial resolutions. Here we present fluorogen-activating coincidence encounter sensing (FACES), a chemogenetic tool capable of quantitatively imaging subcellular lipid pools and reporting their transbilayer orientation in living cells. FACES combines bioorthogonal chemistry with genetically encoded fluorogen-activating proteins (FAPs) for reversible proximity sensing of conjugated molecules. We first apply this approach to identify roles for lipid transfer proteins that traffic phosphatidylcholine pools between the ER and mitochondria. We then show that transmembrane domain-containing FAPs can reveal the membrane asymmetry of multiple lipid classes in the trans-Golgi network and be used to investigate the mechanisms that generate it. Finally, we present that FACES can be applied to measure glycans and other molecule classes.
    DOI:  https://doi.org/10.1038/s41589-025-02021-z
  9. ACS Chem Biol. 2025 Sep 15.
    Split NeissLock with Spy-Acceleration Arms Mammalian Proteins for Anhydride-Mediated Cell Ligation.
    Sheryl Y T Lim, Anthony H Keeble, Mark R Howarth.
      Reactive functional groups may be incorporated into proteins or may emerge from natural amino acids in exceptional architectures. Anhydride formation is triggered by calcium in the self-processing module (SPM) of Neisseria meningitidis FrpC, which we previously engineered for "NeissLock" ligation to an unmodified target protein. Here, we explored bacterial diversity, discovering a related module with ultrafast anhydride formation. We dissected this swift SPM to generate a split NeissLock system, providing a second layer of control of anhydride generation: first mixing N- and C-terminal NeissLock moieties and second adding millimolar amounts of calcium. Split NeissLock generated a minimal fusion tag, permitting binder expression in mammalian cells with complex post-translational modifications and avoiding self-cleavage while transiting the calcium-rich secretory pathway. Employing spontaneous amidation between SpyTag003 and SpyCatcher003, we dramatically accelerated split NeissLock reconstitution, allowing a rapid high-yield reaction to naturally occurring targets. We established a specific covalent reaction to endogenous Epidermal Growth Factor Receptor using split NeissLock via Transforming Growth Factor-α secreted from mammalian cells. Modular ligation was demonstrated on living cells through site-specific coupling of the clot-busting enzyme tissue plasminogen activator or a computationally designed cytokine. Split NeissLock provides a modular architecture to generate highly reactive functionality, with inducibility and simple genetic encoding for enhanced cellular modification.
    DOI:  https://doi.org/10.1021/acschembio.5c00515
  10. bioRxiv. 2025 Sep 07. pii: 2025.09.07.674731. [Epub ahead of print]
    A Modular Approach for the Optogenetic Control of Small GTPase Activity in Living Cells.
    Benjamin Faulkner, Yuchen He, Daniel Sitrin, Linda Ziamanesh, Cliff I Stains.
      Small GTPases are critical regulators of cellular processes, such as cell migration, and comprise a family of over 167 proteins in the human genome. Despite the essential role these proteins play in maintaining cell homeostasis, there is no generalizable method for directly controlling the activity of these signaling enzymes with subcellular precision. Herein, we report the design and implementation of a modular, optogenetic platform for the spatial control of small GTPase activity within living cells. By combining split-small GTPases with improved Light-Inducible Dimerization (iLID) domains, we obtain spLIT-small GTPase constructs that enable spatially precise control of cytoskeletal dynamics such as filopodia formation (spLIT-Cdc42), membrane retraction (spLIT-RhoA), and directed cell migration (spLIT-Rac1). These results establish spLIT-small GTPases as a modular optogenetic platform for spatially controlled activation of small GTPase signaling within living cells and demonstrate the ability to probe spatiotemporal aspects of cell signaling using this approach.
    DOI:  https://doi.org/10.1101/2025.09.07.674731
  11. bioRxiv. 2025 Sep 02. pii: 2024.10.02.616356. [Epub ahead of print]
    Tunable Low-Rate Genomic Recombination with Cre-lox in Escherichia coli : A Versatile Tool for Environmental Biosensing and Synthetic Biology.
    Elisa Garabello, Hyun Yoon, Matthew C Reid, Andrea Giometto.
      The ability to induce heritable genomic changes in response to environmental cues is valuable for environmental biosensing, for experimentally probing microbial ecology and evolution, and for synthetic biology applications. Site-specific recombinases provide a route to genetic memory via targeted DNA modifications, but their high specificity and efficiency are offset by leaky expression and limited tunability in prokaryotes. We developed a tightly regulated, titratable Cre recombinase system for Escherichia coli that achieves low recombination rates and minimal basal activity. Implemented on both plasmids and the chromosome, the latter showed superior retention of genetic memory across generations. These features make the system broadly useful for environmental biosensing and other applications. To demonstrate applicability to environmental biosensing, we developed a whole-cell recombination-based biosensor for arsenite, a toxic and ubiquitous pollutant that is primarily mobilized in anoxic environments such as flooded soils, sediments, and aquifers. However, existing arsenite whole-cell biosensors face limitations in sensitivity and workflow in anaerobic settings. Our biosensor reliably recorded anoxic arsenite exposure as a stable genetic memory for delayed fluorescence readout in aerobic conditions, with detection sensitivity comparable to conventional wet chemical methods. By decoupling exposure from measurement, this approach offers a foundation for arsenite biosensing under field-relevant conditions, including redox variability and other physicochemical gradients, without the constraints of anoxic measurement. More broadly, the ability to induce low-rate, heritable genetic changes expands the genetic toolkit for environmentally responsive systems, with applications in environmental monitoring, bioproduction, bioengineering, as well as experimental studies of microbial ecology, evolution, and host-microbe interactions.
    IMPORTANCE: Arsenic is a toxic and globally prevalent pollutant, mobilized primarily under anoxic conditions where detection is challenging. Whole-cell biosensors offer a promising route for monitoring bioavailable arsenic in situ , but their development has largely focused on aerobic conditions, with anoxic assays limited by sensitivity and workflow constraints. Genetic tools that enable heritable, low-frequency genomic changes in bacteria can expand biosensor capabilities by recording transient exposures and supporting applications in environmental monitoring, synthetic biology, and quantitative microbial population dynamics research. Here, we developed a tightly regulated, chemically inducible Cre- lox system in Escherichia coli that enables recombination at low, tunable rates. We demonstrate its utility by constructing an arsenite biosensor that reliably detects low concentrations and records exposures under both aerobic and anoxic conditions. This approach is broadly applicable for biosensors designed for field deployment and for experiments investigating microbial ecology and evolution, where controllable genetic diversification may be desirable.
    DOI:  https://doi.org/10.1101/2024.10.02.616356
  12. ACS Nano. 2025 Sep 15.
    Manufacturing mRNA-Loaded Lipid Nanoparticles with Precise Size and Morphology Control.
    Cedric Devos, Aniket Udepurkar, Peter Sagmeister, Ariana S Hodlewsky, Julie Chen, Andrew Hatas, Nicole Ostrovsky, Mushriq Al-Jazrawe, Joy I Ren, Andy Y Liu, Richard D Braatz, Allan S Myerson.
      Lipid nanoparticles (LNPs) are the leading platform for delivering nucleic acid therapeutics, produced by rapidly mixing lipids in ethanol with nucleic acid cargo in an aqueous buffer. LNP production is often approached with a mixing-focused mindset that reduces the entire self-assembly process to a single step, obscuring the relationship between the process inputs and LNP properties. Here, we present a method for producing mRNA-loaded LNPs, with independent and predictive control over both the size and morphology and without compromising other quality attributes. By decoupling particle design from mixing and formulation changes, this method enables the rational engineering of LNPs with defined properties. The method leverages mixing under high fusogenicity conditions, achieved by modulating the solvent composition, followed by timed postinjection of an aqueous buffer to kinetically arrest LNPs at the desired properties. We demonstrate the method using benchmark LNP formulations in an impinging jet mixer, a state-of-the-art technology for LNP manufacturing. The resulting LNPs exhibit up to an 8-fold increase in in vitro transfection efficacy compared to those produced by the conventional method. In addition, the method facilitates quality control and supports predictive modeling and rational process translation.
    Keywords:  formulation; lipid nanoparticle; mRNA; mixing; morphology; nucleic acid; size
    DOI:  https://doi.org/10.1021/acsnano.5c09800
  13. ACS Synth Biol. 2025 Sep 18.
    Broad-Host-Range Synthetic Biology: Rethinking Microbial Chassis as a Design Variable.
    Dennis Tin Chat Chan, Johan Bjerg, Hans C Bernstein.
      Broad-host-range synthetic microbiology is redefining the role of microbial hosts in genetic design by moving beyond the traditional organisms. Historically, synthetic biology has focused on optimizing engineered genetic constructs within a limited set of well-characterized chassis, often treating host-context dependency as an obstacle. However, emerging research demonstrates that host selection is a crucial design parameter that influences the behavior of engineered genetic devices through resource allocation, metabolic interactions, and regulatory crosstalk. By leveraging microbial diversity, broad-host-range synthetic biology enhances the functional versatility of engineered biological systems, enabling a larger design space for biotechnology applications in biomanufacturing, environmental remediation, and therapeutics. The continued development of broad-host-range tools─including modular vectors and host-agnostic genetic devices─facilitates the expansion of chassis selection, improving system predictability and stability. This perspective highlights the advantages of incorporating host selection into synthetic biology design principles, positioning microbial chassis as tunable components rather than passive platforms.
    DOI:  https://doi.org/10.1021/acssynbio.5c00308
  14. bioRxiv. 2025 Sep 04. pii: 2025.08.29.673155. [Epub ahead of print]
    PyCLM: programming-free, closed-loop microscopy for real-time measurement, segmentation, and optogenetic stimulation.
    Harrison R Oatman, Beena C Lad, Jared Toettcher.
      In cell biology, optical techniques are increasingly used to measure cells' internal states (biosensors) and to stimulate cellular responses (optogenetics). Yet the design of all-optical experiments is often manual: a pre-determined stimulus pattern is applied to cells, biosensors are measured over time, and the resulting data is processed off-line. With the advent of machine learning for segmentation and tracking, it becomes possible to envision closed-loop experiments where real-time information about cells' positions and states are used to dynamically determine optogenetic stimuli to alter or control their behavior. Here, we develop PyCLM, a Python-based suite of tools to enable real-time measurement, image segmentation, and optogenetic control of thousands of cells per experiment. PyCLM is designed to be as simple for the end user as possible, and multipoint experiments can be set up that combine a wide variety of imaging, image processing, and stimulation modalities without any programming. We showcase PyCLM on diverse applications: studying the effect of epidermal growth factor receptor activity waves on epithelial tissue movement, simultaneously stimulating ~1,000 single cells to guide tissue flows, and performing real-time feedback control of cell-to-cell fluorescence heterogeneity. This tool will enable the next generation of dynamic experiments to probe cell and tissue properties, and provides a first step toward precise control of cell states at the tissue scale.
    DOI:  https://doi.org/10.1101/2025.08.29.673155
  15. Small. 2025 Sep 18. e07138
    Nano-Confined Hydrogel Microspheres with Programmable Mechanics and Molecular Lubricity.
    XiaoXiao Li, Xingchen Li, Zehao Chen, Xiaojian Ye, Lianfu Deng, Xiangyang Xu, Wenguo Cui.
      The simultaneous integration of high elasticity and lubricity-hallmarks of biological tissues-remains a fundamental challenge in synthetic hydrogels due to the intrinsic trade-off between "dehydration-induced" elasticity and "hydration-dependent" lubrication. Herein, inspired by the dynamic architecture of living systems, the construction of "living" biodegradable hydrogel microspheres is reported that reconcile this contradiction through internal nano-reinforcement and external molecular lubrication. Crystalline disc-like Laponite nanosheets are intercalated within GelMA networks, acting as dynamic, spatially confining crosslinkers that inhibit water infiltration and preserve network cohesion. Concurrently, zwitterionic brushes are grafted onto the microsphere surface, forming a robust hydration layer via dynamic charge-dipole interactions to enable long-lasting lubrication. This synergistic design endows the microspheres with tunable elasticity (14-4000 Pa) and adjustable friction coefficients (0.12-0.04), achieving a functional convergence of mechanical resilience and surface lubricity. Experimental evaluations confirm their efficacy in inhibiting excessive mechanical stress-induced calcium ion influx and downstream calcium signaling to prevent chondrocyte damage. This work offers a universal strategy to overcome the elasticity-lubrication paradox in hydrogels, unlocking their potential in biomedical engineering, drug delivery, and soft robotic interfaces.
    Keywords:  cartilage lubrication; microfluidic microspheres; nano enhancement; osteoarthritis; spatial confinement
    DOI:  https://doi.org/10.1002/smll.202507138
  16. Nature. 2025 Sep;645(8081): 600-601
    Bioelectronic implants built from rolled-up stretchy circuits.
    Hyunjin Lee, Dae-Hyeong Kim.
      
    Keywords:  Biotechnology; Engineering; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-02704-6
  17. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2425459122
    Parametrically guided design of beta barrels and transmembrane nanopores using deep learning.
    David E Kim, Joseph L Watson, David Juergens, Sagardip Majumder, Ria Sonigra, Stacey R Gerben, Alex Kang, Asim K Bera, Xinting Li, David Baker.
      Francis Crick's global parameterization of coiled coil geometry has been widely useful for guiding design of new protein structures and functions. However, design guided by similar global parameterization of beta barrel structures has been less successful, likely due to the deviations from ideal barrel geometry required to maintain interstrand hydrogen bonding without introducing backbone strain. Instead, beta barrels have been designed using two-dimensional structural blueprints; while this approach has successfully generated new fluorescent proteins, transmembrane nanopores, and other structures, it requires expert knowledge and provides only indirect control over the global shape. Here, we show that the simplicity and control over shape and structure provided by parametric representations can be generalized beyond coiled coils by taking advantage of the rich sequence-structure relationships implicit in RoseTTAFold-based design methods. Starting from parametrically generated barrel backbones, both RFjoint inpainting and RFdiffusion readily incorporate backbone irregularities necessary for proper folding with minimal deviation from the idealized barrel geometries. We show that for beta barrels across a broad range of beta sheet parameterizations, these methods achieve high in silico and experimental success rates, with atomic accuracy confirmed by an X-ray crystal structure of a rare barrel topology, and de novo designed transmembrane nanopores with conductances ranging from 200 to 500 pS. By combining the simplicity and control of parametric generation with the high success rates of deep learning-based protein design methods, our approach makes the design of proteins where global shape confers function, such as beta barrel nanopores, more precisely specifiable and accessible.
    Keywords:  beta barrels; deep learning; nanopores; protein design
    DOI:  https://doi.org/10.1073/pnas.2425459122
  18. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2508310122
    Reprogrammable sequencing for physically intelligent underactuated robots.
    Leon M Kamp, Mohamed Zanaty, Ahmad Zareei, Benjamin Gorissen, Robert J Wood, Katia Bertoldi.
      Programming physical intelligence into mechanisms holds great promise for machines that can accomplish tasks such as navigation of unstructured environments while utilizing a minimal amount of computational resources and electronic components. In this study, we introduce a design approach for physically intelligent underactuated mechanisms capable of autonomously adjusting their motion in response to environmental interactions. Specifically, multistability is harnessed to sequence the motion of different degrees of freedom in a programmed order. A key aspect of this approach is that this order can be passively reprogrammed through mechanical stimuli arising from interactions with the environment. To showcase our approach, we construct a mechanism that passively sorts objects based on their mass and a four-degree-of-freedom robot capable of autonomously moving away from obstacles. Remarkably, these devices operate without relying on traditional computational architectures and utilize only a single linear actuator.
    Keywords:  autonomous interactions; mechanical sensing; multistability; physical intelligence
    DOI:  https://doi.org/10.1073/pnas.2508310122
  19. PLoS One. 2025 ;20(9): e0332156
    The density of Braun's Lipoprotein determines vesicle production in E. coli.
    Brian P Weaver, Fengjie Zhao, Yuanli Gao, James Q Boedicker, Christoph A Haselwandter.
      Production of extracellular vesicles by Gram-negative bacteria is known to be associated with blebbing of the outer membrane. Several proteins within Gram-negative bacteria crosslink the outer membrane to the cell wall, and thereby stabilize the cell envelope. Prior work in Escherichia coli demonstrated that crosslinking proteins reduce membrane blebbing and vesicle formation, and that deletion of crosslinking proteins, most notably Braun's lipoprotein (Lpp), can increase vesicle production by about two orders of magnitude. To examine the quantitative relation between crosslinking proteins and bacterial vesicle formation, we develop here a simple physical model that predicts how vesicle production depends on the Lpp density. We test our model by measuring vesicle production in a strain of E. coli with tunable Lpp expression. Our experimental observations agree with our model predictions for most measured Lpp densities. For low Lpp densities, our experiments yield more pronounced vesicle production than predicted by our model, which can be explained if the mechanical properties of the cell envelope depend on the Lpp density. Our results shed light on basic principles and molecular mechanisms governing bacterial vesicle production.
    DOI:  https://doi.org/10.1371/journal.pone.0332156
  20. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2505718122
    Circular RNA lipid nanoparticle vaccine against SARS-CoV-2.
    Kelsey L Swingle, Alex G Hamilton, Xuexiang Han, Kuo-Chieh Liao, Hannah C Safford, Ajay S Thatte, Hannah C Geisler, Junchao Xu, Tzuen Yih Saw, Yue Wan, Michael J Mitchell.
      With the advent and widespread use of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), RNA vaccines have emerged as an exciting class of vaccine offering low cost, rapid development, and high modularity and manufacturability. Protein-coding circular RNA (circRNA) is an emerging class of RNA cargo that offers increased stability compared to mRNA with potentially reduced immunogenicity, but delivery technologies for intracellular delivery of circRNA remain underexplored. Here, we develop an optimized lipid nanoparticle (LNP) platform for circRNA delivery to immune cells, observing strong and durable transgene expression in vitro and in vivo. We employ a design-of-experiments (DoE) methodology to identify key formulation parameters for enhanced circRNA delivery and, upon intramuscular administration of our optimized circRNA LNPs to mice, observe substantial accumulation within draining lymph nodes and strong dendritic cell (DC) maturation at short time points. Applying this optimized circRNA LNP platform to vaccination against SARS-CoV-2, we demonstrate robust antibody production and enhanced immune responses in mice compared to vaccination with mRNA LNPs, including strong Th1-biased cellular responses and a 3.8-fold increase in antigen-specific reciprocal endpoint IgG titers. These results provide insights into design criteria for circRNA LNP formulations and support the use of circRNA LNPs for vaccination against infectious diseases.
    Keywords:  RNA; SARS-CoV-2; circular RNA; lipid nanoparticle; vaccine
    DOI:  https://doi.org/10.1073/pnas.2505718122
  21. Macromol Biosci. 2025 Sep 17. e00204
    Cell Behavior and Complex Mechanical Properties of 3D Printed Cell-Laden Alginate-Gelatin Macroporous Mesostructures.
    Nicoletta Murenu, Jessica Faber, Anahita Ahmadi Soufivand, Monika Buss, Natascha Schaefer, Silvia Budday.
      Bioprinting involves additive manufacturing of materials containing living cells, known as bioinks, which are formulated from cytocompatible hydrogel precursors. The bioink's characteristics before, during, and after crosslinking are critical for its printability, structural resolution, shape fidelity, and cell viability. The mechanical properties of printed constructs can be strongly influenced by their macroporous mesostructure, including pore size, filament diameter, and layer height, and are crucial for the intended applications in tissue engineering or regenerative medicine. It is known that the mechanical properties of hydrogels influence cell performance, but in turn, cells can also alter the mechanical properties of bioprinted constructs, which remain poorly understood. To explore these interdependencies, we selected an alginate-gelatin hydrogel (ALG-GEL), due to its well-known biocompatibility, combined with U87 cells and bioprinted three different multilayer macroporous mesostructures with varying porosity and filament diameter. We investigate how different macroporous mesostructures affect cells, how cells, in turn, influence mechanical properties, and whether the stability and mechanical properties of bioprinted macroporous mesostructures change over time. Our findings show that the bioprinted constructs are stable over the course of 14 days and highlight that cells can significantly influence their mechanical properties. This has important implications for biofabrication and tissue engineering applications.
    Keywords:  ALG‐GEL; bioprinting; cyclic compression‐tension; long‐term cell viability; pore size
    DOI:  https://doi.org/10.1002/mabi.202500204
  22. Adv Mater. 2025 Sep 15. e05830
    Polyphenol-Mediated Engineering of Lipid Nanoparticles With Crystalline Mesophases.
    Shiyao Li, Patrick Charchar, Haitao Yu, Zhixing Lin, Hamish G Brown, Wanjun Xu, Chan-Jin Kim, Irene Yarovsky, Yi Ju, Frank Caruso.
      Lipids self-assemble into lipid nanoparticles (LNPs) with different crystalline mesophases, including lamellar and nonlamellar (e.g., cubic and hexagonal) mesophases. Although various additives can modulate lipid curvature, the formation of nonlamellar crystalline mesophases in LNPs typically depends on specific phase-forming lipids, which limits the overall design space and structural versatility for cargo loading. Herein, a new class of nonlamellar LNPs is engineered through the one-step assembly of two components-a polyphenol and a lipid-where the lipid mesophases are modulated by the polyphenols in a concentration-dependent manner. The polyphenol-based LNPs exhibit ordered Im3m micellar cubic or hexagonal nanostructures and can load metal ions, small-molecule drugs, polypeptides, proteins, polysaccharides, and mRNA. The present study establishes an approach to generate nonlamellar LNPs with ordered nanostructures and functional cargos for diverse applications.
    Keywords:  drug delivery; nanostructures; nonlamellar mesophases; polyphenols; self‐assembly
    DOI:  https://doi.org/10.1002/adma.202505830
  23. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2522200122
    Designers join scientists to make living architecture a reality.
    Carolyn Beans.
      
    DOI:  https://doi.org/10.1073/pnas.2522200122
  24. Nature. 2025 Sep;645(8081): 656-664
    High-density soft bioelectronic fibres for multimodal sensing and stimulation.
    Muhammad Khatib, Eric Tianjiao Zhao, Shiyuan Wei, Jaeho Park, Alex Abramson, Estelle Spear Bishop, Anne-Laure Thomas, Chih-Hsin Chen, Pamela Emengo, Chengyi Xu, Ryan Hamnett, Samuel E Root, Lei Yuan, Matthias J Wurdack, Tomasz Zaluska, Yeongjun Lee, Kostas Parkatzidis, Weilai Yu, Dorine Chakhtoura, Kyun Kyu Kim, Donglai Zhong, Yuya Nishio, Chuanzhen Zhao, Can Wu, Yuanwen Jiang, Anqi Zhang, Jinxing Li, Weichen Wang, Fereshteh Salimi-Jazi, Talha A Rafeeqi, Nofar Mintz Hemed, Jeffrey B-H Tok, Xiang Qian, Xiaoke Chen, Julia A Kaltschmidt, James C Y Dunn, Zhenan Bao.
      There is an increasing demand for multimodal sensing and stimulation bioelectronic fibres for both research and clinical applications1,2. However, existing fibres suffer from high rigidity, low component layout precision, limited functionality and low density of active components. These limitations arise from the challenge of integrating many components into one-dimensional fibre devices, especially owing to the incompatibility of conventional microfabrication methods (for example, photolithography) with curved, thin and long fibre structures2. As a result, limited applications have been demonstrated so far. Here we use 'spiral transformation' to convert two-dimensional thin films containing microfabricated devices into one-dimensional soft fibres. This approach allows for the fabrication of high-density multimodal soft bioelectronic fibres, termed Spiral-NeuroString (S-NeuroString), while enabling precise control on the longitudinal, angular and radial positioning and distribution of the functional components. Taking advantage of the biocompatibility of our soft fibres with the dynamic and soft gastrointestinal system, we proceed to show the feasibility of our S-NeuroString for post-operative multimodal continuous motility mapping and tissue stimulation in awake pigs. We further demonstrate multi-channel single-unit electrical recording in mouse brain for up to 4 months, and a fabrication capability to produce 1,280 channels within a 230-μm-diameter soft fibre. Our soft bioelectronic fibres offer a powerful platform for minimally invasive implantable electronics, where diverse sensing and stimulation functionalities can be effectively integrated.
    DOI:  https://doi.org/10.1038/s41586-025-09481-2
  25. Adv Mater. 2025 Sep 15. e06383
    Programmable Continuous Electrowetting of Liquid Metal for Reconfigurable Electronics.
    Wedyan Babatain, Christine Park, Deiaa M Harraz, Ozgun Kilic Afsar, Cedric Honnet, Sarah Lov, Jean-Baptiste Labrune, Michael D Dickey, Hiroshi Ishii.
      Dynamic manipulation of the shape and position of liquid metal (LM), a conductive and deformable conductor, presents new opportunities for reconfigurable electronics, fluidic logic, and soft-actuation systems. This study combines continuous electrowetting (CEW) with electrochemical modulation of the interface of LM in electrolyte to achieve tunable and directional LM manipulation in 2D spaces. A key finding is that under a fixed external electric field, the LM moves in a direction that depends on its electrochemical potential. The LM potential is controlled using a substrate featuring patterns of laser-induced graphene (LIG) since it is non-wetting to LM and electrically conductive. This strategy enables a range of functionalities, including "valves" for on-demand LM control, LM droplet sorting, feedback sensing, and fluidic logic gates. The strategy can also control the motion of LM droplets across 2D spaces. Finally, it is utilized within a reconfigurable circuit platform where the LM functions as a dynamic interconnect for sequential activation, parallel switching, and self-healing circuits. By coupling the electrically-driven motion of LM and the versatility of LIG patterning, this work establishes a versatile framework for reconfigurable electronics, programmable fluidic systems, and adaptive systems.
    Keywords:  electrochemical actuation; electrowetting; fluidic valves; liquid metal; programmable matter; reconfigurable electronics
    DOI:  https://doi.org/10.1002/adma.202506383
  26. Adv Sci (Weinh). 2025 Sep 18. e10649
    Balancing Cell Growth and Product Synthesis for Efficient Microbial Cell Factories.
    Linxia Liu, Dongqin Ding, Huiying Wang, Xinyi Ren, Sang Yup Lee, Dawei Zhang.
      The sustainable, bio-based production of industrially valuable chemicals and materials from renewable, non-edible biomass through biorefineries has emerged as a vital strategy for tackling urgent global challenges, including climate change, and for realizing the "net zero carbon" commitments recently pledged by nations worldwide. Metabolic engineering has played a central role in enabling the development of microbial strains capable of efficiently overproducing a diverse array of target compounds. Nevertheless, engineered microbial cell factories often face inherent trade-offs between product synthesis and cell growth, frequently resulting in diminished fitness or loss-of-function phenotypes. This review highlights recent advances in metabolic engineering strategies aims at reconciling this conflict, encompassing pathway optimization, dynamic regulation, orthogonal system design, microbial consortia engineering, fermentation process control, and integrative metabolic modeling. It also explores the remaining challenges and future directions for reprogramming microbial metabolism to harmonize growth with high-level production.
    Keywords:  cell growth; dynamic regulation; fermentation process control; microbial cell factories; microbial consortia engineering; orthogonal system design; product synthesis
    DOI:  https://doi.org/10.1002/advs.202510649
  27. Mol Syst Biol. 2025 Sep 15.
    Mutation-induced filaments of folded proteins are inert and non-toxic in a cellular system.
    Tal Levin, Hector Garcia-Seisdedos, Arseniy Lobov, Matthias Wojtynek, Alexander Alexandrov, Ghil Jona, Dikla Levi, Ohad Medalia, Emmanuel D Levy.
      Filamentous protein assemblies are essential for cellular functions but can also form aberrantly through mutations that induce self-interactions between folded protein subunits. These assemblies, which we refer to as agglomerates, differ from aggregates and amyloids that arise from protein misfolding. While cells have quality control mechanisms to identify, buffer, and eliminate aggregates, it is unknown whether similar mechanisms exist for agglomerates. Here, we define and characterize this distinct class of assemblies formed by the polymerization of folded proteins. To systematically assess their cellular impact, we developed a simple in-cell assay that distinguishes agglomerates from aggregates based on co-assembly with wild-type subunits. Unlike misfolded aggregates, we show that agglomerates retain their folded state, do not colocalize with the proteostasis machinery, and are not ubiquitinated. Moreover, agglomerates cause no detectable growth defects. Quantitative proteomics also revealed minor changes in protein abundance in cells expressing agglomerates. These results position agglomerates as a structurally and functionally distinct class of protein assemblies that are largely inert in cells, highlighting their potential as building blocks for intracellular engineering and synthetic biology.
    Keywords:  Cell Fitness; Protein Filamentation; Protein Self-assembly; Proteome; Yeast Biology
    DOI:  https://doi.org/10.1038/s44320-025-00144-y
  28. Nat Chem. 2025 Sep 17.
    Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines.
    Isaac J Knudson, Taylor L Dover, Diondra A Dilworth, Cameron Paloutzian, Orel Paz, Jieye Lin, Hannah Cho, Tamir Gonen, Alanna Schepartz, Scott J Miller.
      Potent peptide ligands for therapeutically relevant targets are regularly returned from screening trillion-member libraries of ribosomally synthesized peptides containing non-canonical amino acids and macrocyclic architectures. Yet the chemical space explored by these peptides is a fraction of that embodied by natural products and pharmaceuticals, and most peptide leads require exhaustive medicinal chemistry optimization to improve potency and physicochemistry. To address the need for strategies to introduce chemical complexity and conformational control into peptide macrocycles, we report here that linear peptides with a reactive N-terminal β-keto or γ-keto amide can be synthesized ribosomally. Subsequent Friedländer reactions generate quinoline-peptide hybrids, some of which contain stable biaryl atropisomeric axes. We also demonstrate intramolecular Friedländer macrocyclization reactions-sufficiently mild to be employed on unprotected and in vitro-translated peptides-that embed a quinoline pharmacophore directly within the peptide backbone. The introduction of N-terminal ketone motifs into genetically encoded materials and their post-translational derivatization provides a paradigm for the programmed synthesis of peptide-derived materials that more closely resemble complex natural products.
    DOI:  https://doi.org/10.1038/s41557-025-01935-4
  29. Nat Methods. 2025 Sep;22(9): 1846-1856
    Cancer subclone detection based on DNA copy number in single-cell and spatial omic sequencing data.
    Chi-Yun Wu, Jiazhen Rong, Anuja Sathe, Paul R Hess, Billy T Lau, Susan M Grimes, Sijia Huang, Hanlee P Ji, Nancy R Zhang.
      Somatic mutations such as copy number alterations accumulate during cancer progression, driving intratumor heterogeneity that impacts therapy effectiveness. Understanding the characteristics and spatial distribution of genetically distinct subclones is essential for unraveling tumor evolution and improving cancer treatment. Here we present Clonalscope, a subclone detection method using copy number profiles, applicable to spatial transcriptomics and single-cell sequencing data. Clonalscope implements a nested Chinese Restaurant Process to identify de novo tumor subclones, which can incorporate prior information from matched bulk DNA sequencing data for improved subclone detection and malignant cell labeling. On single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing data from gastrointestinal tumors, Clonalscope successfully labeled malignant cells and identified genetically different subclones with thorough validations. On spatial transcriptomics data from various primary and metastasized tumors, Clonalscope labeled malignant spots, traced subclones and identified spatially segregated subclones with distinct differentiation levels and expression of genes associated with drug resistance and survival.
    DOI:  https://doi.org/10.1038/s41592-025-02773-5
  30. bioRxiv. 2025 Sep 11. pii: 2025.09.07.674790. [Epub ahead of print]
    A programmable genetic platform for engineering noninvasive biosensors.
    Asish N Chacko, Kaamini M Dhanabalan, Jinyang Wan, Roy Chien, Nolan T Anderson, Binzhi Xu, Katie Pham, Ritu Tiwari, Arnab Mukherjee.
      Creating genetic sensors for noninvasive visualization of biological activities in deep, optically opaque tissues holds immense potential for basic research and the development of genetic and cell-based therapies. MRI stands out among deep-tissue imaging methods for its ability to generate high-resolution images without ionizing radiation. However, the adoption of MRI as a mainstream biomolecular technology has been hindered by the lack of adaptable methods to link molecular events with genetically encodable MRI contrast. To address this challenge, we introduce universal reporter circuit-based activatable sensors (URCAS), a highly programmable platform for the systematic creation of genetic sensors for MRI. In developing URCAS, we engineered protease-activatable MRI reporters using two distinct approaches: protein stabilization and subcellular trafficking. We established the applicability of URCAS in five diverse mammalian cell types and showcased its versatility by assembling a toolkit of genetic sensors for viral proteins, small-molecule drugs, logic gates, protein-protein interactions, and calcium, without requiring new customization for each target. Our findings suggest that URCAS provides a modular, programmable platform for streamlining the development of noninvasive, nonionizing, and genetically encoded sensors for biomedical research and in vivo diagnostics.
    DOI:  https://doi.org/10.1101/2025.09.07.674790
  31. Adv Mater. 2025 Sep 18. e10482
    Force-Induced Selective Carbon-Carbon Bond Cleavage in Mechanoresponsive Topochemical Polymers.
    Zitang Wei, Hanul Kim, Nazmul Haque, Qixuan Hu, Ke Ma, Kang Wang, Shuchen Zhang, Xuyi Luo, Yoon Ho Lee, Siyoung Q Choi, Chelsea S Davis, Brett M Savoie, Letian Dou.
      Mechanoresponsive polymeric materials that respond to mechanical deformation are highly valued for their potential in sensors, degradation studies, and optoelectronics. However, direct visualization and detection of these responses remain significant obstacles. In this study, novel mechanoresponsive polybiidenedionediyl (PBIT) derivative topochemical polymers are developed that depolymerize under mechanical forces, exhibiting a distinct and irreversible color change in response to grinding, milling, and compression. This color change is attributed to the alteration of polymer backbone conjugation during elongated Carbon-Carbon (C─C) single bond cleavage. Quantum chemical pulling simulations on PBIT polymers reveals a force range of 4.3-5.0 nN associated with the selective cleavage of elongated C─C single bonds. This force range is comparable to that observed for typical homolytic mechanophores, supporting the mechanistic interpretation of homolytic bond scission under mechanical stress. C─C bond cleavage kinetic studies of PBIT under compression indicates that strong interchain interactions significantly increase the pressure needed to cleave the elongated C─C bonds. Additionally, PBIT polymer thin films are composited with polydimethylsiloxane to create free-standing and robust thin films, which can serve as ink-free and rewritable paper for writing and stress visualization applications. This advancement opens new possibilities for utilizing crystalline and brittle topochemical polymers in practical applications.
    Keywords:  composite films; mechanoresponsive materials; stress visualization; topochemical polymers
    DOI:  https://doi.org/10.1002/adma.202510482
  32. ACS Synth Biol. 2025 Sep 19.
    Genetically Encoded Control of In Vitro Transcription-Translation Coupled DNA Replication.
    Sebastian Barthel, Maximilian Hoffmann-Becking, Islomjon G Karimov, Tobias J Erb.
      The bottom-up reconstruction of cellular functions has gained increasing attention for studying biological complexity and for developing advanced biotechnological tools, including synthetic cells. A fundamental challenge is the ability to control and replicate DNA-encoded information within basic in vitro transcription-translation (IVTT) systems. Here, we constructed a transcription-translation coupled DNA replication (TTcDR) system that is based on a modified PURE (Protein synthesis Using Recombinant Elements) IVTT system and Φ29 DNA polymerase, which is controlled by external signals. To this end, we first established and characterized a PUREfrex 1.0-based TTcDR system. We then constructed and optimized TetR-based control of TTcDR activity, either by DNA-encoded TetR or by supplying purified TetR. Our final DNA-encoded TetR circuit allows ∼1000-fold DNA replication, ∼100-fold repression, and ∼4-fold induction with anhydrotetracycline. Our results demonstrate the potential and challenges of controlling in vitro DNA replication, for example, for the evolution of in vitro systems.
    Keywords:  PURE system; genetic circuit; genetically encoded system control; in vitro systems; synthetic cell; transcription−translation coupled DNA replication (TTcDR)
    DOI:  https://doi.org/10.1021/acssynbio.5c00477
  33. ACS Appl Mater Interfaces. 2025 Sep 14.
    Matrix-Engineered Self-Assembly of Fluorophores Based on Acidic Annealing for Robust Cellular Imaging.
    Xueshan Chen, Jie Tang, Lingqiao Zhang, Zhankuo Zhang, Jinyi Zhang, Chengbin Zheng.
      A key limitation of fluorescein derivatives is acid-induced aggregation, resulting in an inactivation. However, the aggregates obtained after acid annealing showed a 50-fold enhancement of fluorescence compared with the original powder. Herein, we incorporated a polymer or surfactant matrix into the acidic annealing procedure, and the self-assembling properties of fluorescein derivatives in the presence of the matrix are exploited to alter the molecular structure, thereby modifying the optical properties and ultimately producing fluorescent materials with enhanced brightness. Varying the type and concentration of dyes and matrices as well as the assembly time can modulate the geometry of the particles. These biocompatible particles exhibit efficient cellular uptake and superior imaging capabilities, positioning them as potent carriers for traceability. The stability of the assembly against light exposure and high temperatures demonstrates its practical application capabilities. By synergizing host-guest recognition with supramolecular engineering, this work not only redefines acid adaptation mechanisms but also establishes a universal design strategy for multifunctional supramolecular architecture, which expands applications in complex biological systems and opens new pathways for engineering advanced superstructures.
    Keywords:  acidic annealing; cellular imaging; fluorophores; matrix-engineered; self-assembly
    DOI:  https://doi.org/10.1021/acsami.5c12871
  34. Biomacromolecules. 2025 Sep 15.
    Collagen-Fibronectin Crosstalk in Engineered Matrices: Synergistic Assembly Orchestrates Fibrillar Morphogenesis and Cell Adhesion-Migration Dynamics.
    Yuan J Hou, Rui M Guo, Fang Li, De S Fan, Cheng Z Xu, Lian Zhu, Jun T Zhang, Ben M Wei, Hai B Wang.
      The cooperative interplay between type I collagen (COL) and fibronectin (FN) in the extracellular matrix (ECM) guides both matrix organization and cell behavior. While COL-based materials are widely used, their limited capacity to integrate FN-mediated regulatory cues restricts functional biomimicry. Here, we investigate how COL/FN composites in distinct assembly states (monomeric vs fibrillar) differentially regulate cellular responses. Biophysical characterization confirmed FN binding to COL α chains promotes coassembly into hybrid fibrils with accelerated kinetics and enhanced mechanical rigidity. Strikingly, HT1080 cells exhibited opposing adhesion behaviors on monomeric versus fibrillar COL/FN matrices. In monomeric matrices, escalating FN ratios progressively reduced adhesion, while in fibrillar matrices, low-FN ratios enhanced adhesion synergistically. Cell migration followed an inverse pattern, with monomeric hybrids promoting motility and fibrillar matrices suppressing it. Our findings highlight that COL/FN assembly states, independent of compositional changes, dictate cell-matrix reciprocity through structural reconfiguration. This work establishes a paradigm for engineering ECM-inspired materials with phase-specific topographies to guide cellular decision-making, advancing applications in tissue regeneration and mechanobiology studies.
    DOI:  https://doi.org/10.1021/acs.biomac.5c01404
  35. Nat Protoc. 2025 Sep 19.
    Aspiration-assisted bioprinting of spheroids.
    Myoung Hwan Kim, Ibrahim T Ozbolat.
      Aspiration-assisted bioprinting (AAB) is a versatile biofabrication technique that enables the precise and selective patterning of biologics, such as tissue spheroids and organoids, addressing limitations of conventional bioprinting techniques. AAB facilitates the fabrication of (1) tissues with physiologically relevant cell densities using spheroids and (2) advanced tissue models that replicate three-dimensional microenvironments essential for studying cellular responses, disease development and drug testing. Here we provide reliable and reproducible guidelines for the precise positioning of abovementioned biologics, incorporating two operational modes: (1) a single-nozzle mode for precise, one-by-one bioprinting and (2) a high-throughput mode using a digitally controllable nozzle array, enabling the rapid and simultaneous placement of multiple spheroids for scalable tissue fabrication. Comprehensive instructions are included for setting up the AAB platform, operating software and key operational procedures, including optimization of bioprinting conditions. This Protocol enables users to build and operate their own AAB platform depending on target applications, achieving fine control over spheroid positioning through successful aspiration and their precise placement under optimized conditions. This Protocol enables the setup of the AAB platform within 1-2 d. Bioprinting time varies depending on the number of spheroids to bioprint: the single-nozzle mode requires ~30 s per spheroid, while the high-throughput mode can print 64 spheroids in 3-4 min. Designed for accessibility and adaptability, this Protocol is suitable for users from a variety of backgrounds, including engineering, biology, pharmacy and medical sciences, who require bioprinting of spheroids for creating microphysiological systems for drug testing and disease modeling and implantable grafts for regenerative medicine.
    DOI:  https://doi.org/10.1038/s41596-025-01240-x
  36. Nat Electron. 2025 Aug;8(8): 721-737
    Monolithic three-dimensional neural probes from deterministic rolling of soft electronics.
    Yi Qiang, Wen Gu, Dongyeol Jang, Yieljae Shin, Delin Shi, Kyung Jin Seo, Gen Li, Sandra Vinnikova, Shiqiang Wu, Aditya Iyer, Pietro Artoni, Jaehyeon Ryu, Tianyu Bai, Vaishnavi Dhawan, Maria Medalla, Douglas L Rosene, Tara L Moore, Abigail N Koppes, Ryan Koppes, Jyun-You Liou, Chandramouli Chandrasekaran, Xinyan Tracy Cui, Shuodao Wang, Hui Fang.
      Cognition and behaviour rely on coordinated activity from neural circuits distributed across three-dimensions. However, typical probes for recording neural activity in the brain are limited to two-dimensional interfacing due to the planar semiconductor fabrication process. Here, we report a rolling-of-soft-electronics approach to create monolithic 3D neural probes with high scalability and design flexibility. Compared to previous stacking or assembly methods, the approach directly transforms a planar device into a 3D probe by leveraging the softness of flexible electrodes. The electrode shanks are initially fabricated in a single plane and then connected to flexible spacer. By varying features of the planar design, such as shank pitch and spacer layer thickness, the device can then be deterministically rolled into several versatile 3D probe designs containing hundreds of electrodes. With the system, we demonstrate single-unit spike recording in vivo in rodent and non-human primate models. We also show that the probe can provide microscopy-like 3D spatiotemporal mapping of spike activities in the rodent visual cortex, with five-week-long recording stability and promising 3D decoding performance of visual orientation.
    DOI:  https://doi.org/10.1038/s41928-025-01431-0
  37. ACS Nano. 2025 Sep 20.
    Multifunctional Physical and Chemical Stimuli Detection in Single-Module Device for Health Monitoring.
    Jianwei Zhang, Dong Li, Yanan Zhong, Wenchong Wang, Miao Wu, Kunli Cao, Jie Lu, Lizhen Huang, Yuan Fang, He Yang, Zhiqiang Liang, Lifeng Chi, Lin Jiang.
      Flexible multifunctional sensors that can perceive multiple human physiological and environmental stimuli simultaneously are of paramount importance for the advancement of smart health monitoring, human-machine interface, and intelligent robotics. Nevertheless, both the integration of single-function sensors into multifunctional devices and the development of single-module multifunctional sensors (SMS) remain extremely challenging due to difficulties in device structure design, functional integration, and controlled preparation of on-demand composite active materials. Herein, we demonstrate a single-module multifunctional sensor (SMS) based on three-dimensional (3D) printed graphene-based platform for the multifunctional detection of various physical and chemical stimuli that features structural and functional programmability. By integrating selected active materials into one graphene-based sensing platform, we developed multifunctional sensors with five functions that can sensitively monitor pulse rate, body temperature, sweat (Na+), gas (NO2), and light (solar UV radiation) simultaneously. The programmability of the structure and function of 3D-printed sensing materials, coupled with the modular device structure design, enables the integration of diverse functionalities according to various application scenarios, thus facilitating the development of smart healthcare wearables.
    Keywords:  health monitoring; multifunctional sensor; programmability; three-dimensional printing; wearable electronics
    DOI:  https://doi.org/10.1021/acsnano.5c09821
  38. Science. 2025 Sep 18. 389(6766): eadx2202
    Kinetic organization of the genome revealed by ultraresolution multiscale live imaging.
    Joo Lee, Liang-Fu Chen, Simon Gaudin, Kavvya Gupta, Ana Novacic, Andrew Spakowitz, Alistair Nicol Boettiger.
      Genome function requires regulated genome motion. However, tools to directly observe this motion in vivo have been limited in coverage and resolution. Here we introduce an approach to tile mammalian chromosomes with self-mapping fluorescent labels and track them at ultraresolution. We find that sequences separated by submegabase distances transition to proximity in tens of seconds. This rapid search is dependent on cohesin and is exhibited only within domains. Domain borders act as kinetic impediments to this search process, rather than structural boundaries. The genomic separation-dependent scaling of the search time for cis interactions violated predictions of diffusion, suggesting motor-driven folding. We also uncover cohesin-dependent processive motion at 2.7 kilobases per second. Together, these multiscale dynamics reveal the organization of the genome into kinetically associated domains.
    DOI:  https://doi.org/10.1126/science.adx2202
  39. bioRxiv. 2025 Sep 11. pii: 2025.09.10.674980. [Epub ahead of print]
    Engineered histones reshape chromatin in human cells.
    Siddhartha G Jena, Surya Nagaraja, Andrew S Earl, Amalia R Driller-Colangelo, Michael A Quezada, Ena Oreskovic, Max A Horlbeck, Ruochi Zhang, Wilson Gomarga, Jason D Buenrostro.
      Histone proteins and their variants have been found to play crucial and specialized roles in chromatin organization and the regulation of downstream gene expression; however, the relationship between histone sequence and its effect on chromatin organization remains poorly understood, limiting our functional understanding of sequence variation between distinct subtypes and across evolution and frustrating efforts to rationally design synthetic histones that can be used to engineer specified cell states. Here, we make the first advance towards engineered histone-driven chromatin organization. By expressing libraries of sequence variants of core histones in human cells, we identify variants that dominantly modulate chromatin structure. We further interrogate variants using a combination of imaging, proteomics, and genomics to reveal both cis and trans- acting mechanisms of effect. Functional screening with transcription factor libraries identifies transcriptional programs that are facilitated by engineered histone expression. Double mutation screens combined with protein language models allow us to learn sequence-to-function patterns and design synthetic histone proteins optimized to drive specific chromatin states. This work establishes a foundation for the high-throughput evaluation and engineering of chromatin-associated proteins and positions histones as tunable nodes for understanding and modulating mesoscale chromatin organization.
    DOI:  https://doi.org/10.1101/2025.09.10.674980
  40. bioRxiv. 2025 Sep 08. pii: 2025.09.08.674823. [Epub ahead of print]
    De novo design of semisynthetic protein nanopores.
    Lee Schnaider, A Katherine Hatstat, Alistair J Scott, Sophia K Tan, Richard G Hambley, William M Dawson, Rhys C Griffiths, Rian C Kormos, Arthur A Melo, Eric Tse, Nicholas F Polizzi, E Jayne Wallace, Gregory E Merz, William F DeGrado.
      Protein nanopores are essential components of single-molecule oligonucleotide sequencing and sensing devices. Here, we demonstrate that installing additional de novo subunits enables large-scale architectural changes of nanopore complexes. We design de novo proteins that integrate seamlessly with the CsgG pore to form 18-subunit, 315-kilodalton complexes with precisely sculpted pore architectures and tailored ion conduction, opening new possibilities for engineering enhanced nanopores with customized structural and functional properties.
    DOI:  https://doi.org/10.1101/2025.09.08.674823
  41. Mater Today Bio. 2025 Jun;32 101787
    A multifunctional living hydrogel for the synergistic management of infected diabetic wounds.
    Yanchi Liu, Mingrui Yang, Yuqiu Li, Yingyang Liu, Hongying Su, Wenping Zhang, Yuan Liu, Qiling Zhang, Chengxiao Wang.
      The primary causes of poor healing in diabetic wounds are bacterial infection, immune imbalance, and chronic inflammation. In this study, we employed the "fighting bacteria with bacteria" strategy to develop a dynamic living hydrogel system that comprehensively coordinates antibacterial, antioxidant, and regenerative functions for infectious diabetic wounds. Through engineered integration of functionalized probiotics and adaptive hydrogel networks, Lactobacillus rhamnosus CLK 101 (LRh) was biosynthesized with intracellular nano-selenium (nanoSe) and surface-coated with ceramide (CAD). The probiotics were then encapsulated within a biocompatible phospholipid polymer hydrogel that maintained probiotic viability. This living hydrogel system synergistically accelerated healing through multiple regulatory mechanisms. First, the probiotics exhibit inherent antibacterial properties, effectively eliminating Methicillin-resistant Staphylococcus aureus (MRSA) from the wound. Moreover, the intracellular nanoSe is released into the hydrogel, effectively scavenging excess reactive oxygen species (ROS). It also presents a synergistic effect with the probiotics by modulating macrophage polarization and reversing the inflammatory microenvironment of the wound. Finally, the ceramide coating plays a crucial role in restoring the barrier function of the skin. This novel strategy opens new avenues for living bacterial therapy as an effective treatment in the management of infected diabetic wounds.
    Keywords:  Diabetes; Infected wound healing; Living hydrogel; NanoSe; Probiotics
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101787
  42. Cell Syst. 2025 Sep 17. pii: S2405-4712(25)00224-8. [Epub ahead of print]16(9): 101391
    Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2.
    Roy A Ehling, Mason Minot, Max D Overath, Daniel J Sheward, Jiami Han, Beichen Gao, Joseph M Taft, Margarita Pertseva, Cédric R Weber, Lester Frei, Thomas Bikias, Ben Murrell, Sai T Reddy.
      The COVID-19 pandemic showcased a coevolutionary race between the human immune system and SARS-CoV-2, during which the immune system generated neutralizing antibodies targeting the SARS-CoV-2 spike protein's receptor-binding domain (RBD), crucial for host cell invasion, while the virus evolved to evade antibody recognition. Here, we establish a synthetic coevolution system combining high-throughput screening of antibody and RBD variant libraries with protein mutagenesis, surface display, and deep sequencing. Additionally, to significantly extend our interrogation of sequence space, we train a protein language model that predicts antibody escape to RBD variants and demonstrate its capability to generalize to a larger mutational load and mutations at positions unseen during training. Through explainable AI techniques, we probe the model and identify biologically meaningful coevolution trends. Synthetic coevolution reveals antagonistic and compensatory mutational trajectories of neutralizing antibodies and SARS-CoV-2 variants, enhancing the understanding of this evolutionary conflict.
    Keywords:  antibody engineering; deep learning; immune escape; machine learning; mammalian display; protein language models; synthetic coevolution; viral evolution; yeast display
    DOI:  https://doi.org/10.1016/j.cels.2025.101391
  43. ACS Appl Mater Interfaces. 2025 Sep 18.
    Development of Reversible Color-Changing Three-Dimensional Structures Using a Thermochromic Resin in Digital Light Processing-Based Vat Photopolymerization.
    Jae Won Choi, Cheol Woo Ha.
      The digital light processing-based vat photopolymerization (DLP-VPP) technology has demonstrated remarkable versatility and precision in producing complex structures across various fields. In this study, a thermochromic DLP-VPP system that achieves reversible color changes based on the temperature by combining thermochromic microcapsules (TM) with an acrylic photopolymer resin is proposed. Experiments are conducted to determine the optimal ratio of TM to achieve an ideal layer thickness without structural failure. The thermochromic properties of the TM resin composites are confirmed using differential scanning calorimetry and thermogravimetric analysis. Furthermore, experiments are performed to analyze the thermochromic reaction times at different heights, areas, and temperatures. Subsequently, a regression model is developed using machine learning techniques to predict the thermochromic reaction times. This study demonstrates the use of three-dimensional (3D) passive thermochromic sensors for visual temperature monitoring. Multimaterial DLP-VPP printing allows for the creation of 3D thermochromic QR codes, offering enhanced information security through temperature-dependent visibility. Overall, the proposed thermochromic DLP-VPP system has significant potential for applications in smart temperature sensors, anticounterfeiting, and cryptography. This study offers ideas for further research and development of functional materials for additive manufacturing.
    Keywords:  digital light processing (DLP); reversible color change; temperature-responsive devices; thermochromic; vat photopolymerization (VPP)
    DOI:  https://doi.org/10.1021/acsami.5c16395
  44. Nature. 2025 Sep 17.
    Covariation MS uncovers a protein that controls cysteine catabolism.
    Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.
      The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.
    DOI:  https://doi.org/10.1038/s41586-025-09535-5
  45. Nucleic Acids Res. 2025 Sep 05. pii: gkaf904. [Epub ahead of print]53(17):
    In vivo pathway optimization in yeast via loxpsym-mediated shuffling of upstream activating sequences.
    Ciaran Ruehmkorff, Ali Tafazoli Yazdi, Lena Hochrein.
      The budding yeast Saccharomyces cerevisiae plays an integral role in the bioeconomy as a powerful host for industrial bio-manufacturing, driving the production of diverse bio-based products. Achieving optimal product yields requires precise fine-tuning of the expression levels of multiple pathway genes, which often relies on cloning-intensive methods. Here, we present PULSE, an in vivo promoter engineering tool based on a streamlined workflow combining FACS-based screening of a randomized DNA library to identify active promoter elements, and their subsequent assembly into synthetic hybrid promoters where each element is flanked by loxPsym sites. Multiple promoter cassettes can be genome-integrated to generate "ready-to-use" platform strains, allowing users to easily place their genes of interest under the control of PULSE promoters. By activating Cre-mediated recombination, loxPsym-flanked promoter elements can be recombined, effectively bringing the target genes under control of a vast set of promoters spanning a wide range of expression levels in one simple step. Applying PULSE on two heterologous pathways, an eight-fold increase in β-carotene production and improved growth on high xylose concentrations by Saccharomyces cerevisiae was achieved. These results demonstrate the power and efficiency of PULSE as a versatile platform for metabolic engineering, enabling rapid, cloning-free optimization of biosynthetic pathways in vivo.
    DOI:  https://doi.org/10.1093/nar/gkaf904
  46. bioRxiv. 2025 Sep 01. pii: 2025.08.21.671434. [Epub ahead of print]
    STARNet enables spatially resolved inference of gene regulatory networks from spatial multi-omics data.
    Lei Hu, Shichen Zhang, Xuting Zhang, Yihai Luo, Haoteng Gu, Peng Liu, Sheng Mao, Li Chen, Yuhao Xia, Minghao Yang, Sai Zhang, Yaosen Min, Han Li, Peizhuo Wang, Hongtao Yu, Jianyang Zeng.
      Biological tissues are composed of distinct microenvironments that spatially orchestrate gene expression and cell identity. However, the regulatory principles governing domain-specific cellular functions remain poorly understood due to the lack of effective methods for mapping gene regulatory networks (GRNs) in situ . To address this gap, we introduce STARNet, a representation learning approach that leverages heterogeneous hypergraph modeling of spatial transcriptomic and epigenomic data to resolve tissue-domain-specific regulatory interactions. By integrating graph neural networks with contrastive learning in a self-supervised framework, STARNet learns unified embeddings that preserve both multi-modal molecular features and anatomical spatial context, enabling accurate and domain-resolved GRN reconstruction within complex tissues. Benchmarking on both simulated and real datasets demonstrates that STARNet achieves state-of-the-art performance. We further demonstrate its broad applicability across diverse biological contexts, including neural development, genetic disease risk, and drug-induced developmental toxicity. In the mouse brain, it delineates region-specific regulatory networks and reconstructs spatiotemporal programs underlying neural stem cell differentiation. In human genetics, it provides a mechanistic link between genotypes and phenotypes by showing how genome-wide association study (GWAS) variants for complex diseases perturb hippocampus-specific GRNs. In developmental toxicology, STARNet reveals that drug-induced disruptions of GRNs in defined embryonic regions underlie tissue-specific vulnerability. Collectively, STARNet offers a powerful and versatile framework for resolving the spatial regulatory logic of complex tissues, providing multi-angle insights into tissue patterning, development, and disease mechanisms.
    DOI:  https://doi.org/10.1101/2025.08.21.671434
  47. ArXiv. 2025 Sep 03. pii: arXiv:2509.03765v1. [Epub ahead of print]
    Randomness with constraints: constructing minimal models for high-dimensional biology.
    Ilya Nemenman, Pankaj Mehta.
      Biologists and physicists have a rich tradition of modeling living systems with simple models composed of a few interacting components. Despite the remarkable success of this approach, it remains unclear how to use such finely tuned models to study complex biological systems composed of numerous heterogeneous, interacting components. One possible strategy for taming this biological complexity is to embrace the idea that many biological behaviors we observe are "typical" and can be modeled using random systems that respect biologically-motivated constraints. Here, we review recent works showing how this approach can be used to make close connection with experiments in biological systems ranging from neuroscience to ecology and evolution and beyond. Collectively, these works suggest that the "random-with-constraints" paradigm represents a promising new modeling strategy for capturing experimentally observed dynamical and statistical features in high-dimensional biological data and provides a powerful minimal modeling philosophy for biology.
  48. Angew Chem Int Ed Engl. 2025 Sep 19. e202515264
    Ultraviolet and Visible Light-Responsive RNA Photofluids.
    Jia-Yao Wang, Ming-Di Gao, Chao-Yang Guan, Jin-Ying Qi, Nan-Nan Deng.
      Incorporating artificial molecular machines into soft matter offers a compelling strategy for engineering active materials with life-like behavior. Here, we report ultraviolet and visible light-responsive RNA photofluids formed via liquid-liquid phase separation of azobenzene-functionalized RNA nanomachines. These RNA photofluids can harness the molecular motions of RNA nanomachines to produce macroscopic cell-like behaviors under both ultraviolet and visible light irradiation. We show that the number of azobenzene moieties in the RNA nanomachines controls the deformation kinetics and critical transition temperatures between structural deformation and dissociation. The ultraviolet-visible RNA photofluids not only enable direct solar energy harvesting for light-powered soft robotics, but also expand the toolkit for developing advanced multi-responsive biomaterials and programmable artificial cells.
    Keywords:  Active matter; Azobenzene; Photofluids; RNA nanomachines; Synthetic cells
    DOI:  https://doi.org/10.1002/anie.202515264
  49. Matter. 2025 Sep 11. pii: 102413. [Epub ahead of print]
    Cell Contractile Forces Drive Spatiotemporal Morphogenesis in 4D Bioprinted Living Constructs.
    Aixiang Ding, David S Cleveland, Kaelyn L Gasvoda, Eben Alsberg.
      Current 4D materials typically rely on external stimuli such as heat or light to accomplish changes in shape, limiting the biocompatibility of these materials. Here, a composite bioink consisting of oxidized and methacrylated alginate (OMA), methacrylated gelatin (GelMA), and gelatin microspheres is developed to accomplish free-standing 4D bioprinting of cell-laden structures driven by an internal stimulus: cell-contractile forces (CCFs). 4D changes in shape are directed by forming bilayer constructs consisting of one cell-free and one cell-laden layer. Human mesenchymal stem cells (hMSCs) are encapsulated to demonstrate the ability to simultaneously induce changes in shape and chondrogenic/osteogenic differentiation. Finally, the capability to pattern each layer of the printed constructs is exhibited to obtain complex geometric changes, including bending around two separate, non-parallel axes. Bioprinting of such 4D constructs mediated by CCFs empowers the formation of more complex constructs, contributing to a greater degree of in vitro biomimicry of biological 4D phenomena.
    DOI:  https://doi.org/10.1016/j.matt.2025.102413
  50. Small. 2025 Sep 16. e07312
    3D-Printed Nitrogen-Doped Carbon Interlayers for Spatially Modulating Lithium-Sulfur Reactions.
    Zhilin Wu, Jingkang Li, Lixian Song, Haitao Hu, Yingze Song.
      The practical commercialization of lithium-sulfur (Li-S) batteries mainly confronts two fundamental obstacles associated with sulfur cathode: sluggish sulfur redox conversion kinetics and the detrimental polysulfide shuttling phenomenon. As an "external" optimization strategy, the functional interlayers demonstrate considerable promise for enhancing battery performance through sophisticated spatial-chemical multidimensional working mechanisms. Herein, a nitrogen-doped 3D carbon (3D-NC) functional interlayer is designed and fabricated by using direct ink writing (DIW) 3D printing technology. The precisely engineered 3D architecture provides abundant sulfur with active sites and establishes continuous 3D electron-conductive networks, effectively mitigating polysulfide migration while simultaneously optimizing sulfur conversion reaction kinetics. The resulting Li-S battery with a sulfur mass loading of 3.0 mg cm-2 delivers a specific exceptional capacity of 955.4 mA h g-1 at 0.2 C with outstanding capacity retention of 90.2% per cycle over 100 cycles. Furthermore, under the high sulfur mass loading of 8.3 mg cm-2 and lean electrolyte dosage of 5.0 µL mg-1, the Li-S battery still achieves a remarkable areal capacity of 6.0 mA h cm-2 and favorable lifespan.
    Keywords:  3D printing; Lithium–sulfur battery; direct ink writing; functional interlayer; sulfur conversion reaction
    DOI:  https://doi.org/10.1002/smll.202507312
  51. J Am Chem Soc. 2025 Sep 16.
    Sono-uncaging for Spatiotemporal Control of Chemical Reactivity.
    Erik Schrunk, Sunho Lee, Przemysław Dutka, Di Wu, Mikhail G Shapiro.
      Photo-uncaging─the use of light to reveal the active part of a chemical compound by photolysis of a protecting group─has long been used to study and actuate biochemical processes. However, light scattering limits the applications of photo-uncaging in opaque specimens or tissues. Here, we introduce sono-uncaging, a process in which a chemical functional group becomes exposed upon the application of ultrasound, which can be applied and focused in optically opaque materials. We engineered gas vesicles (GVs), air-filled protein nanostructures sensitive to ultrasound, to contain cysteines on their concealed inner surface, hypothesizing that the application of ultrasound would collapse the GV shell and reveal the cysteines. The resulting SonoCage construct reacted with monobromobimane (mBBr), a fluorogenic, thiol-reactive molecule, only after treatment with ultrasound, establishing the sono-uncaging proof of concept. We then demonstrated the spatial patterning capability of sono-uncaging by embedding the SonoCages in an mBBr-containing hydrogel and creating fluorescent patterns with phased array ultrasound. This patterning could be accomplished using a diagnostic imaging transducer with mild ultrasound conditions. This work establishes sono-uncaging as a method for spatiotemporal control over chemical reactivity using widely available ultrasound technology.
    DOI:  https://doi.org/10.1021/jacs.5c09181
  52. ACS Mater Au. 2025 Sep 10. 5(5): 878-885
    Lipid-Inspired Low Melting Ionic Liquids via Synergistic Cyclopropanation and Branching of Terpenoids.
    Muhammadiqboli Musozoda, Richard A O'Brien, Zachary J Metott, Raychell A Jerdo, Christopher M Butch, Matthias Zeller, Gregory R Boyce, Patrick C Hillesheim, Arsalan Mirjafari.
      Bacteria employ cyclopropane motifs as bioisosteres for unsaturations to modulate lipid bilayer fluidity and protect cellular membranes under environmental stress. Drawing inspiration from this biological strategy, we investigated how cyclopropanation impacts the thermophysical properties of lipid-inspired ionic liquids. We synthesized a series of imidazolium-based ionic liquids incorporating cyclopropanated derivatives of three renewable terpenoids: phytol, farnesol, and geraniol. Through an integrated approach combining property-driven design, thermophysical analysis, X-ray crystallography, and computational modeling, we systematically examined how these structural modifications influence quantitative structure-property relationships. Our findings demonstrate that ionic liquids with long alkyl appendages respond to side-chain modificationsparticularly the synergistic combination of cyclopropanation and branchingin a manner that mimics homeoviscous adaptation in living organisms. The strategic incorporation of cyclopropyl moieties combined with chiral methyl branching produced dramatic melting point depressions, with phytol-derived ionic liquids achieving the lowest melting points reported to date for these bioinspired materials. This effectiveness results from positioning these structural elements within the symmetry-breaking region of alkyl chains, where they maximally disrupt molecular packing and enhance fluidity. X-ray crystallographic analysis of a cyclopropanated citronellyl-based ionic liquid revealed that the cyclopropyl ring induces significant conformational distortions that prevent efficient molecular organization. The use of terpenoids from the chiral pool as starting materials imparts inherent sustainability to these ILs. Enantiopure ILs can be synthesized from renewable feedstocks like phytol and citronellol while exploiting bioinspired structural design principles. This work provides new insights into IL structure-property relationships that both complement and extend previous discoveries, establishing a framework for the rational design of lipidic ionic liquid systems with enhanced fluidity and chemical stability from renewable resources.
    Keywords:  bioinspired materials; chiral materials; cyclopropane; ionic liquids; lipid-like ionic liquids; molecular engineering; structure−property relationship
    DOI:  https://doi.org/10.1021/acsmaterialsau.5c00089
  53. Nat Rev Drug Discov. 2025 Sep 17.
    RNA modification systems as therapeutic targets.
    Linda Zhang, Jiangbo Wei, Zhongyu Zou, Chuan He.
      Ribonucleotide bases can be chemically modified by cellular enzymes such as methyltransferases to regulate RNA metabolism and biological processes. The association between abnormal levels of RNA modification effector proteins and human diseases has spurred interest in therapeutic targeting of RNA modification systems, and an agent that inhibits the RNA-methylating enzyme METTL3 has entered clinical trials. Despite the promise of these pathways, therapeutic agents targeting proteins that write, read and erase RNA modifications are still limited. In this Review, we describe the cellular functions and disease associations of proteins that regulate RNA modifications. We focus on the N6-methyladenosine pathway, highlighting early-stage advances in inhibitor development such as against the YTH reader proteins, but we also discuss the potential of targeting other RNA modification pathways. Targeting RNA modification systems offers a new strategy for treating cancer, improving immunotherapy and enhancing stem cell therapies.
    DOI:  https://doi.org/10.1038/s41573-025-01280-8
  54. PLoS Comput Biol. 2025 Sep 16. 21(9): e1013300
    NeKo: A tool for automatic network construction from prior knowledge.
    Marco Ruscone, Eirini Tsirvouli, Andrea Checcoli, Denes Turei, Emmanuel Barillot, Julio Saez-Rodriguez, Loredana Martignetti, Åsmund Flobak, Laurence Calzone.
      Biological networks provide a structured framework for analyzing the dynamic interplay and interactions between molecular entities, facilitating deeper insights into cellular functions and biological processes. Network construction often requires extensive manual curation based on scientific literature and public databases, a time-consuming and laborious task. To address this challenge, we introduce NeKo, a Python package to automate the construction of biological networks by integrating and prioritizing molecular interactions from various databases. NeKo allows users to provide their molecules of interest (e.g., genes, proteins or phosphosites), select interaction resources and apply flexible strategies to build networks based on prior knowledge. Users can filter interactions by various criteria, such as direct or indirect links and signed or unsigned interactions, to tailor the network to their needs and downstream analysis. We demonstrate some of NeKo's capabilities in two use cases: first we construct a network based on transcriptomics from medulloblastoma; in the second, we model drug synergies. NeKo streamlines the network-building process, making it more accessible and efficient for researchers.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013300
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