bims-enlima Biomed News
on Engineered living materials
Issue of 2025–09–07
fifty-six papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. The role of non-linear viscoelastic hydrogel mechanics in cell culture and transduction.
  2. Revisiting the biophysical aspects of extracellular-matrix-mimicking hydrogels: what cells see vs. what cells feel.
  3. Tunable photoinitiated hydrogel microspheres for quantifying cell-generated forces in complex three-dimensional environments.
  4. Polydopamine-Coating Nanoarchitectonics of Cellulose Hydrogels with Promoted Sustainable and Alkali-Resistant Natures for 3D Cell Culture Application.
  5. Diversifying Substrates and Reaction Conditions for Polymerase Strand Recycling.
  6. Human progenitor T-cell differentiation regulated by the mechanical resistance of thymus-mimetic extracellular matrices.
  7. One-pot cloning and protein expression platform for genetic engineering.
  8. Reversible self-assembly of small molecules for recyclable solid-state battery electrolytes.
  9. Magnetic decoupling as a proofreading strategy for high-yield, time-efficient microscale self-assembly.
  10. 3D printed anisotropic tissue simulants with embedded fluid capsules for medical simulation and training.
  11. Soft Robotic Engines with Non-Reciprocal Motion by Physical Intelligence.
  12. Photodegradable Hydrogel Matrices for Spatiotemporal Control of Bacteria Transport and Delivery.
  13. Chemists cram record nine metals into trendy 2D material.
  14. From sequence to scaffold: computational design of protein nanoparticle vaccines from AlphaFold2-predicted building blocks.
  15. Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
  16. Complementary biomolecular coassemblies direct energy transport for cardiac photostimulators.
  17. Active learning-guided optimization of cell-free biosensors for lead testing in drinking water.
  18. Consecutive Hybrid Bioprinting of Microfiber-Reinforced Living Muscle Constructs with Highly-Aligned Cellular Organizations.
  19. Imparting new stimuli-responsive behaviors in protein-polymers via self-immolative linker conjugation.
  20. Internal Delivery and Transport within Cellular Aggregates via Perfusable Glass-Sheathed Hydrogel Microtubes.
  21. A Single Mutation in the "DSL" Motif of the Acyl Carrier Protein Can Prevent Its In Vivo Phosphopantetheinylation by E. coli Holo-Acyl Carrier Protein Synthase (AcpS).
  22. Origami frustration and its influence on energy landscapes of origami assemblies.
  23. Self-Regulating Hydrogel Actuators.
  24. Protocol for label-free ribosome-associated protein enrichment from mammalian cells by RAPIDASH.
  25. Engineering Bacteria as Living Therapeutics in Cancer Therapy.
  26. Cation-Controlled Assembly, Activity, and Organization of Biomimetic DNA Receptors in Synthetic Cell Membranes.
  27. Bioorthogonal Mussel-Inspired Elastin-like Nanocoatings for Indwelling Devices.
  28. GCAD: a Computational Framework for Mammalian Genetic Program Computer-Aided Design.
  29. Supervised learning in DNA neural networks.
  30. Bioinspired micro-nano photonic materials.
  31. Achieving Mechanical Evolution in Polymer Materials Through Phase Evolution Induced by Visible Light.
  32. The viscoelastic living matter from biomolecular condensates to tissues: Comment on "viscoelastic mechanics of living cells" by Zhou et al.
  33. Adaptive and context-aware volumetric printing.
  34. Simple Two-Component CDs/PVA Hydrogels Possess Dynamic High-Definition and Two-Stage Information Encryption Capability.
  35. Combing Directed Enzyme Evolution with Metabolic Engineering to Develop Efficient Microbial Cell Factories.
  36. Modular multi-enzyme cascades enable green and sustainable synthesis of non-canonical amino acids from glycerol.
  37. Hierarchical Assembly of Proteinosomes and Coacervates Communities into 3D Protocellular Networks.
  38. Biohybrid corneal stromal tissue formation using keratocytes encapsulated in supramolecular microgels.
  39. Strategies for fabricating aligned nano- and microfiber scaffolds: an overview for cell culture applications.
  40. Spatial joint profiling of DNA methylome and transcriptome in tissues.
  41. A general genome editing strategy using CRISPR lipid nanoparticle spherical nucleic acids.
  42. Tissue-specific mRNA delivery and prime editing with peptide-ionizable lipid nanoparticles.
  43. Magnetic activation of spherical nucleic acids enables the remote control of synthetic cells.
  44. Squidiff: Predicting cellular development and responses to perturbations using a diffusion model.
  45. Write and Read: Harnessing Synthetic DNA Modifications for Nanopore Sequencing.
  46. Capillary interactions drive the self-organization of bacterial colonies.
  47. Engineering filamentous myosins for optical control of contractility.
  48. PTMs as molecular encoders: reprogramming chaperones into epichaperomes for network control in disease.
  49. Gene regulatory network structure informs the distribution of perturbation effects.
  50. 3D-printable bio-sourced nanocomposite hydrogels based on two polysaccharide components: hydroxypropyl guar macromolecules and cellulose nanocrystals.
  51. Cleavable Additives for Deconstructable, Recyclable Polyurethane Thermosets.
  52. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  53. Investigating the Impact of Various 2D and 3D Cell Culture Platforms on the Production of Extracellular Vesicles.
  54. Engineering chimeric signaling proteins for microbial whole-cell biosensors: from design to deployment.
  55. Photoactivatable Synthetic Exosomes for RNA-Based Communication Between Artificial Cells and Living Cells.
  56. A host/guest assembled hyaluronic acid-based supramolecular hydrogel with NIR-steered degradation capacity for enhanced tumor therapy through programmable drug release.
  1. Mater Today Bio. 2025 Oct;34 102188
    The role of non-linear viscoelastic hydrogel mechanics in cell culture and transduction.
    Pascal Bertsch, Pasquale Sacco.
      The mechanical complexity of the extracellular matrix (ECM) is central to how cells sense and respond to their environment, yet hydrogel design has often focused narrowly on stiffness. Emerging evidence highlights the importance of viscoelastic stress relaxation and plasticity in cell mechanotransduction. However, a key aspect remains underexplored: non-linear viscoelasticity, where stress relaxation and plasticity depend on the magnitude of applied stress or strain. In this perspective, we examine how such non-linear mechanical behaviors manifest in widely used hydrogels and discuss their biological relevance. We present experimental approaches, including oscillatory shear rheology, to detect non-linear viscoelastic effects, and introduce mathematical modeling approaches to interpret these behaviors. We find evidence in literature that several hydrogels commonly used in cell culture exhibit non-linear viscoelasticity occurring at stress and strain levels relevant to cell-generated forces. Specifically, both softening and stiffening hydrogels were found to exhibit accelerated stress relaxation or increased plasticity due to nonlinear viscoelasticity. By viewing non-linearity as a tunable design parameter, future hydrogel systems may better recapitulate the dynamic mechanical feedback loops cells experience in native tissues. This perspective encourages a paradigm shift in biomaterial design, integrating non-linear viscoelasticity into the next generation of ECM-mimetic hydrogels for cell culture and regenerative applications.
    Keywords:  Cell biology; Hydrogels; Mathematical modelling; Mechanotransduction; Non-linear viscoelasticity; Rheology
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102188
  2. Biomater Sci. 2025 Aug 28.
    Revisiting the biophysical aspects of extracellular-matrix-mimicking hydrogels: what cells see vs. what cells feel.
    Jingchao Sui, Sarah Pragnere, Nicholas A Kurniawan.
      The extracellular matrix (ECM) is critical in regulating cell behavior and tissue function. This recognition has driven the development of ECM surrogates to better understand cell-ECM interactions and advance biomedical applications. Hydrogels are promising candidates for this purpose due to their biocompatibility, tunability, and ability to embed cells in 3D environments. While early efforts in the design of ECM-mimicking hydrogels focused on macromolecular type, it is now clear that their biophysical parameters, such as polymer molecular weight, fibrous versus non-fibrous structures, pore size, and mechanical properties, significantly influence cell behavior. Understanding the interplay of these factors is crucial for the rational design of biomaterials, but remains challenging given the complexity of hydrogel systems and the rapid pace of new findings. This review critically evaluates hydrogels as ECM mimics for 3D cell cultures. We revisit key ECM properties to replicate, examine how hydrogel design can meet these needs, and summarize the impact of biochemical, structural, and mechanical features on cell behavior. We also explore how structural and mechanical properties-what cells "see" and "feel"-are interrelated and jointly affect cell function. Our analysis concludes that strategic combinations of polymeric materials will play an important role for next-generation hydrogels to replicate physiological conditions and independently enable precise control over key parameters. These advancements will enhance our understanding of cell-ECM interactions and support the development of innovative biomaterials for tissue engineering and regenerative medicine.
    DOI:  https://doi.org/10.1039/d5bm00210a
  3. Acta Biomater. 2025 Aug 27. pii: S1742-7061(25)00634-8. [Epub ahead of print]
    Tunable photoinitiated hydrogel microspheres for quantifying cell-generated forces in complex three-dimensional environments.
    Antoni Garcia-Herreros, Yi-Ting Yeh, Yunpeng Tu, Adithan Kandasamy, Juan C Del Alamo, Ernesto Criado-Hidalgo.
      We present a high-throughput method using standard laboratory equipment and microfluidics to produce cellular force microscopy probes with controlled size and elastic modulus. Mechanical forces play crucial roles in cell biology but quantifying these forces in physiologically relevant systems remains challenging due to the complexity of the native cell environment. Polymerized hydrogel microspheres offer great promise for interrogating the mechanics of processes inaccessible to classic force microscopy methods. However, despite significant recent advances, their small size and large surface-to-volume ratio impede the high-yield production of probes with tunable, monodisperse distributions of size and mechanical properties. To overcome these limitations, we use a flow-focusing microfluidic device to generate large quantities of droplets with highly reproducible, adjustable radii. These droplets contain acrylamide gel precursor and the photoinitiator Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as a source of free radicals. LAP provides fine control over microsphere polymerization due to its high molar absorptivity at UV wavelengths and moderate water solubility. The polymerized microspheres can be functionalized with different conjugated extracellular matrix proteins and embedded with fluorescent nanobeads to promote cell attachment and track microsphere deformation. As proof of concept, we measure the mechanical forces generated by a monolayer of vascular endothelial cells engulfing functionalized microspheres. Individual nanobead motions are tracked and analyzed to determine 3D traction forces via direct computation of stress from measured strain. These results reveal that the cell monolayer collectively exerts strong radial compression on the encapsulated probe, suggesting new biomechanical functions of endothelial cells that could modulate diapedesis or pathogen internalization. STATEMENT OF SIGNIFICANCE: Mechanical forces are crucial to many cell biology processes but quantifying them in complex native environments remains challenging. We address this by introducing linearly elastic probes with known mechanical properties, whose deformations can be accurately measured to infer local stresses. Specifically, we present a high-throughput method for producing polyacrylamide (PAAm) hydrogel microspheres embedded with fluorescent nanoparticles. To measure cell-generated forces in physiologically relevant systems, the probes are tracked using a 3D coherent point drift algorithm, yielding high-resolution deformation data with minimal computational cost. This method overcomes key barriers in PAAm microsphere fabrication by ensuring monodisperse size, tunable stiffness, and simple, reproducible processes suitable for most cell biology labs-making it a powerful tool for studying cellular mechanobiology.
    Keywords:  Cell mechanics; Cellular force probes; Mechanobiology; Microfabrication; Microfluidics; Polyacrylamide; Three dimensional hydrogels; Traction force microscopy
    DOI:  https://doi.org/10.1016/j.actbio.2025.08.041
  4. ACS Appl Mater Interfaces. 2025 Sep 04.
    Polydopamine-Coating Nanoarchitectonics of Cellulose Hydrogels with Promoted Sustainable and Alkali-Resistant Natures for 3D Cell Culture Application.
    Yurina Sekine, Michiyo Honda, Asako Sugita, Takuya Nankawa, Rimi Sakanaka, Tomoko Ikeda-Fukazawa, Katsuhiko Ariga.
      Sustainable and chemically resilient hydrogels are critically needed in biointerface engineering, particularly for 3D cell culture systems and surface modification under physiological to mildly alkaline conditions. However, physically cross-linked cellulose nanofiber (CNF) hydrogels─despite their renewable origin and biocompatibility─typically disintegrate at pH > 8, limiting their use in polydopamine (PDA)-based surface functionalization. Here, we present a simple and scalable physical treatment strategy to fabricate alkali-resistant, physically cross-linked hydrogels from carboxymethyl cellulose nanofibers (CMCF). By combining freeze-drying with mild thermal annealing (70 °C), the hydrogel network undergoes partial dehydration and ester bond formation via mild thermal condensation between carboxyl and hydroxyl groups, resulting in enhanced internal densification while preserving porosity and rehydration capacity. The resulting hydrogels remain structurally intact in Tris buffer (pH 9.7) and allow uniform in situ PDA coating at pH 8.5 on a physically cross-linked CMCF scaffold. The PDA-functionalized hydrogels exhibit interconnected porous microstructures, high water content (∼97 wt %), and robust mechanical and chemical stability. They support long-term 3D culture of EGFP-expressing human dermal fibroblasts for over 30 days, demonstrating excellent cytocompatibility and deep cell infiltration. This sustainable platform bridges green material design with functional surface engineering under alkaline conditions, and offers a versatile foundation for applications in regenerative medicine, selective ion adsorption, and environmental remediation.
    Keywords:  3D cell culture; carboxymethyl cellulose nanofibers; freeze-drying; heat treatment; hydrogel stability; polydopamine coating
    DOI:  https://doi.org/10.1021/acsami.5c14529
  5. ACS Synth Biol. 2025 Sep 03.
    Diversifying Substrates and Reaction Conditions for Polymerase Strand Recycling.
    Yueyi Li, Arno Gundlach, Andrew Ellington, Julius B Lucks.
      Cell-free biosensing systems are being engineered as versatile and programmable diagnostic technologies. A core component of cell-free biosensors is programmable molecular circuits that improve biosensor speed, sensitivity, and specificity by performing molecular computations such as logic evaluation and signal amplification. In previous work, we developed one such circuit system called Polymerase Strand Recycling (PSR), which amplifies cell-free molecular circuits by using T7 RNA polymerase off-target transcription to recycle nucleic acid inputs. We showed that PSR circuits can be configured to detect RNA target inputs as well as be interfaced with allosteric transcription factor-based biosensors to amplify signals and enhance sensitivity. Here we expand the development of PSR circuit empirical design guidelines to generalize the platform for detecting a diverse set of microRNA inputs. We show that PSR circuit function can be enhanced through engineering T7 RNAP, and we present troubleshooting strategies to optimize PSR circuit performance.
    Keywords:  PSR; cell-free biosensors; sensitization; signal amplification; strand displacement circuits; synthetic biology
    DOI:  https://doi.org/10.1021/acssynbio.5c00207
  6. bioRxiv. 2025 Aug 27. pii: 2025.08.27.671384. [Epub ahead of print]
    Human progenitor T-cell differentiation regulated by the mechanical resistance of thymus-mimetic extracellular matrices.
    Nicholas Jeffreys, Kyle T Ruark, Joshua M Price, Ella M Serrano-Wu, Blake Hanan, Andrew S Khalil, Wei-Hung Jung, Nuria Lafuente-Gómez, Joshua M Brockman, Andrew Lu, Izabela Zmirska, Kyle H Vining, Junzhe Lou, Kwasi Adu-Berchie, Siyoon Kwon, Hamza Ijaz, Azeem Sharda, David T Scadden, David J Mooney.
      Therapeutic T-cell engineering ex vivo from human hematopoietic stem cells (HSCs) focuses on recapitulating notch1-signaling and α4β1-integrin-mediated adhesion within the thymic niche with supportive stromal cell feeder-layers or surface-immobilized recombinant protein-based engineered thymic niches (ETNs). The relevant Notch1-DLL-4 and α4β1-integrin-VCAM-1 interactions are known to respond to mechanical forces that regulate their bond dissociation behaviors and downstream signal transduction, yet manipulating the mechanosensitive features of these key receptor-ligand interactions in thymopoiesis has been largely ignored in current ETN designs. Here, we demonstrate that human T-cell development from cord blood-derived CD34 + HSCs is regulated via molecular cooperativity in notch1 and integrin-mediated mechanotransduction. Mechanically confining interpenetrating network (IPN) hydrogel-based 3D cell culture comprised of collagen type I and alginate polysaccharides functionalized with DLL-4 and VCAM-1 is used as a model viscoelastic 3D ETN to manipulate human progenitor (pro)T-cell differentiation. This ETN enables orthogonal control of the mechanical and biomolecular features of the thymic niche, including thymopoietic ligand density, modulus, and viscoelastic properties (e.g., stress relaxation kinetics). We identify that soft, viscous matrices that enhance activation of the notch1-pathway, and subsequently notch1 intracellular domain (NICD) nuclear import sustain the T-cell development gene regulatory network during proT-cell differentiation. Conversely, stiff, elastic matrices inhibit HSC commitment to the T-lineage, and rather promotes Myeloid-cell differentiation. Our observations indicate mechanical reciprocity in signaling pathways indispensable to thymopoiesis, and highlights extracellular matrix mechanics as a variable in controlling hematopoietic stem cell fate decisions.
    DOI:  https://doi.org/10.1101/2025.08.27.671384
  7. bioRxiv. 2025 Aug 29. pii: 2025.08.28.672974. [Epub ahead of print]
    One-pot cloning and protein expression platform for genetic engineering.
    Wakana Sato, Judee Sharon, Brock Cash, Christopher Deich, Nathaniel J Gaut, Joseph Heili, Aaron E Engelhart, Katarzyna P Adamala.
      In this work, we present a streamlined one-pot cloning and protein expression platform that integrates mutagenesis, plasmid assembly, and functional protein testing in a single reaction. By combining Golden Gate cloning with cell-free transcription-translation, we demonstrate efficient generation and screening of genetic variants without the need for intermediate purification or bacterial amplification. Using fluorescent proteins, luciferase enzymes, antibiotic-converting enzymes, and the violacein biosynthetic pathway, we validate the versatility of this approach for single-and multi-site mutagenesis, combinatorial variant libraries, metabolic pathway programming, and whole-plasmid assembly. By demonstrating compatibility with multiplexed reactions and multi-cistronic constructs, we establish this approach as a generalizable and automatable method for high-throughput cloning and protein engineering in synthetic biology.
    DOI:  https://doi.org/10.1101/2025.08.28.672974
  8. Nat Chem. 2025 Aug 28.
    Reversible self-assembly of small molecules for recyclable solid-state battery electrolytes.
    Yukio Cho, Cole D Fincher, Guillaume Lamour, Ty Christoff-Tempesta, Xiaobing Zuo, Yet-Ming Chiang, Julia H Ortony.
      Performance often overshadows recyclability in contemporary battery designs, leading to sustainability challenges. Preemptive strategies integrating recyclable chemistry from the outset are thus increasingly critical for addressing the complexities in conventional recycling. Here we harness bio-inspired molecular self-assembly to create inherently recyclable battery materials. We use aramid amphiphiles that self-assemble in water through strong, collective hydrogen bonding and π-π stacking, forming air-stable, high-aspect-ratio nanoribbons with gigapascal-level stiffness. When processed into bulk solid-state electrolytes, these nanoribbons retain their ordered molecular arrangement and exhibit total conductivities of 1.6 × 10-4 S cm-1 at 50 °C, Young's moduli of 70 MPa and toughness values of 1 MJ m-3, despite being stabilized solely by reversible non-covalent bonds. We further demonstrate clean separation of battery components by exposing used cells to an organic solvent, which disrupts the non-covalent cohesion and reverts all battery components to their original forms. This study underscores the potential of molecular self-assembly for specialized recyclable designs in energy storage applications.
    DOI:  https://doi.org/10.1038/s41557-025-01917-6
  9. Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2502361122
    Magnetic decoupling as a proofreading strategy for high-yield, time-efficient microscale self-assembly.
    Zexi Liang, Melody Xuan Lim, Qian-Ze Zhu, Francesco Mottes, Jason Z Kim, Livia Guttieres, Conrad Smart, Tanner Pearson, Chrisy Xiyu Du, Michael Brenner, Paul McEuen, Itai Cohen.
      Life thrives due to its remarkable ability to create complex structures through the self-assembly of proteins, nucleic acids, and other biomolecules. Achieving such complex assemblies with the same level of fidelity, reproducibility, and advanced functionality in synthetic systems, however, has remained a grand challenge. One outstanding problem is the presence of parasitic products and long-lived intermediate states that slow the reaction process and limit the yield of the final product. Biology overcomes this challenge by proofreading to recognize and disassemble parasitic products. Such local checks, however, are currently difficult to implement in available self-assembly platforms. Here, we overcome this challenge by implementing a proofreading mechanism in a self-assembly platform. Specifically, we design intermediate states that strongly couple to an external force but a final product that is decoupled and thus highly stable to external driving, such that application of external forces selectively dissociates parasitic products. To implement this idea, we introduce lithographically patterned magnetic dipoles and an applied magnetic field to drive an assembly process similar to thermal self-assembly, but with additional controls. By applying patterns of magnetic driving that selectively destabilize parasitic states, we effectively implement a proofreading strategy to enable high-yield, time-efficient self-assembly. This realization of a general proofreading mechanism bridges the gap between artificial and biological self-assembly, paving the way for advanced self-assembled materials, with applications in next generation responsive materials, biomimetic devices, and microscale machines.
    Keywords:  kinetic proofreading; magnetic decoupling; selective dissociation; self-assembly
    DOI:  https://doi.org/10.1073/pnas.2502361122
  10. Sci Adv. 2025 Aug 29. 11(35): eadw6446
    3D printed anisotropic tissue simulants with embedded fluid capsules for medical simulation and training.
    Adarsh Somayaji, Matthew S Lawler, Alex T Gong, Zachary J Fuenning, Victoria A Roach, Athira B S, David J Traina, Jason R Speich, Ruikang K Wang, Matthew G Hackett, David M Hananel, Robert M Sweet, Michael C McAlpine.
      Human tissues are primarily composed of collagen and elastin fiber networks that exhibit directional mechanical properties that are not replicable by conventional tissue simulants manufactured via casting. Here, we 3D print tissue simulants that incorporate anisotropic mechanical properties through the manipulation of infill voxel shape and dimensions. A mathematical model for predicting the anisotropy of single- and multimaterial structures with orthogonal infill patterns is developed. We apply this methodology to generate conformal printing toolpaths for replicating the structure and directional mechanics observed in native tissue within 3D printed tissue simulants. Further, a method to embed fluid-filled capsules within the infill structure of these tissue simulants to mimic blood is also presented. The improvements in simulation quality when using 3D printed anisotropic tissue simulants over conventional tissue simulants are demonstrated via a comparative acceptability study. These advances open avenues for the manufacture of next-generation tissue simulants with high mechanical fidelity for enhanced medical simulation and training.
    DOI:  https://doi.org/10.1126/sciadv.adw6446
  11. Adv Mater. 2025 Sep 01. e11630
    Soft Robotic Engines with Non-Reciprocal Motion by Physical Intelligence.
    Oliver Skarsetz, Piet J M Swinkels, Jacqueline Figueiredo da Silva, Giulia Vozzolo, Marcos Masukawa, Giorgio Fusi, Brigitta Dúzs, Yanis Lassiat, Christoph Drees, Viacheslav Slesarenko, Andreas Walther.
      Movement is essential for living systems, enabling access to food, habitats, or escape from threats. Across scales, a key unifying principle is symmetry breaking to achieve non-reciprocal motion and accumulate work. In soft robotics, many actuators mimic biological responsiveness, but they typically exhibit reciprocal motion, where forward work is canceled in the return stroke - preventing work accumulation in cyclic operation. Here, a simple and broadly applicable hydrogel engine concept is presented that overcomes this limitation by encoding kinetic asymmetry into swelling and deswelling transitions. This hard-coded asymmetry yields non-reciprocal motion trajectories, enabling continuous mechanical work extraction under a single, uniform stimulus - without complex external control. The strategy embodies a material-based ratchet mechanism rooted in physical intelligence, independent of geometry or scale, and generalizable across stimuli. This hydrogel engine is implemented in soft robotic systems, including artificial cilia for fluid pumping and conveyor belts for object transport. Starting from macroscopic thermoresponsive systems, the design is extended to microscale formats via 3D printing and to other stimuli-responsive materials. This approach shifts the paradigm in soft robotics - from increasing chemical complexity to leveraging intrinsic material properties for emergent function - paving the way for scalable, autonomous systems driven by physical intelligence.
    Keywords:  adaptive materials; embodied intelligence; hydrogels; intelligent matter; soft robotics
    DOI:  https://doi.org/10.1002/adma.202511630
  12. ACS Appl Mater Interfaces. 2025 Sep 02.
    Photodegradable Hydrogel Matrices for Spatiotemporal Control of Bacteria Transport and Delivery.
    Jeffrey A Reed, Scott T Retterer, Ryan R Hansen.
      Stimuli-responsive hydrogels that provide controlled degradation can be used as bacteria delivery systems for advanced therapeutic applications. Here, we report the first use of photodegradable hydrogels as materials that can direct bacterial movement, tune mean bacteria speed, and control bacteria delivery through spatiotemporal control of degradation. Hydrogels were formed using base-catalyzed Michael addition reactions between photodegradable poly(ethylene glycol) (PEG) o-nitrobenzyl diacrylate macromers and PEG tetra-thiol cross-linkers within microfluidic channels. Nutrient gradients were generated across the channel, and micron-scale regions of the hydrogel were partially degraded by exposure to controlled doses (2.1-168 mJ/mm2) of patterned 365 nm light. Hydrogel degradation was then characterized in situ using fluorescence visualization of fluorescein-labeled hydrogels. Following characterization, Bacillus subtilis expressing green fluorescent protein was introduced into the device, and its movement up the nutrient gradient was monitored using time-lapse fluorescence microscopy to enable a systematic study of bacteria chemotaxis through the hydrogels at varied levels of degradation. B. subtilis showed minimal adhesion to partially degraded PEG hydrogels, and bacteria mean speed and mean directional change were tunable according to the level of hydrogel photodegradation, with a 2.6-fold difference in mean cell speed measured across the partially degraded hydrogel regions. Finally, the ability to alter bacteria speed and directionality through tunable degradation and without significant adhesion was used to achieve controlled release profiles of bacteria to delivery sites. These findings advance the use of PEG-based hydrogel materials as delivery vehicles for bacterial therapeutic applications and other living material applications that require controlled bacteria transport.
    Keywords:  bacteria; biotherapeutics; chemotaxis; hydrogels; living materials; photodegradation; poly(ethylene glycol)
    DOI:  https://doi.org/10.1021/acsami.5c14670
  13. Nature. 2025 Sep 04.
    Chemists cram record nine metals into trendy 2D material.
    Katherine Bourzac.
      
    Keywords:  Chemistry; Materials science
    DOI:  https://doi.org/10.1038/d41586-025-02839-6
  14. bioRxiv. 2025 Aug 20. pii: 2025.08.20.671178. [Epub ahead of print]
    From sequence to scaffold: computational design of protein nanoparticle vaccines from AlphaFold2-predicted building blocks.
    Cyrus M Haas, Naveen Jasti, Annie Dosey, Joel D Allen, Rebecca Gillespie, Jackson McGowan, Elizabeth M Leaf, Max Crispin, Cole A DeForest, Masaru Kanekiyo, Neil P King.
      Self-assembling protein nanoparticles are being increasingly utilized in the design of next-generation vaccines due to their ability to induce antibody responses of superior magnitude, breadth, and durability. Computational protein design offers a route to novel nanoparticle scaffolds with structural and biochemical features tailored to specific vaccine applications. Although strategies for designing new self-assembling proteins have been established, the recent development of powerful machine learning-based tools for protein structure prediction and design provides an opportunity to overcome several of their limitations. Here, we leveraged these tools to develop a generalizable method for designing novel self-assembling proteins starting from AlphaFold2 predictions of oligomeric protein building blocks. We used the method to generate six new 60-subunit protein nanoparticles with icosahedral symmetry, and single-particle cryo-electron microscopy reconstructions of three of them revealed that they were designed with atomic-level accuracy. To transform one of these nanoparticles into a functional immunogen, we reoriented its termini through circular permutation, added a genetically encoded oligomannose-type glycan, and displayed a stabilized trimeric variant of the influenza hemagglutinin receptor binding domain through a rigid de novo linker. The resultant immunogen elicited potent receptor-blocking and neutralizing antibody responses in mice. Our results demonstrate the practical utility of machine learning-based protein modeling tools in the design of nanoparticle vaccines. More broadly, by eliminating the requirement for experimentally determined structures of protein building blocks, our method dramatically expands the number of starting points available for designing new self-assembling proteins.
    Keywords:  Biochemistry (minor); Biological Sciences (major); influenza; nanoparticles; protein design; vaccines
    DOI:  https://doi.org/10.1101/2025.08.20.671178
  15. Nat Mater. 2025 Sep 05.
    Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
    Donia W Ahmed, Matthew L Tan, Yuchen Liu, Jackson Gabbard, Esther Gao, Avinava Roy, Michael M Hu, Firaol S Midekssa, Miriam Stevens, Fulei Wuchu, Minal Nenwani, Jingyi Xia, Adam Abraham, Deepak Nagrath, Lin Han, Rachel L Zemans, Brendon M Baker, Claudia Loebel.
      Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study pathophysiologic cell function. However, the initiation of fibrosis has largely been overlooked, due to challenges in recapitulating early stages of disease progression within the native extracellular microenvironment. Here, using visible-light-mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo mouse and human lung tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell mechanosensing, differentiation, and nascent protein deposition and remodelling. However, the inhibition of cytoskeletal tension, mechanosensitive signalling pathways or integrin engagement reduced epithelial cell spreading and differentiation. Our findings emphasize the role of local extracellular matrix crosslinking and nascent protein deposition in early stage tissue fibrosis and have implications for ex vivo disease modelling and applications to other tissues.
    DOI:  https://doi.org/10.1038/s41563-025-02329-0
  16. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2509467122
    Complementary biomolecular coassemblies direct energy transport for cardiac photostimulators.
    Ze-Fan Yao, Sujeung Lim, Yuyao Kuang, Emil M Lundqvist, Natalie Celt, Caleb O Chung, Kathryn K Lee, Krystal Nguyen, Lanie Le, Sheng Wei Tang, Griffin M Milligan, Phillip Kohl, Tarunya Rao Sudarshan, Youli Li, Asuka Eguchi, Anant K Paravastu, Michael V Zaragoza, Dmitry A Fishman, Herdeline Ann M Ardoña.
      Charge and energy transport within living systems are fundamental processes that enable the autonomous function of excitable cells and tissues. To date, localized control of these transport processes has been enabled by genetic modification approaches to render light sensitivity to cells. Here, we present peptidic nanoassemblies as constituents of a cardiac biomaterial platform that leverages complementary sequence interactions to direct photoinduced energy transport at the cellular interface. Photophysical characterizations and conductivity measurements confirm the occurrence of energy/charge transfer and photocurrent generation upon optical excitation in both dry and electrolytic environments. Comparing an electrostatic sequence pair against a sequence-matched donor-acceptor coassembly, we demonstrate that the sequence design with charge complementarity shows more prominent photocurrent behavior. With the flanking bioadhesive units, the primary and stem cell-derived cardiomyocytes interfaced with covalently stabilized films of the optoelectronic nanostructures exhibited material-stimulated genotypic, structural, or functional cardiac features. Collectively, our findings introduce an optoelectronic cardiac biomaterial where coassembled peptide nanostructures are molecularly designed to induce light sensitivity in excitable cells without gene modification, influencing in vitro cardiac contractile behavior and expression of cardiac markers.
    Keywords:  biomaterials; cardiac tissue engineering; peptide nanostructures; photostimulation; self-assembly
    DOI:  https://doi.org/10.1073/pnas.2509467122
  17. bioRxiv. 2025 Aug 22. pii: 2025.08.20.671382. [Epub ahead of print]
    Active learning-guided optimization of cell-free biosensors for lead testing in drinking water.
    Brenda M Wang, Nicole Chiang, Holly M Ekas, Dylan M Brown, Garrett Dildine, Tyler J Lucci, Siyuan Feng, Vanessa Bly, Jean-François Gaillard, Julius B Lucks, Ashty S Karim, Diwakar Shukla, Michael C Jewett.
      Point-of-use diagnostics based on allosteric transcription factors (aTFs) are promising tools for environmental monitoring and human health. However, biosensors relying on natural aTFs rarely exhibit the sensitivity and selectivity needed for real-world applications, and traditional directed evolution struggles to optimize multiple biosensor properties at once. To overcome these challenges, we develop a multi-objective, machine learning (ML)-guided cell-free gene expression workflow for engineering aTF-based biosensors. Our approach rapidly generates high-quality sequence-to-function data, which we transform into an augmented paired dataset to train an ML model using directional labels that capture how aTF mutations alter performance. We apply our workflow to engineer the aTF PbrR as a point-of-use diagnostic for lead contamination in water. We tune the sensitivity of PbrR to sense at the U.S. Environmental Protection Agency (EPA) action level for lead and modify the selectivity away from zinc, a common metal found in water supplies. Finally, we show that the engineered PbrR functions in freeze-dried cell-free reactions, enabling a diagnostic capable of detecting lead in drinking water down to ~5.7 ppb. Our ML-driven, multi-objective framework-powered by directional tokens-can generalize to other biosensors and proteins, accelerating the development of synthetic biology tools for biotechnology applications.
    DOI:  https://doi.org/10.1101/2025.08.20.671382
  18. Adv Mater. 2025 Sep 02. e10222
    Consecutive Hybrid Bioprinting of Microfiber-Reinforced Living Muscle Constructs with Highly-Aligned Cellular Organizations.
    Zhennan Qiu, Zijie Meng, Ayiguli Kasimu, Ziyu Wang, Pei He, Le Wang, Ruosen Zhao, Mao Mao, Yilong Tian, Liang Kong, Dichen Li, Jiankang He.
      Replicating the highly-organized extracellular matrix microfibrillar networks and directional cellular organization of native skeletal muscles is essential for engineering functional muscle constructs. Here, we propose a consecutive hybrid bioprinting (CHB) strategy to fabricate living composite constructs with polymeric microfibers, sacrificial gelatin and cell-laden fibrin hydrogels by combining electrohydrodynamic (EHD) printing and extrusion-based bioprinting, which enables the engineering of mechanically-matched and highly-aligned porous muscle constructs. The bioprinted hydrogel components provide a smooth and dynamically-rising conductive surface for stable EHD printing of well-organized microfibers with centimeter height, which conversely provides mechanical support to ensure the structural integrity of the resultant composite constructs. Upon removal of the sacrificial hydrogel, the porous composite constructs maintain their original shape, and native muscle-like mechanical properties can be achieved by modulating the microfiber configurations. Notably, these microfibrous structures facilitate cell-induced anisotropic remodeling of fibrin filaments, resulting in cross-sectional contraction to form highly-aligned myoblast bundles along the bioprinting trajectory. This enables the CHB of circumferentially or layer-specifically aligned cellular constructs. The aligned myoblast constructs can be differentiated into multinucleated myotubes with enhanced muscle-specific protein and gene expression. This CHB strategy provides a promising platform to directly engineer living composite constructs with native anisotropic mechanical properties and cellular organizations.
    Keywords:  aligned muscle construct; consecutive hybrid bioprinting; electrohydrodynamic printing; fibrin remodeling; microfiber‐reinforced hydrogel composite construct
    DOI:  https://doi.org/10.1002/adma.202510222
  19. J Mater Chem B. 2025 Sep 05.
    Imparting new stimuli-responsive behaviors in protein-polymers via self-immolative linker conjugation.
    Federico Kaufman, Maya David, Michal Zaiden, Doron Shabat, Miriam Amiram.
      The development of "smart" polymers capable of responding to physiologically relevant stimuli is essential for engineering dynamic sensing and actuation systems that leverage biological signals under specific (patho)physiological conditions. In this study, we present a general and versatile strategy to engineer novel stimuli-responsive behaviors in temperature-responsive protein-based polymers (PBPs) via site-specific conjugation with self-immolative molecules. Specifically, we developed hydrogen peroxide (H2O2)- and β-galactosidase (β-gal)-responsive elastin-like polypeptides (ELPs) and resilin-like polypeptides (RLPs). Using a library of ELPs with varying numbers of conjugation sites, we demonstrate that this approach enables precise modulation of stimulus-responsive phase transitions, providing a tunable temperature window of up to 50 °C for stimuli-controlled phase transition. We further show that incorporation of these responsive ELPs into collagen hydrogels allows for controlled, dose- and time-dependent release of the ELPs, accompanied by stimulus-induced changes in the hydrogel's transparency, and storage and loss moduli. Additionally, we engineered diblock copolymer nanostructures comprising ELP-ELP or RLP-ELP segments for encapsulation and stimulus-triggered release of a hydrophobic model payload (Nile red) with varying release profiles. Together, these results establish a robust platform for imparting environmentally responsive functionalities to PBPs by integrating recombinant synthesis with chemically triggered actuation, thereby enabling the rational design of adaptive biomaterials with tunable physicochemical and biological properties for a wide range of biomedical and biotechnological applications.
    DOI:  https://doi.org/10.1039/d5tb01334h
  20. Langmuir. 2025 Sep 04.
    Internal Delivery and Transport within Cellular Aggregates via Perfusable Glass-Sheathed Hydrogel Microtubes.
    Chen Li, Nikita Kalashnikov, Christopher Moraes.
      Measuring the transport dynamics of soluble molecules such as nutrients, growth factors, and therapeutics within cell aggregates is essential to understand the transport-limiting effects of 3D cell culture models. Traditional methods to study molecular transport within engineered tissues often face challenges related to access for delivery and sampling and require sacrificing the culture. Here, we introduce an accessible, device-innovation platform that allows spatially defined delivery into a living cell aggregate. By integrating a highly perfusable, hollow-core agarose hydrogel microtube into a polyacrylamide microwell, our system allows local access to the aggregate's interior without advanced microfabrication or complex vascularization. Transport out of the hydrogel tube is limited to a specific spatial region within the aggregate by the deliberate placement and fracturing of a glass capillary sheath. We demonstrate an application of this system in an engineered model of placental trophoblast plugs, which arise temporarily during the first trimester of pregnancy to protect the placenta during development. Partial cell fusion occurs within these plugs, which would alter local transport characteristics, whether this morphological feature affects transport in a 3D tissue remains undefined. To address this, we created cylindrical plug-like aggregates and applied quantitative fluorescence measurements coupled with finite element modeling to determine that patterns of diffusivity are heterogeneous, with enhanced transport at the aggregate core compared to the periphery. This specific application highlights the platform's potential to study molecular transport dynamics within cell aggregates and provides a foundation for further exploration of diffusion-limited processes in 3D culture systems.
    DOI:  https://doi.org/10.1021/acs.langmuir.5c02197
  21. Biochemistry. 2025 Sep 03.
    A Single Mutation in the "DSL" Motif of the Acyl Carrier Protein Can Prevent Its In Vivo Phosphopantetheinylation by E. coli Holo-Acyl Carrier Protein Synthase (AcpS).
    Chetna Dhembla, Debodyuti Sadhukhan, Rashima Prem, Shivangi Vaish, Shalini Verma, Suman Kundu, Monica Sundd.
      The Escherichia coli expression system is the method of choice to obtain high yields of a pure protein. Since most biological pathways are evolutionarily conserved from bacteria to mammals, there is always a chance that a non-native protein shares sequence or structural homology with the natural substrate of an E. coli enzyme. In such cases, when this foreign protein is overexpressed in E. coli, it may be processed as a substrate by that enzyme, resulting in its modification. A notable example is the heterologous expression of Type II acyl carrier proteins (ACPs) in E. coli. Due to the conservation of a type II fatty acid synthesis pathway (FAS) across bacteria to mammals, the non-native type II ACPs are often recognized as a substrate by the E. coli 4'-phosphopantetheinyl transferase, also known as the Holo-acyl carrier protein synthase (AcpS). This undesirable modification is a concern when the objective is to obtain milligram amounts of apo-ACP. Here, using an approach combining mutagenesis, enzyme activity, and NMR, we have probed for the E. coli ACP (AcpP) residues that can prevent this in vivo modification. Taking cues from the AcpP-AcpS crystal structure (PDB entry 1F80), five charge-neutralization mutations were designed on the AcpP surface, i.e., D35N, E41A, E47A, E48A, and E47A/E48A, to disrupt the AcpP-AcpS interaction. All the AcpP mutants except D35N expressed as partially phosphopantetheinylated proteins in E. coli, presenting D35N mutagenesis as an attractive approach to prevent undesired modification of AcpP in vivo. The strategy was tested on two other non-native type II ACPs that express predominantly as phosphopantetheinylated proteins in E. coli, Mus musculus mitochondrial FAS ACP (mACP), and Salmonella Typhimurium invasion acyl carrier protein (IacP). A single D35N mutation in the "DSL" motif of these ACPs prevented their in vivo phosphopantetheinylation by AcpS, demonstrating D35N mutagenesis as a viable strategy to express apo-ACP in E. coli.
    DOI:  https://doi.org/10.1021/acs.biochem.4c00822
  22. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2426790122
    Origami frustration and its influence on energy landscapes of origami assemblies.
    Shixi Zang, Tuo Zhao, Diego Misseroni, Glaucio H Paulino.
      Harnessing instabilities of multicomponent multistable structural assemblies can potentially lead to scalable and reversible functionalities, which can be enhanced by exploring frustration. For instance, standard Kresling origami cells exhibit nontunable intrinsic energy landscapes determined by their geometry and material properties, limiting their adaptability after fabrication. To overcome this limitation, we introduce frustration to enable fine-tuning of the energy landscape and resulting deformation states. By prestressing the Kresling cell by means of special springs with individual control, we induce either global or localized (i.e., crease level) frustration, which allows changing the energy barrier (cell or assembly). We investigate the mechanical behavior of frustrated Kresling assemblies, both theoretically and experimentally, under various loading and boundary conditions. Our findings reveal that changing the frustration state leads to precise control of folding sequences, enabling previously inaccessible folding paths. The proposed concept paves the way for applications in mechanical metamaterials and other fields requiring highly programmable and reconfigurable systems - e.g., prosthetic limbs.
    Keywords:  Kresling; energy landscape; geometrical frustration; origami
    DOI:  https://doi.org/10.1073/pnas.2426790122
  23. Chem Rev. 2025 Sep 06.
    Self-Regulating Hydrogel Actuators.
    Taehun Chung, Jaewon Choi, Takafumi Enomoto, Soyeon Park, Saehyun Kim, Youn Soo Kim.
      Self-regulating hydrogels represent the next generation in the development of soft materials with active, adaptive, autonomous, and intelligent behavior inspired by sophisticated biological systems. Nature provides exemplary demonstrations of such self-regulating behaviors, including muscle tissue's precise biochemical and mechanical feedback mechanisms, and coordinated cellular chemotaxis driven by dynamic biochemical signaling. Building upon these natural examples, self-regulating hydrogels are capable of spontaneously modulating their structural and functional states through integrated negative feedback loops. In this review, the key design principles and implementation strategies for self-regulating hydrogel actuators are comprehensively summarized. We first systematically classify self-regulating hydrogels into sustained regulation, involving continuous modulation cycles under constant stimuli and one-cycle regulation, characterized by transient transitions driven by specific chemical fuels. Thereafter, the underlying mechanisms, types of hydrogels used, fuels, oscillation periods, amplitudes, and potential applications are highlighted. Finally, current scientific challenges and future opportunities for enhancing the robustness, modularity, and practical applicability of self-regulating hydrogel actuators are discussed. This review aims to provide structured guidelines and inspire interdisciplinary research to further develop advanced hydrogel-based regulatory systems for applications such as soft robotics, autonomous sensors, responsive biomedical devices, and adaptive functional materials.
    DOI:  https://doi.org/10.1021/acs.chemrev.5c00358
  24. STAR Protoc. 2025 Sep 01. pii: S2666-1667(25)00458-7. [Epub ahead of print]6(3): 104052
    Protocol for label-free ribosome-associated protein enrichment from mammalian cells by RAPIDASH.
    Victoria Hung, Teodorus Theo Susanto, Maria Barna.
      Ribosome-associated proteins (RAPs) enable modulation of gene expression at the level of mRNA translation in response to cellular needs. Here, we describe a method called ribosome-associated protein identification by affinity to sulfhydryl-charged resin (RAPIDASH) for tag-free isolation of RAP-bound ribosomes from mammalian samples for mass spectrometry-based proteomics. Samples are first lysed and then undergo sucrose cushion ultracentrifugation and subsequent chromatography using a sulfhydryl-charged resin. While RAPIDASH is optimized for mammalian samples, we expect that it can be adapted for non-mammalian samples. For complete details on the use and execution of this protocol, please refer to Susanto et al.1.
    Keywords:  Cell Biology; Molecular Biology; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2025.104052
  25. Adv Sci (Weinh). 2025 Aug 28. e07820
    Engineering Bacteria as Living Therapeutics in Cancer Therapy.
    Jiangfeng Chen, Jiaqi Chen, Yixuan Chen, Wenxuan Yuan, Jiao Zhang, Guoqing Wang, Zhuojun Dai.
      Cancer is the second-leading cause of death globally, yet traditional therapies like chemotherapy face significant limitations. Recent advances in synthetic biology enable the design of various genetic circuits and the reprogramming of biological systems. Collectively, these efforts have led to the repurposing of engineered bacteria as therapeutics to achieve tumor targeting, tumor microenvironment modulation, and anticancer drug release. Here, these recent efforts are reviewed and discussed the challenges and future opportunities.
    Keywords:  cancer immunotherapy; engineered bacteria; synthetic biology; targeted drug delivery; tumor microenvironment modulation
    DOI:  https://doi.org/10.1002/advs.202507820
  26. J Am Chem Soc. 2025 Sep 06.
    Cation-Controlled Assembly, Activity, and Organization of Biomimetic DNA Receptors in Synthetic Cell Membranes.
    Elita Peters, Diana A Tanase, Lorenzo Di Michele, Roger Rubio-Sánchez.
      Biological cells use cations as signaling messengers to regulate a variety of responses. Linking cations to the functionality of synthetic membranes is thus crucial to engineering advanced biomimetic agents such as synthetic cells. Here, we introduce bioinspired DNA-based receptors that exploit noncanonical G-quadruplexes for cation-actuated structural and functional responses in synthetic lipid membranes. Membrane confinement grants cation-dependent control over receptor assembly and, when supplemented with hemin cofactors, their peroxidase DNAzyme activity. Cation-mediated control extends to receptor lateral distribution to localize DNA-based catalysis within phase-separated membrane domains of model synthetic cells, imitating the localization of multimeric membrane complexes to signaling hubs in living cells. Our modular strategy paves the way for engineering from the bottom-up cation-responsive pathways for sensing, signaling, and communication in synthetic cellular systems.
    DOI:  https://doi.org/10.1021/jacs.5c09928
  27. ACS Appl Mater Interfaces. 2025 Sep 01.
    Bioorthogonal Mussel-Inspired Elastin-like Nanocoatings for Indwelling Devices.
    Sergio Acosta, Viktoriya Chaskovska, Ikram El-Maachi, Jenny Englert, María Puertas-Bartolomé, Stefan Jockenhoevel, José Carlos Rodríguez-Cabello, César Rodriguez-Emmenegger, Alicia Fernández-Colino.
      Medical devices such as vascular grafts, stents, and catheters are crucial for patient treatment but often suffer suboptimal integration with host tissues due to the nature of their surfaces. The materials commonly used, including metals and synthetic polymers, frequently lead to undesired immune responses and device failure. In this context, coating their surfaces with designer proteins has arisen as a promising strategy to improve the device's biointegration. Here, we present a bioinspired method for coating biomaterial surfaces with protein-engineered polymers designed to mimic tailored functions from the native extracellular matrix (ECM). Combining mussel-inspired catechol chemistry with bioorthogonal click chemistry, we developed a modular grafting method for the surface functionalization of metallic and polymeric implants using a bifunctional peptide containing azide and DOPA (3,4-dihydroxyphenylalanine) groups. This simple dip-coating process enabled the fabrication of bioactive elastin-like coatings with precise peptide presentation. The results reveal enhanced bioactivity and cytocompatibility, as evidenced by improved endothelial cell adhesion, proliferation, and heparin-binding capacity on coated surfaces. The versatility and effectiveness of this bioorthogonal coating method suggest significant potential for creating implant surfaces tailored to diverse clinical applications.
    Keywords:  DOPA; biofunctional coatings; click chemistry; elastin-like recombinamers; surface functionalization
    DOI:  https://doi.org/10.1021/acsami.5c10327
  28. bioRxiv. 2025 Aug 23. pii: 2025.08.23.671908. [Epub ahead of print]
    GCAD: a Computational Framework for Mammalian Genetic Program Computer-Aided Design.
    Kathleen S Dreyer, Anh V Nguyen, Gauri G Bora, Lauren E Redus, Hailey I Edelstein, Jocelyn Zonnefeld, Eleftheria Anastasia, Kate E Dray, Joshua N Leonard, Niall M Mangan.
      Genetic programs can direct living systems to perform diverse, pre-specified functions. As the library of parts available for building such programs continues to expand, computation-guided design is increasingly helpful and necessary. Yet key gaps exist for designing programs for use in mammalian cells in particular. Predictive models aid the challenging design process, but iterative simulation and experimentation are intractable for complex functions. Computer-aided design accelerates this process, but existing tools do not yet capture the behavior of mammalian-specific parts and population-level effects needed for mammalian synthetic biologists. To address these needs, we developed a framework for mammalian genetic program computer-aided design. Starting with a user-defined design specification to quantify circuit performance, the framework uses a genetic algorithm to search through possible designs. Circuit space is defined by a library of experimentally characterized parts and dynamical systems models for gene expression in a heterogeneous cell population. We developed this genetic algorithm using a directed graph-based formulation with biologically constrained rules to explore regulatory connections and parts. We evaluated the framework for design problems of varying complexity, including programs we describe as an amplifier, signal conditioner, and pulse generator, demonstrating that the algorithm can successfully find optimal circuit designs. Finally, we experimentally evaluated selected circuits, demonstrating the path from a predicted circuit design to experimental testing and highlighting the importance of characterization for enabling predictive design. Overall, this framework establishes general approaches that can be refined and expanded, accelerating the design and implementation of mammalian genetic programs.
    DOI:  https://doi.org/10.1101/2025.08.23.671908
  29. Nature. 2025 Sep 03.
    Supervised learning in DNA neural networks.
    Kevin M Cherry, Lulu Qian.
      Learning enables biological organisms to begin life simple yet develop immensely diverse and complex behaviours. Understanding learning principles in engineered molecular systems could enable us to endow non-living physical systems with similar capabilities. Inspired by how the brain processes information, the principles of neural computation have been developed over the past 80 years1, forming the foundation of modern machine learning. More than four decades ago, connections between neural computation and physical systems were established2. More recently, synthetic molecular systems, including nucleic acid and protein circuits, have been investigated for their abilities to implement neural computation3-7. However, in these systems, learning of molecular parameters such as concentrations and reaction rates was performed in silico to generate desired input-output functions. Here we show that DNA molecules can be programmed to autonomously carry out supervised learning in vitro, with the system learning to perform pattern classification from molecular examples of inputs and desired responses. We demonstrate a DNA neural network trained to classify three different sets of 100-bit patterns, integrating training data directly into memories of molecular concentrations and using these memories to process subsequent test data. Our work suggests that molecular circuits can learn tasks more complex than simple adaptive behaviours. This opens the door to molecular machines capable of embedded learning and decision-making in a wide range of physical systems, from biomedicine to soft materials.
    DOI:  https://doi.org/10.1038/s41586-025-09479-w
  30. Chem Soc Rev. 2025 Aug 27.
    Bioinspired micro-nano photonic materials.
    Chengben Liu, Xiaoyu Hou, Zixin Zhu, Mingzhu Li.
      The development of micro- and nano-scale photonic materials represents a cornerstone of modern science and technology. Nature, as a master architect, has served us with the most compelling and time-tested innovations and bio-designs. From the vibrant iridescent wings of butterflies to the anti-reflective eyes of moths, biological systems have long perfected the art of light manipulation through intricate micro- and nanoscale architectures. By decoding these biological mechanisms, harnessing nature-inspired design and interdisciplinary innovation, researchers unlock pathways to create materials with tailored optical properties, durability, and environmental adaptability. In the evolving landscape of photonic materials science, bioinspired micro-nano photonic materials emerge as a transformative frontier, bridging the ingenuity of biological evolution with cutting-edge photonic technologies. In this review, we provide an overview of research efforts on bioinspired micro-nano photonic materials, which offer multifunctional, adaptive, and sustainable solutions for next generation environmentally sustainable photonic materials and ultra-compact, energy-efficient photonic devices. We summarize the typical foundational principles of biological systems where nanostructures have evolved over millennia to master light. Furthermore, we highlight recent advances in bioinspired micro-nano photonic materials which have led to tremendous progress in eco-friendly structural color display, visual chroma sensor, high-security information encryption, energy-efficient functional optoelectrical devices, and so on. Finally, we discuss the challenges and prospects of bioinspired micro-nano photonic materials, including nature-inspired design, fabrication sustainability, and interdisciplinary synergy, for applications in telecom, energy, and biomedicine in the future.
    DOI:  https://doi.org/10.1039/d5cs00606f
  31. Adv Mater. 2025 Sep 03. e08549
    Achieving Mechanical Evolution in Polymer Materials Through Phase Evolution Induced by Visible Light.
    Cheng Liu, Chaowei He, Xiaobin Dai, Li-Tang Yan, Huaping Xu.
      Can artificial polymer materials exhibit the characteristic of "evolution" over time, similar to biological tissue? The limitations arise from their inherently static nature and the absence of dynamic structures. A strategy is proposed for designing polymer materials whose phases and mechanical properties can be continuously transformed and enhanced temporally. Specifically, the polymer phases experience a sequence of transitions involving generation, separation, and fusion. Each period enhances mechanical properties in distinct and significant ways, demonstrating a mechanical evolution. This evolution is initiated through in situ polymerization within the material and can be precisely controlled using visible light. Applied to a hydrogel system, this approach achieves a record-breaking increase in Young's modulus by over 2400-fold, from 18.5 kPa to 44.5 MPa. The findings highlight the potential for tailoring mechanical properties on demand and constructing metamaterials with multilevel moduli and composite architectures.
    Keywords:  in situ polymerization; mechanical evolution; phase evolution; seleno radicals; visible light responsiveness
    DOI:  https://doi.org/10.1002/adma.202508549
  32. Phys Life Rev. 2025 Aug 22. pii: S1571-0645(25)00128-9. [Epub ahead of print]55 52-54
    The viscoelastic living matter from biomolecular condensates to tissues: Comment on "viscoelastic mechanics of living cells" by Zhou et al.
    Dongshi Guan.
      None.
    Keywords:  Cell mechanics; Power-law rheology; Protein condensates; Tissues; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.plrev.2025.08.010
  33. Nature. 2025 Sep;645(8079): 108-114
    Adaptive and context-aware volumetric printing.
    Sammy Florczak, Gabriel Größbacher, Davide Ribezzi, Alessia Longoni, Marième Gueye, Estée Grandidier, Jos Malda, Riccardo Levato.
      We introduce Generative, Adaptive, Context-Aware 3D Printing (GRACE), a new approach combining 3D imaging, computer vision and parametric modelling to create tailored, context-aware geometries using volumetric additive manufacturing. GRACE rapidly and automatically generates complex structures capable of conforming directly around features ranging from cellular to macroscopic scales with minimal user intervention. Here we demonstrate its versatility in applications ranging from synthetic objects to biofabrication, including adaptive vascular-like geometries around cell-laden bioinks, resulting in improved functionality. GRACE also enables precise alignment of sequential prints, as well as the detection and overprinting of opaque surfaces through shadow correction. Compatible with various printing modalities1-4, GRACE transcends traditional additive manufacturing limitations in automating overprinting and adapting the printed designs to the content of the printable material. This opens new possibilities in tissue engineering and regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-025-09436-7
  34. ACS Appl Mater Interfaces. 2025 Sep 05.
    Simple Two-Component CDs/PVA Hydrogels Possess Dynamic High-Definition and Two-Stage Information Encryption Capability.
    Kun Huang, Yong Jin, Rong Zhou, Jiangyang Mei, Haonan Chen, Zhexian Mao, Jia Wang.
      Ensuring the fidelity and security level of stored information is essential for information carrier materials to safeguard data and prevent counterfeiting. However, low resolution, limited encryption modes, and complex fabrication hinder existing information carriers from meeting evolving technological demands. Herein, a solvent exchange strategy from DMSO to water is employed to stably anchor hydrophobic fluorescent carbon dots (CDs) with multiple emission states onto a 3D framework of poly(vinyl alcohol) (PVA) chains, forming a simple two-component CDs/PVA hydrogel with tunable fluorescent colors and recyclability. The hydrogel can accommodate a high CDs loading of up to 15% and remains functional even after 5 solvent exchange cycles. Through a noncontact photobleaching oxidation process of CDs, high-definition images that are distinct from the blurred ones induced by traditional chemical ink stimuli can be recorded onto the hydrogel, decrypted under UV light, and dynamically erased after being read. Additionally, the chemical stimulus response of CDs and the easy processability of PVA provide the CDs/PVA hydrogel with more diverse encryption modes. The combination of light and chemical stimuli enables two-stage encryption, where light writing ensures high-fidelity information storage, while chemical ink introduces interference, further increasing the decryption difficulty and enhancing the security of stored information. Furthermore, the reversible physical cross-linking allows this hydrogel to be easily recycled and reprocessed after use. This versatile strategy endows the material with enhanced information security and provides insights into the development of advanced information carrier materials.
    Keywords:  fluorescent hydrogels; high-definition information storage; hydrophobic carbon dots; information encryption; two-stage information encryption
    DOI:  https://doi.org/10.1021/acsami.5c12262
  35. Chem Bio Eng. 2025 Aug 28. 2(8): 449-459
    Combing Directed Enzyme Evolution with Metabolic Engineering to Develop Efficient Microbial Cell Factories.
    Yuyao Ren, Ewelina Celińska, Peng Cai, Yongjin J Zhou.
      The booming field of synthetic biology and metabolic engineering provides promising approaches for sustainable manufacturing of chemicals from renewable feedstocks with microbial cell factories. Classical metabolic engineering strategies mainly focus on altering gene expression levels and enzyme concentrations to improve the metabolic fluxes of specific pathways. However, the impact and limitations of enzyme properties, which are usually ignored in classical metabolic engineering efforts, can hinder further optimization of microbial cell factories. Protein engineering and directed evolution are powerful tools for modifying proteins to achieve desirable properties, and they have been integrated into metabolic engineering efforts to build highly efficient metabolic pathways and optimal industrial chassis. In this review, we present traditional and data-driven strategies and techniques of directed evolution, including random library design, semirational design, smart library design, and in vivo continuous evolution. We also discuss how these directed evolution strategies have been applied in metabolic engineering toward superphenotypes that cannot be achieved through simple gene overexpression or knockout. Finally, we discuss the challenges of applying protein engineering in metabolic engineering and the prospects for accelerating the directed evolution workflow using the state-of-art technologies.
    Keywords:  Protein engineering; artificial intelligence; directed evolution; in vivo evolution; metabolic engineering
    DOI:  https://doi.org/10.1021/cbe.5c00002
  36. Nat Commun. 2025 Aug 29. 16(1): 8079
    Modular multi-enzyme cascades enable green and sustainable synthesis of non-canonical amino acids from glycerol.
    Shuai Xu, Shu-Hong Wang, Long-Wei Lou, Yu Ji, Ulrich Schwaneberg, Zhi-Min Li, Feng Cheng, Zong-Lin Li.
      Non-canonical amino acids (ncAAs) bearing diverse functional groups hold transformative potential in drug discovery, protein engineering, and biomaterial science. However, their industrial-scale production remains constrained by the inefficiency, high cost, and environmental burden of conventional chemical and enzymatic methods. Here, we present a modular multi-enzyme cascade platform that leverages glycerol-an abundant and sustainable byproduct of biodiesel production-as a low-cost substrate for ncAAs synthesis. Directed evolution of O-phospho-L-serine sulfhydrylase (OPSS) enhances the catalytic efficiency of C-N bond formation by 5.6-fold, enabling the efficient synthesis of triazole-functionalized ncAAs. By integrating a plug-and-play enzymatic strategy, our system enables gram- to decagram-scale production of 22 ncAAs with C-S, C-Se, and C-N side chains and can be readily scaled up to a 2 liter reaction system. Notably, water is the sole byproduct, and all products exhibit an atomic economy of >75%, highlighting the environmental compatibility of this platform. This work establishes a green, cost-effective, and industrially viable approach to expanding amino acid diversity, providing a versatile toolkit for applications in pharmaceuticals, synthetic biology, and next-generation biomaterials.
    DOI:  https://doi.org/10.1038/s41467-025-63341-1
  37. Small. 2025 Aug 29. e07338
    Hierarchical Assembly of Proteinosomes and Coacervates Communities into 3D Protocellular Networks.
    Xiaoliang Wang, Xin Qiao, Haiyue Yang, Yan Huang, Haixu Chen, Lei Wang, Xiaoman Liu, Chenghai Xu, Xin Huang.
      Drawing inspiration from the living cells, various life-inspired assemblies have been developed to mimic their remarkable properties and functionalities, and offer valuable insights into the origin of life and the understanding of life behaviors. Advancing the design and construction of multi-compartmentalized hierarchical systems with more advanced structures and functions has always increasingly attracted attention in this field. Here, a type of 3D protocellular networks are designed and constructed, which is formed by the hybrid of two types of protocells communities based on phenylboronic acid-grafted proteinosomes and polysaccharide-based coacervate microdroplets. Progressive self-assembly process is investigated to understand their characteristics and functions, including the host-guest self-assembly, the multi-compartmentalized hierarchical self-assembly, and bulk aqueous self-assembly. Notably, the 3D protocellular networks-based bulk condensate phase, which is bulk aqueous self-assembled by physical support between vesicles- and droplets-based protocells communities, exhibit the regulation of enzymatic reactions based on the enzyme enrichment and adhesiveness of the condensate phase. The results establish a platform for investigating the interactions between protocell communities and provide opportunities for the fabrication of functional 3D protocellular networks with a new view to engineer biomimetic prototissues.
    Keywords:  coacervate microdroplets; condensate phase; enzymatic reactions regulation; proteinosomes; protocellular networks
    DOI:  https://doi.org/10.1002/smll.202507338
  38. Mater Today Bio. 2025 Oct;34 102214
    Biohybrid corneal stromal tissue formation using keratocytes encapsulated in supramolecular microgels.
    Maritza M Rovers, Annika F Vrehen, Patricia Y W Dankers.
      Compared to bulk hydrogels, microgels offer distinct advantages for biomedical applications. Their increased modularity and heterogeneity compared to hydrogels, combined with their small size and reversible dynamic bonding, enhance their suitability for minimally invasive cell delivery. Additionally, microgels offer greater control over porosity, resulting in the formation of intricate porous microstructures. In this work, keratocytes encapsulated in ureidopyrimidinone (UPy) supramolecular microgels functionalized with UPy-cRGD were fabricated to generate a micro stromal tissue in vitro. Both the human corneal keratocyte cell line (HCK) and primary keratocytes (PK) demonstrated effective cell-cell and cell-matrix mediated microgel assembly, resulting in the formation of self-generated scaffolds. The void spaces between the assembled microgels facilitate migration and infiltration of the cells through the biohybrid stromal tissue construct. The retention time of the cells within the microgels can be controlled by altering the microgel composition. Immunohistochemical analyses of PKs assembled tissues demonstrated the formation of stromal micro tissues, cellular extracellular matrix deposition and substantial upregulation of nuclear yes-associated-protein (YAP) during culture. This work highlights a novel supramolecular approach with promising potential for minimally invasive therapies aimed at treating corneal defects in clinical settings.
    Keywords:  Droplet-based microfluidics; Granular hydrogel; Injectability; Microgels; Stromal construct; Supramolecular chemistry
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102214
  39. Nanoscale. 2025 Aug 28.
    Strategies for fabricating aligned nano- and microfiber scaffolds: an overview for cell culture applications.
    Kristina Peranidze, Nataraja Sekhar Yadavalli, Brianna Blevins, Mikhail Parker, Tushita Jain, Mohammad Aghajohari, Sergiy Minko, Vladimir Reukov.
      The rapidly growing demand for cell manufacturing and in vitro tissue fabrication has led to the development of various technologies for biomimetic artificial extracellular matrix (ECM), including three major materials: hydrogels, fibrous scaffolds, and decellularized tissues. The latter two materials are closer to the biomimetic goal of replicating natural ECM. The scalability of the scaffolds made of decellularized tissues is limited. The development of 3D fibrous ECM is at the initial stage owing to the recent advantages of novel nanofiber spinning technologies. These novel technologies brought about simultaneous control over a range of critical characteristics, such as fiber diameter, length, material, draw ratio, spacing, and alignment into well-controlled 3D constructs. There is still a long way to go in designing 3D fibrous scaffolds based on cell response studies. The primary objective of this review is to provide an analysis of the recent progress in novel nano- and microfiber spinning methods and uncover their potential for precise fiber alignment into 3D structures.
    DOI:  https://doi.org/10.1039/d5nr02078f
  40. Nature. 2025 Sep 03.
    Spatial joint profiling of DNA methylome and transcriptome in tissues.
    Chin Nien Lee, Hongxiang Fu, Angelysia Cardilla, Wanding Zhou, Yanxiang Deng.
      The spatial resolution of omics analyses is fundamental to understanding tissue biology1-3. The capacity to spatially profile DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation4,5, is lacking. Here we introduce a method for whole-genome spatial co-profiling of DNA methylation and the transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and the postnatal mouse brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The concordance and distinction in spatial patterns of the two modalities highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics that underlie mammalian embryogenesis for both the epigenome and transcriptome, revealing details of sequence-, cell-type- and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to include DNA cytosine methylation, enabling a more comprehensive understanding of tissue biology across development and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09478-x
  41. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2426094122
    A general genome editing strategy using CRISPR lipid nanoparticle spherical nucleic acids.
    Zhenyu Han, Chi Huang, Taokun Luo, Chad A Mirkin.
      Genome editing with CRISPR-Cas systems hold promise for treating a wide range of genetic disorders and cancers. However, efficient delivery of genome editors remains challenging due to the requirement for the simultaneous delivery or intracellular generation of Cas proteins, guide RNAs, and, in some applications, donor DNAs. Furthermore, the immunogenicity and toxicity of delivery vehicles can limit the safety and efficacy of genetic medicines. Here, we combine two nucleic acid delivery approaches to create CRISPR lipid nanoparticle-spherical nucleic acids (LNP-SNAs) that are both efficient and biocompatible. Compared to lipid nanoparticles (LNPs) lacking a surface-bound DNA shell, CRISPR LNP-SNAs exhibit two- to three-fold higher cellular uptake, reduced cytotoxicity, and improved gene transfection efficiency. Across multiple cell lines and genomic loci, CRISPR LNP-SNAs induce insertion-deletion mutations at average frequencies two- to three-fold higher than those observed with LNPs. When codelivered with donor templates, CRISPR LNP-SNAs enable homology-directed repair at an average efficiency of 21 ± 7%, a 2.5-fold improvement over LNPs (8 ± 4%). The ease of synthesis and biocompatibility of CRISPR LNP-SNAs highlight their potential as a versatile delivery platform for CRISPR-Cas and other gene therapies.
    Keywords:  CRISPR; genome editing; lipid nanoparticle; repair template; spherical nucleic acid
    DOI:  https://doi.org/10.1073/pnas.2426094122
  42. Nat Mater. 2025 Sep 01.
    Tissue-specific mRNA delivery and prime editing with peptide-ionizable lipid nanoparticles.
    Yi Lin, Mengyao Li, Zijin Luo, Yanan Meng, Yan Zong, Hongyu Ren, Xiaolu Yu, Xiaoqiong Tan, Fan Liu, Tuo Wei, Qiang Cheng.
      Lipid nanoparticles for mRNA delivery and gene editing have the potential to transform the current therapeutic landscape. Nonetheless, a major bottleneck using this technology is the difficulty in achieving cell- and tissue-specific delivery and avoiding liver accumulation. Here we report the rational design of peptide ionizable lipids to assemble lipid nanoparticles with organ-selective mRNA delivery. Structure-activity and structure-selectivity relationship analyses enable us to obtain a general and predictable strategy for peptide ionizable lipid design. By incorporating artificial ionizable and natural amino acids and/or functional molecules into peptide ionizable lipids, we create lipid nanoparticles with tissue-specific targeting, including the lungs, liver, spleen, thymus and bone. In particular, lipid nanoparticles containing peptide lipids targeting the liver show comparable efficacy and safety compared with FDA-approved formulations. Furthermore, lipid nanoparticles with peptide lipids achieve the efficient co-delivery of PEmax mRNA and engineered prime editing guide RNA for prime editing of the liver and lungs. Overall, our platform offers a predictable methodology for the rational design of tissue-targeting lipid nanoparticles that might aid the development of improved mRNA-based gene editing therapeutics.
    DOI:  https://doi.org/10.1038/s41563-025-02320-9
  43. Nat Chem. 2025 Sep 02.
    Magnetic activation of spherical nucleic acids enables the remote control of synthetic cells.
    Ellen Parkes, Assala Al Samad, Giacomo Mazzotti, Charlie Newell, Brian Ng, Amy Radford, Michael J Booth.
      The flexible and modular design of synthetic cells, comprising lipid vesicles capable of imitating the structure and function of living cells, facilitates their application as drug delivery devices. The ability to control the synthesis of biomolecules within synthetic cells using a tissue-penetrating stimulus opens up additional levels of functionality that has the potential to improve biological potency and circumvent drug leakage from preloaded vesicles. To this end, we have designed spherical nucleic acids comprising DNA promoter sequences decorating magnetic nanoparticle cores. These spherical nucleic acids allowed us to harness the heat dissipated from magnetic hyperthermia (a clinically approved anticancer therapy) to regulate cell-free protein synthesis and release cargo on demand. Furthermore, this magnetic regulation of biosynthesis was achieved using clinically tolerable magnetic field strengths and frequencies. We then deployed an opaque blocking material that is impenetrable by current activation methods to highlight the potential of this technology for targeting and controlling the in situ synthesis of biomolecules using tissue-penetrating magnetic fields deep within the body.
    DOI:  https://doi.org/10.1038/s41557-025-01909-6
  44. bioRxiv. 2025 Aug 26. pii: 2024.11.16.623974. [Epub ahead of print]
    Squidiff: Predicting cellular development and responses to perturbations using a diffusion model.
    Siyu He, Yuefei Zhu, Daniel Naveed Tavakol, Haotian Ye, Yeh-Hsing Lao, Zixian Zhu, Cong Xu, Sharadha Chauhan, Guy Garty, Raju Tomer, Gordana Vunjak-Novakovic, James Zou, Elham Azizi, Kam W Leong.
      Single-cell sequencing has revolutionized our understanding of cellular heterogeneity and responses to environmental stimuli. However, mapping transcriptomic changes across diverse cell types in response to various stimuli and elucidating underlying disease mechanisms remains challenging. Studies involving physical stimuli, such as radiotherapy, or chemical stimuli, like drug testing, demand labor-intensive experimentation, hindering mechanistic insight and drug discovery. Here we present Squidiff, a diffusion model-based generative framework that predicts transcriptomic changes across diverse cell types in response to environmental changes. We demonstrate Squidiff's robustness across cell differentiation, gene perturbation, and drug response prediction. Through continuous denoising and semantic feature integration, Squidiff learns transient cell states and predicts high-resolution transcriptomic landscapes over time and conditions. Furthermore, we applied Squidiff to model blood vessel organoid development and cellular responses to neutron irradiation and growth factors. Our results demonstrate that Squidiff enables in silico screening of molecular landscapes, facilitating rapid hypothesis generation and providing valuable insights for precision medicine.
    DOI:  https://doi.org/10.1101/2024.11.16.623974
  45. bioRxiv. 2025 Aug 31. pii: 2025.04.14.648727. [Epub ahead of print]
    Write and Read: Harnessing Synthetic DNA Modifications for Nanopore Sequencing.
    Uri Bertocchi, Assaf Grunwald, Gal Goldner, Eliran Eitan, Sigal Avraham, Shani Dvir, Jasline Deek, Yael Michaeli, Brian Yao, Jennifer Listgarten, Jared T Simpson, Winston Timp, Yuval Ebenstein.
      An exciting feature of nanopore sequencing is its ability to record multi-omic information on the same sequenced DNA molecule. Well-trained models allow the detection of nucleotide-specific molecular signatures through changes in ionic current as DNA molecules translocate through the nanopore. Thus, naturally occurring DNA modifications, such as DNA methylation and hydroxymethylation, may be recorded simultaneously with the genetic sequence. Additional genomic information, such as chromatin state or the locations of bound transcription factors, may also be recorded if their locations are chemically encoded into the DNA. Here, we present a versatile "write-and-read" framework, where chemo-enzymatic DNA labeling with unnatural synthetic tags results in predictable electrical fingerprints in nanopore sequencing. As a proof-of-concept, we explore a DNA glucosylation approach that selectively modifies 5-hydroxymethylcytosine (5hmC) with glucose or glucose-azide adducts. We demonstrate that these modifications generate distinct and reproducible electrical shifts, enabling the direct detection of chemically altered nucleotides. We further demonstrate that enzymatic alkylation, such as the enzymatic transfer of azide residues to the N6 position of adenines, also produces characteristic nanopore signal shifts relative to the native adenine and 6-methyladenine. Beyond direct nucleotide detection, this approach introduces new possibilities for bio-orthogonal DNA labeling, enabling an extended alphabet of sequence-specific detectable moieties. The future use of programmable chemical modifications for simultaneous analysis of multiple omics features on individual molecules opens new avenues for genetic research and discovery.
    DOI:  https://doi.org/10.1101/2025.04.14.648727
  46. Nat Phys. 2025 Jul 28.
    Capillary interactions drive the self-organization of bacterial colonies.
    Matthew E Black, Chenyi Fei, Ricard Alert, Ned S Wingreen, Joshua W Shaevitz.
      Many bacteria inhabit thin water layers on solid surfaces. These thin films occur both naturally - in soils, on hosts, on textiles - and in the lab on agar hydrogels. In these environments, cells the water menisci formed around bacteria lead to capillary attraction between cells while still allowing them to slide past one another. We develop an experimental apparatus that allows us to control bacterial collective experience capillary forces but it is unclear how these forces shape bacterial collective behavior. Here, we show that behavior by varying the strength and range of capillary forces. Combining three-dimensional imaging and cell tracking with agent-based modelling, we demonstrate that capillary attraction organizes rod-shaped bacteria into densely packed, nematic groups, and influences their collective dynamics and morphologies. Our results suggest that capillary forces may be a ubiquitous physical ingredient in shaping microbial communities in partially hydrated environments.
    DOI:  https://doi.org/10.1038/s41567-025-02965-y
  47. bioRxiv. 2025 Aug 23. pii: 2025.08.19.666446. [Epub ahead of print]
    Engineering filamentous myosins for optical control of contractility.
    Sasha Zemsky, Paul V Ruijgrok, Zev Bryant.
      Understanding the behaviors of contractile actomyosin systems requires precise spatiotemporal control of filamentous myosin activity. Here, we develop a tool for optical control of contractility by extending the MyLOV family of gearshifting motors to create engineered filamentous myosins that change velocity in response to blue light. We characterize these minifilaments using in vitro single-molecule tracking assays, contractility assays in reconstituted actin networks, and imaging of contractile phenotypes in Drosophila S2 cells. The minifilaments change speed and/or direction when illuminated, display speeds that fall within and beyond the relevant physiological range, and display high processivities. Additionally, minifilament-driven contraction rates increase in blue light both in vitro and in S2 cells. Finally, we develop an alternative design for minifilaments that only interact processively with actin in blue light. Engineered minifilaments can be used to dissect behaviors such as self-organization and mechanotransduction in contractile systems both in vitro and in cells and tissues.
    DOI:  https://doi.org/10.1101/2025.08.19.666446
  48. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00169-0. [Epub ahead of print]
    PTMs as molecular encoders: reprogramming chaperones into epichaperomes for network control in disease.
    Feixia Chu, Sahil Sharma, Stephen D Ginsberg, Gabriela Chiosis.
      Recent discoveries reveal that post-translational modifications (PTMs) do more than regulate protein activity - they encode conformational states that transform chaperones into epichaperomes: multimeric scaffolds that rewire protein-protein interaction networks. This emerging paradigm expands the framework of chaperone biology in disease and provides a structural basis for systems-level dysfunction in disorders such as cancer and Alzheimer's disease. This review explores how PTMs within intrinsically disordered regions drive epichaperome formation, how these scaffolds selectively regulate disease-enabling functions, and why their disruption normalizes pathological networks. By highlighting PTMs as molecular encoders of supramolecular assemblies, we propose a shift from targeting proteins to targeting network architectures that sustain and perpetuate disease - a concept with broad implications for cell biology, disease propagation, and therapeutic design.
    Keywords:  chaperone reprogramming; intrinsically disordered regions; network-centric therapeutics; post-translational control; protein–protein interaction networks; supramolecular scaffolds
    DOI:  https://doi.org/10.1016/j.tibs.2025.07.006
  49. PLoS Comput Biol. 2025 Sep 02. 21(9): e1013387
    Gene regulatory network structure informs the distribution of perturbation effects.
    Matthew Aguirre, Jeffrey P Spence, Guy Sella, Jonathan K Pritchard.
      Gene regulatory networks (GRNs) govern many core developmental and biological processes underlying human complex traits. Even with broad-scale efforts to characterize the effects of molecular perturbations and interpret gene coexpression, it remains challenging to infer the architecture of gene regulation in a precise and efficient manner. Key properties of GRNs, like hierarchical structure, modular organization, and sparsity, provide both challenges and opportunities for this objective. Here, we seek to better understand properties of GRNs using a new approach to simulate their structure and model their function. We produce realistic network structures with a novel generating algorithm based on insights from small-world network theory, and we model gene expression regulation using stochastic differential equations formulated to accommodate modeling molecular perturbations. With these tools, we systematically describe the effects of gene knockouts within and across GRNs, finding a subset of networks that recapitulate features of a recent genome-scale perturbation study. With deeper analysis of these exemplar networks, we consider future avenues to map the architecture of gene expression regulation using data from cells in perturbed and unperturbed states, finding that while perturbation data are critical to discover specific regulatory interactions, data from unperturbed cells may be sufficient to reveal regulatory programs.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013387
  50. J Colloid Interface Sci. 2025 Aug 28. pii: S0021-9797(25)02227-1. [Epub ahead of print]702(Pt 1): 138836
    3D-printable bio-sourced nanocomposite hydrogels based on two polysaccharide components: hydroxypropyl guar macromolecules and cellulose nanocrystals.
    Alexander S Ospennikov, Andrey V Shibaev, Yuri M Chesnokov, Andrey S Samokhin, Nikolay V Leontiev, Pavel V Evdokimov, Alexander I Kuklin, Olga E Philippova.
      Hydrogels are soft and wet materials which require enhanced mechanical properties and toughness. For this aim, double-network hydrogels were prepared from soft network of covalently crosslinked hydroxypropyl guar and hard self-assembled network of carboxymethylated cellulose nanocrystals (CNCs) reversibly crosslinked by calcium ions. The gels exhibited a dramatic enhancement of mechanical strength and toughness with increasing content of CNCs and demonstrated remarkable fatigue resistance. For the first time, a 3D-visualization of CNC network within the double-network hydrogel was achieved using cryo-electron tomography. It revealed the presence of thick, fibrillar-like aggregates composed of bundles of two to five stacked nanocrystals, which are linked to adjacent bundles at their ends. These long aggregates can be responsible for significant enhancement of mechanical properties of the hydrogels by CNCs. Also, we first demonstrate the formation of hydrophobic cross-links between individual nanocrystals or bundles when end-to-end connections involve multiple arms. They may play an important role in effective energy dissipation providing higher toughness of the gels. Visualization suggests that added polymer induces microphase separation with the formation of polymer-rich and CNC-rich microdomains. The local concentrating of CNCs within CNC-rich domains should promote the aggregation of nanocrystals and their crosslinking by calcium ions, thereby strengthening the CNC network. The ability of the prepared hydrogels for 3D printing was evaluated for the first time. It was shown that the incorporation of a rigid network into a soft one provides greater shape fidelity for hydrogels.
    Keywords:  Cellulose nanocrystals; Hydrogel; Hydroxypropyl guar; Polymer network; Rheological properties
    DOI:  https://doi.org/10.1016/j.jcis.2025.138836
  51. ACS Cent Sci. 2025 Aug 27. 11(8): 1355-1363
    Cleavable Additives for Deconstructable, Recyclable Polyurethane Thermosets.
    Kwangwook Ko, David J Lundberg, Valerie L Lensch, Yasmeen S AlFaraj, Keith E L Husted, Jacob P Brutman, Alaaeddin Alsbaiee, Patrick N Hamilton, Suong T Nguyen, Jeremiah A Johnson.
      Polyurethane (PU) thermosets, particularly those derived from aliphatic components, are challenging to chemically deconstruct due to their permanent cross-linking. Current approaches to impart deconstructability typically rely on complete substitution of network precursors with cleavable analogs, limiting practicality. Cleavable additives (CAs) offer a potentially simple and cost-effective alternative, yet their application has been largely confined to chain-growth networks and remains unexplored in end-linked systems such as PUs. Here, we present a generalizable reverse gel-point theory that predicts the minimum CA loading required for deconstruction of end-linked networks. We validate this framework experimentally through the incorporation of two classes of silyl ether-based CAsbifunctional cleavable strands (BCSs) and trifunctional cleavable junctions (TCJs)into PU thermosets. Both additives enable selective PU dissolution at low loadings (5-12 wt %), with TCJs demonstrating enhanced efficiency. The combined use of BCSs and TCJs also allows fine-tuning of material properties. Furthermore, we show that polyol fragments generated from the deconstruction of TCJ-containing PUs can be chemically repolymerized to regenerate PU materials without loss of mechanical performance over multiple cycles. This work establishes CAs as a viable strategy for advancing PU circularity and offers a foundational framework for their broader application in end-linked polymer networks.
    DOI:  https://doi.org/10.1021/acscentsci.5c00689
  52. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  53. ACS Appl Bio Mater. 2025 Aug 28.
    Investigating the Impact of Various 2D and 3D Cell Culture Platforms on the Production of Extracellular Vesicles.
    Kara Cook, Gisela Ströhle, Huiyan Li.
      Extracellular vesicles (EVs) play a critical role in intercellular communication and hold great promise as diagnostic biomarkers and therapeutic agents. Due to the limited availability of patient samples, in vitro cell culture models have become indispensable tools for generating EVs under controlled conditions and investigating their biological roles. While conventional 2D cultures are widely used, they lack the complexity of native tissues. In contrast, 3D culture platforms better mimic in vivo conditions and may influence EV secretion dynamics and characteristics. However, there is a lack of research directly comparing these various 2D and 3D platforms for EV production. In this study, we temporarily compared 2D culture with three 3D platforms composed of distinct biomaterials: ultralow attachment (ULA) plates with a nonadherent surface, collagen-coated plates with a biologically active matrix, and AlgiMatrix plates with porous alginate sponges. Cell growth and EV production were evaluated over multiple time points using the human mammary epithelial cell (HMEC) as a model, including assessments of cell morphology, EV yield, size distribution, and morphology. The results showed that both ULA and collagen-based platforms effectively produced smaller and more uniform EVs compared to the 2D platform, with yields exceeding those observed in 2D. In contrast, the AlgiMatrix system was unsuitable for size-based EV quantification due to contamination from scaffold-related materials. These results demonstrate distinct EV production shaped by the physical and biochemical features of each culture platform, highlighting the importance of biomaterial selection and time-course analysis when optimizing EV production for downstream applications, such as diagnostics and therapeutic development.
    Keywords:  3D culture; alginate; biomaterials; collagen; extracellular vesicles; spheroids
    DOI:  https://doi.org/10.1021/acsabm.5c01171
  54. Trends Biotechnol. 2025 Sep 02. pii: S0167-7799(25)00320-8. [Epub ahead of print]
    Engineering chimeric signaling proteins for microbial whole-cell biosensors: from design to deployment.
    Güniz Özer Bergman, Sonia Mecacci, Vitor A P Martins Dos Santos, Enrique Asin-Garcia.
      Microbial whole-cell biosensors (MWCBs) harness living cells to detect analytes and produce measurable outputs, enabling continuous, low-cost, and in situ sensing. Central to MWCB function are modular sensing architectures, which can be reprogrammed to respond to diverse signals. Particularly, two-component systems (TCSs) and allosteric transcription factors (aTFs) offer modular, engineerable frameworks for building chimeric proteins. Recent advances in domain swapping, fusion point selection, and protein engineering are expanding the versatility and specificity of these systems, presenting new opportunities for tailored and multiplexed detection. However, translating chimeric MWCBs into real-world applications still faces multiple hurdles. This review examines current strategies for engineering TCS- and aTF-based biosensors and outlines key opportunities and challenges for their deployment in applications such as diagnostics, environmental monitoring, and biomanufacturing.
    Keywords:  chimeric proteins; domain swapping; ligand specificity engineering; microbial whole-cell biosensors; modular biosensor design; prototype integration
    DOI:  https://doi.org/10.1016/j.tibtech.2025.08.002
  55. Angew Chem Int Ed Engl. 2025 Sep 04. e202514041
    Photoactivatable Synthetic Exosomes for RNA-Based Communication Between Artificial Cells and Living Cells.
    Alexander B Cook, Siwen Sun, Yudong Li, Jari Scheerstra, Jan C M van Hest.
      Artificial cells are self-assembled microstructures engineered to replicate the functions of natural cells, such as the capacity to interact and communicate. Until now, communication between artificial and living cells has mainly been based on the exchange of small molecules. An important communication pathway in living systems, however, involves the exchange of bioactive molecules such as neurotransmitters and nucleic acids via their protected transport with vesicles or exosomes. Here, we describe a modular strategy to construct artificial cells able to regulate mammalian cell protein expression via vesicle-based RNA communication. These artificial cells are assembled from amylose-based complex coacervates stabilized by a terpolymer membrane, with polymersomes containing RNA sequestered inside. The block copolymer vesicles have photocleavable surface groups, allowing charge switching behavior and expulsion from the overall positively charged coacervate lumen. The ability of our system to transmit RNA signals to natural cells was demonstrated with in vitro artificial cell-natural cell cocultures. Considering the crucial role of extracellular vesicles in genetic information transfer in nature, this artificial exosome design is an important step toward replicating nucleic acid communication pathways, further improving life-like behavior in artificial cell systems.
    Keywords:  Artificial cells; Biomaterials; Polymersomes; RNA communication; Supramolecular systems
    DOI:  https://doi.org/10.1002/anie.202514041
  56. Carbohydr Polym. 2025 Nov 15. pii: S0144-8617(25)00883-5. [Epub ahead of print]368(Pt 1): 124098
    A host/guest assembled hyaluronic acid-based supramolecular hydrogel with NIR-steered degradation capacity for enhanced tumor therapy through programmable drug release.
    Zejun Xu, Li Liu, Junkun Duan, Bei Guo, Jiayi Liu, Dongyan Liu, Fei Qin, Ruizhi Guo, Yingxia Bao, Jiansong Wang, Chuanbin Wu, Yi Zhang.
      Recently, a variety of stimulus-responsive hydrogel platforms have been developed, specifically designed to respond to changes in physiological signals within the disease microenvironment. However, due to the restricted regulation of drug release behavior in vivo by such hydrogel systems, the precise control of drug release kinetics has not been achieved. Therefore, developing precise drug delivery platforms that enable programmable and "on-off" delivery remains a challenge in this field. This study involved a supramolecular hydrogel platform (HACF) constructed with β-cyclodextrin-modified hyaluronic acid (HA-CD) and ferropentaene-modified hyaluronic acid (HA-Fc) for precise drug delivery and chemo-photothermal therapy by leveraging host-guest interactions between CD and Fc. The phthalocyanine green (ICG) and doxorubicin (DOX) were incorporated into the hydrogel network as photosensitizer and anticancer model drugs. Results demonstrated that ICG facilitated controlled disintegration of the hydrogel and led to responsive release of DOX in vitro under near-infrared (NIR) light stimulation. Furthermore, in vivo findings confirmed that NIR-steered programmed drug release from the hydrogel effectively enhanced anti-tumor efficacy and prevented tumor recurrence. In conclusion, this innovative NIR-driven supramolecular hydrogel platform not only presented a novel approach for remote and precise drug release but also provides a new platform for locally intelligent treatment across various clinical conditions.
    Keywords:  Chemo-photothermal therapy; Hyaluronic acid; Near-infrared; Precise drug release; Supramolecular hydrogel
    DOI:  https://doi.org/10.1016/j.carbpol.2025.124098
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