bims-enlima Biomed News
on Engineered living materials
Issue of 2025–10–26
38 papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. Gradients of Aliveness and Engineering: A Taxonomy of Fungal Engineered Living Materials.
  2. Programmable Assembly of Mechanically Robust and Functional Polymer-Spore Biocomposites in Organic Solvent.
  3. Bottom-up design of Ca2+ channels from defined selectivity filter geometry.
  4. DNA computing function switching by programming base stacking interactions with minimal molecular architecture changes.
  5. Engineering wetware and software for the predictive design of compressed genetic circuits for higher-state decision-making.
  6. Dynamic Bond Chemistry in Soft Materials: Bridging Adaptability and Mechanical Robustness.
  7. Polarization-driven spontaneous scrolling of two-dimensional materials.
  8. Enhanced toughness in highly entangled hydrogels via non-covalent molecular hooks.
  9. Programmable molecular dethreading towards tunable drug release.
  10. Bioinspired photoresponsive soft robotic lens.
  11. Global comparative structural analysis of responses to protein phosphorylation.
  12. Discovery and engineering of retrons for precise genome editing.
  13. scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.
  14. Living Materials Approach for In Situ Bio-Polymers Production Using Bacillus Paralicheniformis in Microneedles.
  15. Inverse Design of DNA-Programmable Protein Colloidal Crystals.
  16. Design and Fabrication of In-House Nozzle System to Extrude Multi-Hydrogels for 3D Bioprinting Process.
  17. Unisensory processing of interleaving memristive nanowires enabling multimodal sensing at human-scale resolution.
  18. A Photoswitchable HaloTag for Spatiotemporal Control of Fluorescence in Living Cells.
  19. Elucidating lipid nanoparticle properties and structure through biophysical analyses.
  20. Active learning framework leveraging transcriptomics identifies modulators of disease phenotypes.
  21. Multifunctional Polyphenolic Nanoparticle-Cross-Linked Aminoglycoside Hydrogels.
  22. Integrating Decision Trees and Clustering for Efficient Optimization of Bioink Rheology and 3D Bioprinted Construct Microenvironments.
  23. Sustainable synthesis of amino-cellulose nanofibers for biomaterial platforms.
  24. Label-free robotic mitochondrial biopsy.
  25. Democratizing protein language model training, sharing and collaboration.
  26. Feedback Controlled Reconfiguration of Ellipsoidal Colloids between Interfacial Liquid, Nematic, and Crystal States.
  27. Simultaneous modulation of chirality and mechanical properties in supramolecular hydrogels by varying alkyl spacer length.
  28. Preparation of Living Material with Metal-Organic Frameworks and Bacteria for the Design of Electrochemical Biosensor to Detect Exosomes.
  29. A porous 3D biofilm-inspired alginate/gellan hydrogel fabricated via dual-wavelength UV-crosslinking printer: Structural and rheological properties.
  30. Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency.
  31. Lighting up yeast: Overview of optogenetics in yeast and their applications to yeast biotechnology.
  32. An AI-driven workflow for the accelerated optimization of cell-free protein synthesis.
  33. Production of bio-based lactones as monomers for a circular polymer economy.
  34. Integrated epigenetic and genetic programming of primary human T cells.
  35. Adaptive Twisting Metamaterials.
  36. Nanostraw Electroporation for Temporal RNA Sampling from Living 2D and 3D Cell Culture Systems.
  37. Multiscale 3D Printing of Nanoporous Scaffolds with Surface Topography for Guiding 3D Cell Alignment.
  38. Proteolytically activated antibacterial toxins inhibit the growth of diverse gram-positive bacteria.
  1. Adv Mater. 2025 Oct 25. e02728
    Gradients of Aliveness and Engineering: A Taxonomy of Fungal Engineered Living Materials.
    Elise Elsacker, Jara Saluena Martin, Annah-Ololade Sangosanya, Anouk Verstuyft, Aurélie Van Wylick, Eveline Peeters.
      Filamentous fungi offer unique potential for engineered living materials (ELMs), enabling self-assembling, adaptive, and sustainable biofabrication. However, the field lacks a systematic framework to classify fungal ELMs, as they vary in biological state (dead, dormant, or living), scaffold composition, and degree of engineering intervention. Here, a classification system is introduced to categorize fungal ELMs, enabling researchers to map existing studies and guide future development. The ability to form resilient 3D networks make filamentous fungi ideal for applications ranging from self-healing composites to materials for bioremediation and real-time sensing, as demonstrated in proof-of-concept applications. A roadmap for next-generation fungal ELMs is outlined, including spatial-temporal control of fungal states, multispecies integration for enhanced complexity, and computational modeling for predictive design. Key challenges, such as contamination control, cell viability, and bio-digital integration, are discussed alongside strategies for genetic engineering. Finally, ethical and environmental considerations are emphasized as crucial factors for the responsible scaling of fungal ELMs.
    Keywords:  biodesign; biofabrication; engineered living materials (ELMs); filamentous fungi; mycelium materials; taxonomical framework
    DOI:  https://doi.org/10.1002/adma.202502728
  2. J Am Chem Soc. 2025 Oct 21.
    Programmable Assembly of Mechanically Robust and Functional Polymer-Spore Biocomposites in Organic Solvent.
    Masamu Kawada, Ziyu Cui, Justin Chen, Reis Dorit, Jaeho Cho, Seunghyun Sim.
      Microbial biocomposites offer genetically programmable and regenerative functionality, but their mechanical tunability remains limited by the mild conditions required for biological activity and viability. Here, we report the programmable self-assembly of Bacillus subtilis spores with benzalcyanoacetate (BCA)-functionalized polymers to form robust composites exhibiting tunable viscoelastic and tensile properties. Surface-exposed cysteines on the spore coat react with BCA motifs, forming dynamic thia-Michael networks with Young's moduli of >100 MPa. Systematic variation of BCA reactivity and comonomer-dependent polymer dynamics enabled control over stiffness, stress-relaxation behavior, microscale morphology, and covalent biocontainment. Incorporation of engineered spores confers catalytic function that can be regenerated following solvent-triggered disassembly. This work establishes a modular platform for constructing biocomposites that are both mechanically and genetically programmable, bridging the synthetic and biological domains through molecularly defined interfaces.
    DOI:  https://doi.org/10.1021/jacs.5c13976
  3. Nature. 2025 Oct 22.
    Bottom-up design of Ca2+ channels from defined selectivity filter geometry.
    Yulai Liu, Connor Weidle, Ljubica Mihaljević, Joseph L Watson, Zhe Li, Le Tracy Yu, Sagardip Majumder, Andrew J Borst, Kenneth D Carr, Ryan D Kibler, Tamer M Gamal El-Din, William A Catterall, David Baker.
      Native ion channels play key roles in biological systems, and engineered versions are widely used as chemogenetic tools and in sensing devices1,2. Protein design has been harnessed to generate pore-containing transmembrane proteins, but the design of selectivity filters with precise arrangements of amino acid side chains specific for a target ion, a crucial feature of native ion channels3, has been constrained by the lack of methods for placing the metal-coordinating residues with atomic-level precision. Here we describe a bottom-up RFdiffusion-based approach to construct Ca2+ channels from defined selectivity filter residue geometries, and use this approach to design symmetric oligomeric channels with Ca2+ selectivity filters having different coordination numbers and different geometries at the entrance of a wider pore buttressed by multiple transmembrane helices. The designed channel proteins assemble into homogeneous pore-containing particles and, for both tetrameric and hexameric ion-coordinating configurations, patch-clamp experiments show that the designed channels have higher conductances for Ca2+ than for Na+ and other divalent ions (Sr2+ and Mg2+) that are eliminated after mutation of selectivity filter residues. Cryogenic electron microscopy indicates that the design method has high accuracy: the structure of the hexameric Ca2+ channel is nearly identical to that of the design model. Our bottom-up design approach now enables the testing of hypotheses relating filter geometry to ion selectivity by direct construction, and provides a roadmap for creating selective ion channels for a wide range of applications.
    DOI:  https://doi.org/10.1038/s41586-025-09646-z
  4. Nat Commun. 2025 Oct 23. 16(1): 9369
    DNA computing function switching by programming base stacking interactions with minimal molecular architecture changes.
    Yongpeng Zhang, Bozhao Li, Xuan Liu, Xuedong Zheng, Shi Liu, Guangjun Nie, Jing Yang, Yonggang Ke, Suping Li, Cheng Zhang.
      In biological systems, molecular network functionalities are usually switched in a flexible, facile, and programmable manner. Mimicking this, substantial studies are directed towards developing synthetic DNA networks that exhibit similar function-switching capabilities, though often hindered by extensive molecular architecture changes and stringent condition controls, which result in a time-consuming and labor-intensive process. Here, we develop a base stacking-mediated allostery strategy to manipulate the DNA computing function switching with minimal molecular architecture changes, usually as few as 1-2 nucleotide changes. We implement up to 20 distinct logic function switching within DNAzyme networks. We also validate our function switching platform to implement totally 84 kinds of gene regulation patterns in cancer cell lines, demonstrating its utility in RNA sensing and green fluorescent protein regulation. This strategy offers a simplified alternative approach to enrich DNA regulations, with potential applications in DNA computing and bioengineering.
    DOI:  https://doi.org/10.1038/s41467-025-64406-x
  5. Nat Commun. 2025 Oct 24. 16(1): 9414
    Engineering wetware and software for the predictive design of compressed genetic circuits for higher-state decision-making.
    Brian D Huang, Yongjoon Yu, Junghwan Lee, Matthew W Repasky, Yao Xie, Matthew J Realff, Corey J Wilson.
      Synthetic genetic circuits enable the reprogramming of cells, advancing the study and application of biology with greater precision. However, quantitative circuit design is hampered by the limited modularity of biological parts. As circuit complexity increases, this imposes a greater metabolic burden on chassis cells, which limits circuit design capacity. Here, we present a generalizable wetware and complementary software to enable the quantitative design of genetic circuits that utilize fewer parts for higher-state decision-making. We term the process of designing smaller genetic circuits as compression. To accomplish this, we develop scalable wetware that leverages sets of synthetic transcription factors (i.e., network capable repressors and anti-repressors) and synthetic promoters that facilitate the full development of 3-input Boolean logic compression circuits. Complementary software enables the design of higher-state circuits with a minimal genetic footprint and quantitatively precise performance setpoints. On average the resulting multi-state compression circuits are approximately 4-times smaller than canonical inverter-type genetic circuits. Our quantitative predictions have an average error below 1.4-fold for >50 test cases. Additionally, we successfully apply this technology toward the predictive design of a recombinase genetic memory circuit, and flux through a metabolic pathway with precise setpoints.
    DOI:  https://doi.org/10.1038/s41467-025-64457-0
  6. Chem Rev. 2025 Oct 24.
    Dynamic Bond Chemistry in Soft Materials: Bridging Adaptability and Mechanical Robustness.
    Haeseung Lee, Jiyun Kim, Minwoo Lee, Jiheong Kang.
      Soft materials are polymer networks that can be easily deformed by external forces. Incorporating dynamic bonds into these networks imparts various functionalities─such as self-healing, recyclability, and 3D printability─by enabling fast and reversible bond formation. However, the relatively short lifetimes of dynamic bonds compared with permanent covalent bonds can compromise the mechanical robustness of the material. This review highlights design strategies that harness dynamic bonds effectively to achieve both functionality and mechanical robustness in soft materials. We first survey the types of dynamic bonds and their characteristic lifetimes, followed by introducing analytical methods to quantify the network dynamicity. Since the required degree of dynamicity varies depending on the target functionality, we further discuss how to incorporate appropriate dynamic bonds for functionality. Through this, we aim to provide design guidelines for soft materials that combine functionalities with mechanical toughness for reliable use in advanced applications.
    DOI:  https://doi.org/10.1021/acs.chemrev.5c00566
  7. Nat Mater. 2025 Oct 24.
    Polarization-driven spontaneous scrolling of two-dimensional materials.
      
    DOI:  https://doi.org/10.1038/s41563-025-02376-7
  8. Mater Horiz. 2025 Oct 20.
    Enhanced toughness in highly entangled hydrogels via non-covalent molecular hooks.
    Élise Ansart, Lucien Cousin, Mark W Tibbitt, Stefan Mommer.
      Hydrogels with enhanced toughness have received increasing attention due to their potential for load-bearing applications. Recent findings have demonstrated that highly entangled networks are capable of forming such materials, yet their fabrication generally necessitates a covalent cross-linker, limiting their processability and applicability. In this work, we found that poly(ethylene glycol) methyl ether acrylate (PEGmeAc) can serve as a non-covalent cross-linker for highly entangled poly(acrylamide) networks in dilute state, imparting extreme stretchability (6600%) and toughness (26 MJ m-3) to the hydrogels that otherwise flow within minutes. Oscillatory and rotational rheology demonstrates that the incorporation of 1 mol% of PEGmeAc is sufficient to provide structural stability to the hydrogel, increase relaxation time and improve elastic response, and severely inhibits disentanglement under shear. We hypothesized that this effect was caused by a combination of hydrogen bonding and topological entanglements, making PEGmeAc act as "hooks" within the network. The mechanism was confirmed through a combination of dissolution assays and nuclear Overhauser enhancement spectroscopy (NOESY), which showed that hydrogen bonding and topological entanglements are at play. Consequently, the incorporation of small quantities of such monomers into hydrogels may open new pathways to enhance the mechanical properties of soft materials.
    DOI:  https://doi.org/10.1039/d5mh01344e
  9. Nat Commun. 2025 Oct 23. 16(1): 9390
    Programmable molecular dethreading towards tunable drug release.
    Shen Sheng, Yuanhe Li, Ryan Ray Yen Lee, Yuxuan Gao, Huize Han, Zhijun Wan, Calvent Owh, Carol-Anne Ming Yi Chua, Zhen Yu Chong, Nicholas Wee Hao Ng, Wei Tang, Chong Tian.
      Precise control of molecular motion is essential for artificial molecular machines. Pseudorotaxane dethreading, a key process within interlocked architectures, offers a means to regulate such motion. However, achieving predictable and programmable control over dethreading kinetics remains challenging. Here, we achieve systematic modulation of dethreading behaviour through component engineering, using a pseudorotaxane platform composed of 24-crown-8-based macrocycles and adjustable benzylic amine stoppers. Activation energies are continuously tunable across the range of 22 to 30 kcal/mol, with a resolution as fine as 0.5-1.5 kcal/mol. Crystallographic analyses and computational modeling elucidate the dethreading pathway and the structure-kinetic relationships. As a proof-of-concept, representative assemblies are functionalized with the anticancer agent camptothecin. The resulting pseudorotaxanes display a consistent trend between their dethreading rates and cytotoxic potency. This work bridges molecular-scale mechanical motion with biological effects and provides a generalizable strategy for the design of programmable drug delivery systems. The pseudorotaxane toolkit reported here lays the foundation for the development of advanced molecular machines in biomedical applications.
    DOI:  https://doi.org/10.1038/s41467-025-64452-5
  10. Sci Robot. 2025 Oct 22. 10(107): eadw8905
    Bioinspired photoresponsive soft robotic lens.
    Corey Zheng, Shu Jia.
      Vision is a critical sensory function for humans, animals, and engineered systems, enabling environmental perception essential for imaging and autonomous operation. Although bioinspired, tunable optical systems have advanced adaptability and performance, challenges remain in achieving biocompatibility, robust yet flexible construction, and specialized multifunctionality. Here, we present a photoresponsive hydrogel soft lens (PHySL) that combines optical tunability, an all-solid configuration, and high resolution. PHySL leverages a dynamic hydrogel actuator that autonomously harnesses optical energy, enabling substantial focal tuning through all-optical control. Beyond mimicking biological vision, the system achieves advanced functionalities, including focus control, wavefront engineering, and optical steering by responding to spatiotemporal light stimuli. PHySL highlights the potential of optically powered soft robotics applied in soft vision systems, autonomous soft robots, adaptive medical devices, and next-generation wearable systems.
    DOI:  https://doi.org/10.1126/scirobotics.adw8905
  11. Nat Commun. 2025 Oct 24. 16(1): 9407
    Global comparative structural analysis of responses to protein phosphorylation.
    Miguel Correa Marrero, Victor Hugo Mello, Pablo Sartori, Pedro Beltrao.
      Post-translational modifications (PTMs), particularly protein phosphorylation, are key regulators of cellular processes, impacting numerous aspects of protein activity. Despite widespread phosphorylation of eukaryotic proteomes, the function of most phosphosites remains unknown. Elucidating the structural mechanisms underlying phosphorylation is crucial for understanding its regulatory roles. Here, we present a comparative structural analysis of phosphorylated and non-phosphorylated proteins taken from the Protein Data Bank (PDB). Our study systematically evaluates how phosphorylation affects backbone conformation, protein dynamics, and mechanical strain. We found that phosphorylation commonly induces small, stabilizing conformational changes through conformational selection and frequently modulates local residue fluctuations, influencing overall protein motion. Notably, a small but significant subset of phosphosites shows mechanical coupling with functional sites, aligning with the domino model of allosteric signal transduction. This work provides a foundation for studying phosphorylation and other PTMs in their structural context, which will guide the rational design of synthetic phosphosites and enable the engineering of PTM-driven regulatory circuits in synthetic biology.
    DOI:  https://doi.org/10.1038/s41467-025-64116-4
  12. Nat Biotechnol. 2025 Oct 23.
    Discovery and engineering of retrons for precise genome editing.
    Jesse D Buffington, Hung-Che Kuo, Kuang Hu, You-Chiun Chang, Kamyab Javanmardi, Brittney Voigt, Yi-Ru Li, Mary E Little, Sravan K Devanathan, Blerta Xhemalçe, Ryan S Gray, Ilya J Finkelstein.
      Retrons can produce multicopy single-stranded DNA in cells through self-primed reverse transcription. However, their potential for inserting genetic cargos in eukaryotes remains largely unexplored. Here we report the discovery and engineering of highly efficient retron-based gene editors for mammalian cells and vertebrates. Through bioinformatic analysis of metagenomic data and functional screening, we identify retron reverse transcriptases that are highly active in mammalian cells. Rational design further improves the editing efficiency to levels comparable with conventional single-stranded oligodeoxynucleotide donors but from a genetically encoded cassette. Retron editors exhibit robust activity with Cas12a nuclease and Cas9 nickase, expanding the genomic target scope and bypassing the need for a DNA double-stranded break. Using a rationally engineered retron editor, we incorporate a split GFP epitope tag for live-cell imaging. Lastly, we develop an all-RNA delivery strategy to enable DNA-free gene editing in cells and vertebrate embryos. This work establishes retron editors as a versatile and efficient tool for precise gene editing.
    DOI:  https://doi.org/10.1038/s41587-025-02879-3
  13. Nat Methods. 2025 Oct 22.
    scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.
    Johannes C Hingerl, Laura D Martens, Alexander Karollus, Trevor Manz, Jason D Buenrostro, Fabian J Theis, Julien Gagneur.
      Understanding how regulatory sequences shape gene expression across individual cells is a fundamental challenge in genomics. Joint RNA sequencing and epigenomic profiling provides opportunities to build models capturing sequence determinants across steps of gene expression. However, current models, developed primarily for bulk omics data, fail to capture the cellular heterogeneity and dynamic processes revealed by single-cell multimodal technologies. Here, we introduce scooby, a framework to model genomic profiles of single-cell RNA-sequencing coverage and single-cell assay for transposase-accessible chromatin using sequencing insertions from sequence at single-cell resolution. For this, we leverage the pretrained multiomics profile predictor Borzoi and equip it with a cell-specific decoder. Scooby recapitulates cell-specific expression levels of held-out genes and identifies regulators and their putative target genes. Moreover, scooby allows resolving single-cell effects of bulk expression quantitative trait loci and delineating their impact on chromatin accessibility and gene expression. We anticipate scooby to aid unraveling the complexities of gene regulation at the resolution of individual cells.
    DOI:  https://doi.org/10.1038/s41592-025-02854-5
  14. Adv Healthc Mater. 2025 Oct 24. e03630
    Living Materials Approach for In Situ Bio-Polymers Production Using Bacillus Paralicheniformis in Microneedles.
    Caroline Hali Alperovitz, Noa Ben David, Adi Gross, Boaz Mizrahi.
      Living biomaterials, which integrate live organisms with traditional macromolecular scaffolds, function as "live manufacturers" capable of sensing their environment, synthesizing, and releasing biomolecules while remaining stable under physiological conditions. While systems that produce small biomolecules continue to advance, in situ production and secretion of high-molecular-weight biopolymers remain relatively underexplored. Here, a microneedle (MN) patch system is presented encapsulating Bacillus paralicheniformis (B. paralicheniformis) - a non-pathogenic, Gram-positive bacterium known for its production of γ-polyglutamic acid (γ-PGA). The MNs are designed to painlessly penetrate the stratum corneum and reach the dermis. Bacteria are uniformly distributed within the patch, and their presence has minimal impact on the microneedles' morphology and mechanical integrity. Upon application, B. paralicheniformis is released from the MNs and successfully produced γ-PGA, with molecular weights ranging from 64 to 563 kDa. Growth studies revealed that Luria-Bertani (LB) medium supports optimal bacterial proliferation, while E medium enhances γ-PGA biosynthesis. In vivo studies confirmed that B. paralicheniformis colonized mouse skin following MN administration and secreted γ-PGA without eliciting toxicity or inflammatory responses. Given the increasing therapeutic use of biopolymers and proteins for treating chronic and acute skin conditions, this living bacterial delivery system offers a promising platform for sustainable and symbiotic dermal therapies.
    Keywords:  PGA; PVA; PVP; bacillus paralicheniformis; living materials; microneedles
    DOI:  https://doi.org/10.1002/adhm.202503630
  15. J Am Chem Soc. 2025 Oct 21.
    Inverse Design of DNA-Programmable Protein Colloidal Crystals.
    Zhenyu Han, Young Jun Kim, Chad A Mirkin.
      Protein crystals are a promising class of porous materials with applications in catalysis, encapsulation, and structural biology. However, the chemical complexity of proteins renders their crystallization a largely empirical process with variable success. In contrast, DNA-functionalized nanoparticles have been crystallized into ordered superlattices with predictable architectures using highly specific and tunable DNA-DNA interactions. Such programmability, however, has not yet been realized in protein crystals. Herein, we chemically modify protein oligomers with a DNA shell and crystallize the resulting protein-DNA conjugates using the principles of colloidal crystal engineering with DNA. When a new type of DNA design comprising three spacer-18 units and a 4-6 nucleotide sticky end was used, structures with greater crystallinity were produced (as compared to when traditional DNA designs used with inorganic assemblies were employed). Using an inverse design strategy, simple cubic, body-centered cubic (bcc), face-centered cubic (fcc), and cesium chloride (CsCl)-type lattices were synthesized by the judicious choice of DNA sequence and protein type. The resulting crystals exhibit Wulff morphologies, including those of fcc lattices, that were directly observable using optical microscopy; such morphologies are rarely achieved in the context of DNA-guided colloidal crystals and reflect the monodisperse protein building blocks. Furthermore, the annealing rate correlates with crystal growth, enabling the formation of crystals up to 80 μm in size. Given the structural, biological, and chemical diversity of natural and engineered proteins, DNA-directed protein colloidal crystallization is a powerful platform for generating a new class of programmable biomaterials with diverse structures and functionalities.
    DOI:  https://doi.org/10.1021/jacs.5c15424
  16. J Manuf Sci Eng. 2024 Feb 01. 146(2): 021003
    Design and Fabrication of In-House Nozzle System to Extrude Multi-Hydrogels for 3D Bioprinting Process.
    Ahasan Habib, Connor Quigley, Rokeya Sarah, Warren Hurd, Scott Clark.
      The field of 3D bioprinting is rapidly expanding as researchers strive to create functional tissues for medical and pharmaceutical purposes. The ability to print multiple materials, each containing various living cells, brings us closer to achieving tissue regeneration. Deliberately transitioning between different material types encapsulating distinct cells and extruding through a single outlet, can lead to the achievement of user-defined material distribution, which is still challenging. In a previous study, we designed a Y-shaped nozzle connector system that allowed for continuous deposition of multiple materials through a single outlet. This system was made of plastic and had a fixed switching angle, rendering it suitable for a single use. In this article, we present the updated version of our nozzle system, which includes a range of angles (30 deg, 45 deg, 60 deg, and 90 deg) between the two materials. Changing the angles helps us figure out how that affects the control of backflow and minimizes the overall material switching time in the nozzle. We used stainless steel as the fabrication material and recorded the overall material switching time, comparing the effects of the various angles. Our previously developed hybrid hydrogel, which comprised 4% alginate and 4% carboxymethyl cellulose (CMC), was used as a test material to flow through the nozzle system. The in-house fabricated nozzle connectors are reusable, sterile, and easy to clean, ensuring a smooth material transition and flow. Our proposition can offer to achieve user-defined material distribution across a given region with appropriate selection of rheology and printing process parameters.
    Keywords:  3D bioprinting; CAD/CAM/CAE; additive manufacturing; biomedical manufacturing; design for manufacturing; hybrid hydrogel; multimaterial; nozzle system; rapid prototyping, solid freeform fabrication; shape fidelity
    DOI:  https://doi.org/10.1115/1.4063357
  17. Nat Mater. 2025 Oct 24.
    Unisensory processing of interleaving memristive nanowires enabling multimodal sensing at human-scale resolution.
    Kyun Kyu Kim, Junhyuk Bang, Munju Kim, Juho Jeong, Inho Ha, Seung Hwan Ko.
      Numerous attempts have been made to emulate the skin's multimodal capabilities using different device architectures, but most suffer from slow response due to reactive components and limited scalability from stacking multiple elements, which restricts their practical use. Here we report a multimodal receptor based on a single memristive nanowire network that captures both thermal and mechanical properties of interacting objects through memristive switching. The device switches between thermal and mechanical sensing at 16 Hz, whereas its intrinsic response times reach submicrosecond (mechanical) and millisecond (thermal) levels due to the nanoscale thickness. To demonstrate practicality, we integrated the receptor with a wireless switching board for daily use, combined it with a machine learning model to identify 20 household objects with 83% accuracy using a single fingertip-mounted sensor, and performed multiarray measurements for spatially distributed sensing. This approach highlights the potential of memristive networks for compact and versatile multimodal sensing in wearable and interactive devices.
    DOI:  https://doi.org/10.1038/s41563-025-02373-w
  18. Angew Chem Int Ed Engl. 2025 Oct 23. e202424955
    A Photoswitchable HaloTag for Spatiotemporal Control of Fluorescence in Living Cells.
    Franziska Walterspiel, Begoña Ugarte-Uribe, Jonas Weidenhausen, Merrin Vincent, Kaarjel K Narayanasamy, Anna Dimitriadi, Arif Ul Maula Khan, Martin Fritsch, Christoph W Müller, Timo Zimmermann, Claire Deo.
      Photosensitive fluorophores, whose emission can be controlled using light, are essential for advanced biological imaging, enabling precise spatiotemporal tracking of molecular features and facilitating super-resolution microscopy techniques. Although irreversibly photoactivatable fluorophores are well established, reversible reporters that can be reactivated multiple times remain scarce, and only a few have been applied in living cells using generalizable protein labeling methods. To address these limitations, we introduce chemigenetic photoswitchable fluorophores, leveraging the self-labeling HaloTag protein with fluorogenic rhodamine dye ligands. By incorporating a light-responsive protein domain into HaloTag, we engineer a tunable, photoswitchable HaloTag (psHaloTag), which can reversibly modulate the fluorescence of a bound dye-ligand via a light-induced conformational change. Our best performing psHaloTag variants show excellent performance in living cells, with large, reversible, deep-red fluorescence turn-on upon 450 nm illumination across various biomolecular targets and SMLM compatibility. Together, this work establishes the chemigenetic approach as a versatile platform for the design of photoswitchable reporters, tunable through both genetic and synthetic modifications, with promising applications for dynamic imaging.
    Keywords:  Chemigenetic; Fluorescence microscopy; HaloTag; Photoswitch; Rhodamine
    DOI:  https://doi.org/10.1002/anie.202424955
  19. Nat Biotechnol. 2025 Oct 23.
    Elucidating lipid nanoparticle properties and structure through biophysical analyses.
    Marshall S Padilla, Sarah J Shepherd, Andrew R Hanna, Martin Kurnik, Xujun Zhang, Michelle Chen, James Byrnes, Ryann A Joseph, Hannah M Yamagata, Adele S Ricciardi, Kaitlin Mrksich, David Issadore, Kushol Gupta, Michael J Mitchell.
      Designing lipid nanoparticle (LNP) delivery systems with specific targeting, potency and minimal side effects is crucial for their clinical use. However, traditional characterization methods, such as dynamic light scattering, cannot accurately quantify physicochemical properties of LNPs and how these are influenced by the lipid composition and mixing method. Here, we structurally characterize polydisperse LNP formulations by applying emerging solution-based biophysical methods that have higher resolution and provide biophysical data beyond size and polydispersity. These techniques include sedimentation velocity analytical ultracentrifugation, field-flow fractionation followed by multiangle light scattering and size-exclusion chromatography in line with synchrotron small-angle X-ray scattering. We show that LNPs have intrinsic polydispersity in size, RNA loading and shape, which depend on both the formulation technique and the lipid composition. Lastly, we predict LNP transfection in vitro and in vivo by examining the relationship between mRNA translation and physicochemical characteristics. Solution-based biophysical methods will be essential for determining LNP structure-function relationships, facilitating the creation of new design rules for LNPs.
    DOI:  https://doi.org/10.1038/s41587-025-02855-x
  20. Science. 2025 10 23. eadi8577
    Active learning framework leveraging transcriptomics identifies modulators of disease phenotypes.
    Benjamin DeMeo, Charlotte Nesbitt, Samuel A Miller, Daniel B Burkhardt, Inna Lipchina, Doris Fu, Peter Holderrieth, David Kim, Sergey Kolchenko, Artur Szalata, Ishan Gupta, Christine Kerr, Thomas Pfefer, Raziel Rojas-Rodriguez, Sunil Kuppassani, Laurens Kruidenier, Parul B Doshi, Mahdi Zamanighomi, James J Collins, Alex K Shalek, Fabian J Theis, Mauricio Cortes.
      Phenotypic drug screening remains constrained by the vastness of chemical space and technical challenges scaling experimental workflows. To overcome these barriers, computational methods have been developed to prioritize compounds, but they rely on either single-task models lacking generalizability or heuristic-based genomic proxies that resist optimization. We designed an active deep-learning framework that leverages omics to enable scalable, optimizable identification of compounds that induce complex phenotypes. Our generalizable algorithm outperformed state-of-the-art models on classical recall, translating to a 13-17x increase in phenotypic hit-rate across two hematological discovery campaigns. Combining this algorithm with a lab-in-the-loop signature refinement step, we achieved an additional two-fold increase in hit-rate and molecular insights. In sum, our framework enables efficient phenotypic hit identification campaigns, with broad potential to accelerate drug discovery.
    DOI:  https://doi.org/10.1126/science.adi8577
  21. Biomacromolecules. 2025 Oct 19.
    Multifunctional Polyphenolic Nanoparticle-Cross-Linked Aminoglycoside Hydrogels.
    Zhan Li, Jianhua Zhang, Hengjie Zhang, Tianyou Wang, Yuxian Song, Pengyu Liu, Yiwen Li, Hong Liu, Wancai Guo, Zhipeng Gu.
      Multifunctional hydrogels with integrated antioxidant and antibacterial activities are vital for modulating the wound microenvironment, mitigating oxidative stress, and preventing infection. However, efficient construction of such hydrogels with programmable responsiveness and structural integrity that can be tailored to therapeutic demands remains challenging. Herein, we developed a modular, functionally programmable hydrogel platform constructed via an in situ Schiff base reaction between aldehyde-functionalized polyphenolic nanoparticles and aminoglycoside antibiotics. The resulting nanocomposite hydrogels exhibited excellent mechanical properties, pH-responsiveness, biodegradability, and biocompatibility, attributed to the synergistic interactions between the functional nanoscale building blocks and cross-linkers. In vitro and in vivo evaluations confirmed the hydrogel's potent antibacterial and antioxidant capabilities, enabling effective infection control and attenuation of oxidative stress in wound environments. This strategy offers a versatile route for engineering adaptive, multifunctional hydrogels for advanced wound management.
    DOI:  https://doi.org/10.1021/acs.biomac.5c01289
  22. J Manuf Sci Eng. 2025 Sep 01. 147(9): 091003
    Integrating Decision Trees and Clustering for Efficient Optimization of Bioink Rheology and 3D Bioprinted Construct Microenvironments.
    Shah M Limon, Rokeya Sarah, Ahasan Habib.
      Among various 3D bioprinting methods, extrusion-based bioprinting stands out for its ability to maintain high cell viability and create intricate scaffold structures. However, working with synthetic polymers or natural shear-thinning hydrogels requires precise control of rheological properties, such as viscosity, to ensure scaffold stability while supporting living cells. Traditionally, researchers address these challenges through extensive experimentation, separately optimizing material properties and bioprinting performance. This process, though effective, is often slow and resource-heavy. To streamline this workflow, computational approaches like machine learning are proving invaluable. In this study, a decision tree model was developed to predict the viscosity of bioinks across various compositions with high accuracy, significantly reducing the trial-and-error phase of experimentation. Once viscosity is optimized, k-means clustering is applied to analyze and group scaffolds based on their mechanical and biological properties. This clustering technique identifies the optimal characteristics for scaffolds, balancing structural fidelity and cell viability. The integration of these computational tools allows researchers to optimize bioink formulations and printing parameters more efficiently. By reducing experimental workload and improving precision, this approach not only accelerates the bioprinting process but also ensures that the resulting scaffolds meet the required mechanical integrity and provide a conducive environment for cell growth. This study represents a significant step forward in tissue engineering, offering a robust, data-driven pathway to enhance both the efficiency and quality of 3D bioprinted constructs.
    Keywords:  3D bioprinting; CAD/CAM/CAE; additive manufacturing; advanced materials and processing; biomedical manufacturing; clustering; decision tree; machine learning; rheology; sustainable manufacturing
    DOI:  https://doi.org/10.1115/1.4068429
  23. Sci Adv. 2025 Oct 24. 11(43): eadx4556
    Sustainable synthesis of amino-cellulose nanofibers for biomaterial platforms.
    Xiaochao Shi, Jian Zhang, Weixin Guan, Cong Li, Wenshuai Chen, Guihua Yu, Haipeng Yu.
      The increasing demand for sustainable materials has driven interest in harnessing renewable resources to develop advanced biomaterials. Cellulose nanofibers, derived from abundant natural reserves, offer excellent mechanical strength and thermal stability but lack inherent biofunctionality. This study presents a method that is green, cost-effective, and scalable to synthesize amino-cellulose nanofibers (A-CNFs) by grafting carboxyl groups and thereon amino groups onto cellulose, followed by ultrasonic nanofibrillation, resulting in ultrafine, lengthy A-CNF with enhanced mechanical properties, biocompatibility, and antibacterial activity. Comparative analyses demonstrate that A-CNF scaffolds exhibit favorable biostability, pore connectivity, and mechanical integrity in tissue engineering applications. Biological assessments further indicate improved cell viability and reduced hemolysis, underscoring A-CNF's potential as robust, biocompatible, and sustainable material platforms for biomedical use.
    DOI:  https://doi.org/10.1126/sciadv.adx4556
  24. Sci Adv. 2025 Oct 24. 11(43): eadx4289
    Label-free robotic mitochondrial biopsy.
    Yanmei Ma, Weikang Hu, Muyang Ruan, Feixiang Bao, Xingguo Liu, Dong Sun, Hongri Gu, Chengzhi Hu.
      Robotic micromanipulation has advanced cellular probing, yet achieving precise, minimally invasive intracellular operations without fluorescent labeling remains challenging. Fluorescent techniques often cause photodamage and cytotoxicity and interfere with downstream analyses. Here, we introduce an automated, multifunctional nanoprobing platform capable of label-free extraction of mitochondria from living cells with high spatiotemporal resolution. The nanoprobe integrates two individually addressable nanoelectrodes that perform electrochemical detection of reactive oxygen and nitrogen species, produced by mitochondrial metabolism, followed by dielectrophoretic trapping, manipulation, and extraction of mitochondria. We successfully demonstrated the extraction of mitochondria from living cells, which is validated through fluorescence labeling before and after extraction. Subsequent quantitative polymerase chain reaction further confirmed that the extracted sample contained mitochondria. The fusion of the transplanted mitochondria within the recipient cell's mitochondrial network confirms their activity. This automated, label-free, in situ organelle extraction micromanipulation system offers a powerful tool for understanding disease mechanisms linked to dysfunctional organelles and enables single-cell surgeries for organelle transplantation.
    DOI:  https://doi.org/10.1126/sciadv.adx4289
  25. Nat Biotechnol. 2025 Oct 24.
    Democratizing protein language model training, sharing and collaboration.
    OPMC
      Training and deploying large-scale protein language models typically requires deep machine learning expertise-a barrier for researchers outside this field. SaprotHub overcomes this challenge by offering an intuitive platform that facilitates training and prediction as well as storage and sharing of models. Here we provide the ColabSaprot framework built on Google Colab, which potentially powers hundreds of protein training and prediction applications, enabling researchers to collaboratively build and share customized models.
    DOI:  https://doi.org/10.1038/s41587-025-02859-7
  26. ACS Appl Mater Interfaces. 2025 Oct 22.
    Feedback Controlled Reconfiguration of Ellipsoidal Colloids between Interfacial Liquid, Nematic, and Crystal States.
    Lechuan Zhang, Michelle Sandag, Alec Pellicciotti, Michael A Bevan.
      We report AC electric field mediated feedback control over the reversible assembly, disassembly, and reconfiguration of elliptical prism colloidal particles between liquid, nematic, and crystal states with continuously varying orientational and positional order. Accessible states are first systematically identified by varying field parameters and quantifying microstructures with nematic and crystallinity order parameters. The same order parameters vs time are used as reaction coordinates to track nonequilibrium microstructure evolution between states. A proportional feedback controller for reaction coordinate trajectories is designed to target microstructures with different degrees of order, where gain constants are tuned to maximize transition rates between states orders of magnitude faster than diffusion limited rates (on second to minute time scales). The resulting feedback control approach is demonstrated for time-dependent reaction coordinate trajectories including sinusoidal, step changes, and programmed multistate profiles. Our results and findings demonstrate a generalizable scalable approach to formally control navigation of dynamic pathways between microstructural states in a system of anisotropic colloidal particles, which can be used to control processing of particle-based materials, coatings, and devices.
    Keywords:  AC electric fields; dipolar interactions; dynamic pathways; nonequilibrium dynamics; time-varying trajectories
    DOI:  https://doi.org/10.1021/acsami.5c15509
  27. Soft Matter. 2025 Oct 24.
    Simultaneous modulation of chirality and mechanical properties in supramolecular hydrogels by varying alkyl spacer length.
    Yanyan Zhang, Yingying Chen, Jiahao Li, Jian Zhang, Chuan-Liang Feng, Jinying Liu.
      Mimicking the extracellular matrix's (ECM's) integration of chiral and mechanical cues remains challenging in synthetic hydrogels. Here, we demonstrate that alkyl spacer engineering in C2-symmetric benzene-para-dicarboxamide phenylalanine derivatives enables simultaneous control of supramolecular handedness and mechanics: helical handedness follows spacer odd-even effects, while spacer elongation (n = 2→4) drives a 17-fold elastic modulus enhancement (0.45→7.64 kPa). This dual regulation provides a versatile strategy for designing biomimetic hydrogels.
    DOI:  https://doi.org/10.1039/d5sm00907c
  28. Small. 2025 Oct 24. e08741
    Preparation of Living Material with Metal-Organic Frameworks and Bacteria for the Design of Electrochemical Biosensor to Detect Exosomes.
    Haojie Xie, Lin Wang, Gaoxiang Wang, Ying Deng, Xiafei Hu, Yifan Lin, Dongmei Zhang, Tao Gao, Ping Xie, Genxi Li.
      As a new generation of intelligent materials, living materials composed of biological elements and non-living matrix may integrate the characteristics of both, so they have received more and more attention. However, their application to biosensor development is insufficient, especially the living materials prepared with bacteria and metal-organic frameworks (MOFs). Herein, an electroactive bacterium (Shewanella oneidensis MR-1, S.oneidensis) and one kind of MOFs (Cu-TCPP) are adopted in this work to prepare an electroactive living material, which is further used to design and fabricate an electrochemical biosensor. It is found that the integration of Cu-TCPP with S.O. can facilitate electrochemical signal output, which may be attributed to synergy effects between S.O. and Cu-TCPP. Furthermore, the living material is explored to bind with aptamers for the electrochemical detection of targets. Taking the analysis of exosomes as an example, the fabricated biosensor can detect exosomes in the range of 1.38 × 103-1.38 × 107 particles mL-1, with the detection limit of 659 particles mL-1, without the requirement of a signal amplification strategy, thus proposing a way of living material-based biosensor fabrication.
    Keywords:  bacteria; biosensor; exosome; living materials; metal–organic framework
    DOI:  https://doi.org/10.1002/smll.202508741
  29. Carbohydr Polym. 2025 Dec 15. pii: S0144-8617(25)01031-8. [Epub ahead of print]370 124246
    A porous 3D biofilm-inspired alginate/gellan hydrogel fabricated via dual-wavelength UV-crosslinking printer: Structural and rheological properties.
    Peyman Asghartabar Kashi, Caroline Bachlechner, Delphine Huc-Mathis, Henry Jäger, Mahdiyar Shahbazi.
      The advancement of additive manufacturing for biopolymers with spatially tailored properties remains challenging, particularly in multi-material structures. Traditional methods relying on automated sample swapping compromise production speed and interlayer adhesion. Critically, existing biofilm models predominantly use 2D formats that fail to replicate essential 3D microenvironments for structural development and antimicrobial resistance-limiting their physiological relevance. To address both manufacturing and modeling limitations, we introduce a novel dual-wavelength in-place UV crosslinking technique using chemo-selective irradiation (UV-A:390 nm and UV-C:260 nm) in combination with a Norrish Type I photoinitiator to fabricate multi-material macroporous biofilm-inspired architecture with enhanced mechanical and rheological properties, as well as effective 3D architectures for biofilm simulation. An alginate/gellan-inspired hydrogel mimicking biofilm materials enables stiffness modulation via photosensitization tuning. Results demonstrated UV-A yielded softer, flexible networks while UV-C produced stiffer, elastic structures. The application of Norrish type I photoinitiators in combination with in-place UV irradiation-coupled with bioprinter considerably broadened the achievable thermo-mechanical and cytocompatibility with improved build efficiency, overcoming traditional UV-curing limitations for functional multi-material components in advanced manufacturing and physiologically relevant biofilm modeling.
    Keywords:  Cytocompatibility; Dual-wavelength 3D bioprinting; Hierarchical porosity; Photosensitizer; Rheological properties; Solid-state NMR; UV-crosslinking; biofilm imitation
    DOI:  https://doi.org/10.1016/j.carbpol.2025.124246
  30. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2505237122
    Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency.
    John Soukar, Kanwar Abhay Singh, Ari Aviles, Sarah Hargett, Harman Kaur, Samantha Foster, Shounak Roy, Feng Zhao, Vishal M Gohil, Irtisha Singh, Akhilesh K Gaharwar.
      Intercellular mitochondrial transfer, the spontaneous exchange of mitochondria between cells, is a recently described phenomenon crucial for cellular repair, regeneration, and disease management. Enhancing this natural process holds promise for developing novel therapies targeting diseases associated with mitochondrial dysfunction. Here, we introduce a nanomaterial-based approach employing molybdenum disulfide (MoS2) nanoflowers with atomic-scale vacancies to stimulate mitochondrial biogenesis in cells to make them mitochondrial biofactories. Upon cellular uptake, these nanoflowers result in a two-fold increase in mitochondrial mass and enhancing mitochondrial transfer to recipient cells by several-fold. This enhanced efficiency of transfer significantly improves mitochondrial respiratory capacity and adenosine triphosphate production in recipient cells under physiological conditions. In cellular models of mitochondrial and cellular damage, MoS2 enhanced mitochondrial transfer achieved remarkable restoration of cell function. This proof-of-concept study demonstrates that nanomaterial-boosted intercellular mitochondrial transfer can enhance cell survivability and function under diseased conditions, offering a promising strategy for treating mitochondrial dysfunction-related diseases.
    Keywords:  biomaterials; cellular medicine; mitochondria; nanomaterials; regenerative medicine
    DOI:  https://doi.org/10.1073/pnas.2505237122
  31. FEMS Yeast Res. 2025 Oct 22. pii: foaf064. [Epub ahead of print]
    Lighting up yeast: Overview of optogenetics in yeast and their applications to yeast biotechnology.
    Jaewan Jang, José L Avalos.
      Optogenetics is an empowering technology that uses light-responsive proteins to control biological processes. Because of its genetic tractability, abundance of genetic tools, and robust culturing conditions, Saccharomyces cerevisiae has served for many years as an ideal platform in which to study, develop, and apply a wide range of optogenetic systems. In many instances, yeast has been used as a steppingstone in which to characterize and optimize optogenetic tools to later be deployed in higher eukaryotes. More recently, however, optogenetic tools have been developed and deployed in yeast specifically for biotechnological applications, including in non-conventional yeasts. In this review, we summarize various optogenetic systems responding to different wavelengths of light that have been demonstrated in diverse yeast species. We then describe various applications of these optogenetic tools in yeast, particularly in metabolic engineering and recombinant protein production. Finally, we discuss emerging applications in yeast cybergenetics-the interfacing of yeast and computers for closed-loop controls of yeast bioprocesses-and the potential impact of optogenetics in other future biotechnological applications.
    DOI:  https://doi.org/10.1093/femsyr/foaf064
  32. iScience. 2025 Oct 17. 28(10): 113599
    An AI-driven workflow for the accelerated optimization of cell-free protein synthesis.
    Mostafa M Khalil, Aisha Elsawah, An N Hoang, Jean-Loup Faulon, Baptiste Panthu, Joan Hérisson.
      Cell-free protein synthesis (CFPS) is a versatile tool for rapid biological prototyping. However, exploring the large number of component combinations is a very time-consuming process. Active learning (AL) is known to reduce the number of experiments required, but is rarely integrated into routine laboratory workflows. To address this, we developed a fully automated Design-Build-Test-Learn (DBTL) pipeline that streamlines this optimization process with an improved AL strategy that selects informative and diverse experimental conditions. The Design phase was created entirely using ChatGPT-4 without manual code revisions, dramatically reducing coding time. This pipeline was implemented in a modular way within the Galaxy platform, following the Findable-Accessible-Interoperable-Reusable (FAIR) principles. When applied to the optimization of colicin M and E1 in both Escherichia coli and HeLa-based CFPS systems, a 2- to 9-fold increase in yield was achieved in just four cycles. This framework enables reliable, automated workflows for routine synthetic biology.
    Keywords:  metabolic engineering; protein; synthetic biology
    DOI:  https://doi.org/10.1016/j.isci.2025.113599
  33. Nat Rev Chem. 2025 Oct 22.
    Production of bio-based lactones as monomers for a circular polymer economy.
    Daniyal Kiani, Ross Eaglesfield, James H May, Allison Z Werner, Eugene Y-X Chen, Yuriy Román-Leshkov, Yomaira J Pagán-Torres, Gregg T Beckham.
      To create a circular plastics economy, new polymers are being developed that can be chemically recycled. Circular polyesters are of particular interest and to this end, lactones are ideal monomers. This Review examines catalytic routes to convert diols, hydroxy acids, and dicarboxylic acids to lactones, focusing on the development of scalable, atom-economic, and energy-efficient conversions of bio-derived feedstocks. Free energy analysis is used to inform process choices, such as reactor type, reaction phase, and use of solvent. Catalyst design principles are summarized for both direct (bio-substrate to lactone) and indirect (bio-substrate to intermediate to lactone) routes. Finally, we summarize literature that shows that many lactone precursors are readily accessible from various metabolic and chemo-catalytic pathways. Transitioning to bio-based monomers offers an opportunity to reduce reliance on fossil carbon resources, but requires advanced catalytic processes informed by mechanistic insights.
    DOI:  https://doi.org/10.1038/s41570-025-00765-9
  34. Nat Biotechnol. 2025 Oct 21.
    Integrated epigenetic and genetic programming of primary human T cells.
    Laine Goudy, Alvin Ha, Ashir A Borah, Jennifer M Umhoefer, Lauren Chow, Carinna Tran, Aidan Winters, Alexis Talbot, Rosmely Hernandez, Zhongmei Li, Sanjana Subramanya, Abolfazl Arab, Nupura Kale, Jae Hyun J Lee, Joseph J Muldoon, Chang Liu, Ralf Schmidt, Philip Santangelo, Julia Carnevale, Justin Eyquem, Brian R Shy, Alex Marson, Luke A Gilbert.
      Targeted epigenetic engineering of gene expression in cell therapies would allow programming of desirable phenotypes without many of the challenges and safety risks associated with double-strand break-based genetic editing approaches. Here, we develop an all-RNA platform for efficient, durable and multiplexed epigenetic programming in primary human T cells, stably turning endogenous genes off or on using CRISPRoff and CRISPRon epigenetic editors. We achieve epigenetic programming of diverse targeted genomic elements without the need for sustained expression of CRISPR systems. CRISPRoff-mediated gene silencing is maintained through numerous cell divisions, T cell stimulations and in vivo adoptive transfer, avoiding cytotoxicity or chromosomal abnormalities inherent to multiplexed Cas9-mediated genome editing. Lastly, we successfully combined genetic and epigenetic engineering using orthogonal CRISPR Cas12a-dCas9 systems for targeted chimeric antigen receptor (CAR) knock-in and CRISPRoff silencing of therapeutically relevant genes to improve preclinical CAR-T cell-mediated in vivo tumor control and survival.
    DOI:  https://doi.org/10.1038/s41587-025-02856-w
  35. Adv Mater. 2025 Oct 22. e13714
    Adaptive Twisting Metamaterials.
    Mattia Utzeri, Maria L Gatto, Edoardo Mancini, Donato Orlandi, Daniele Cortis, Marco Sasso, Shanmugam Kumar.
      Next-generation protective systems require adaptive materials capable of reconfiguring their response to impact type and severity, thereby offering multiple force-displacement pathways. Here, the study introduces twisting metamaterials, a subclass of architected lattices whose mechanics are captured by micropolar elasticity. Derived from twisting operations on primitive lattices, these structures exhibit geometry-induced torsional actuation and nonlinear responses, enabling adaptive crashworthiness. A multiscale predictive framework-combining Cosserat continuum mechanics, finite element modeling, and experiments-demonstrates its viability. Twisting sheet-based gyroid structures (10% relative density) are additively manufactured in FE7131 steel and tested under quasi-static and dynamic compression with varied torsional constraints, revealing adaptive energy absorption. When rotation is constrained, the structures achieve high axial stiffness (4.8 GPa), collapse stress (21 MPa), and specific energy absorption (15.36 J g-1), while free-to-twist and over-rotation conditions reduce these values by up to 25%, 24%, and 33%, respectively. A macroscale model captures both axial and torsional responses, while SEM and µCT analyses of process-induced defects inform a parametric finite element study extended to 5% and 15% relative densities. Mapping their performance onto an Ashby chart highlights twisting metamaterials as a promising class of mechanically adaptive, crashworthy materials for advanced protection systems in automotive, rail, aerospace, and defence applications.
    Keywords:  Cosserat continuum mechanics; adaptive crashworthiness; additive manufacturing; twisting gyroid; twisting metamaterials
    DOI:  https://doi.org/10.1002/adma.202513714
  36. ACS Nano. 2025 Oct 21.
    Nanostraw Electroporation for Temporal RNA Sampling from Living 2D and 3D Cell Culture Systems.
    Ying Jie Quek, Arun R K Kumar, Giulia Adriani, Andy Tay.
      Traditional gene expression studies extract RNA through destructive cell lysis, restricting analysis to single time points and necessitating parallel samples. This prevents temporal tracking in the same cells and poses challenges for scarce primary samples. To overcome this, we present nanoelectroextraction (NEE), a minimally perturbative, unbiased RNA sampling technique compatible with both 2D and 3D culture systems. NEE utilizes hollow nanostraw membranes with mild electroporation to extract intracellular RNA without compromising cell viability or gene expression, as confirmed by RNA sequencing. The method is compatible with multiple detection platforms, including qPCR and bulk RNA sequencing. We validate NEE across 2D A549 cells, primary normal human lung fibroblasts, human monocyte-derived macrophages, and 3D cancer spheroids. Over 3 days, NEE enables longitudinal tracking of gene expression dynamics, capturing cytokine-induced reprogramming and siRNA-mediated knockdown with strong agreement to lysis controls. NEE thus provides a powerful platform for studying dynamic gene expression in both conventional and complex biological models.
    Keywords:  3D culture; electroporation; extraction; longitudinal analysis; nanostraws; rna; sampling
    DOI:  https://doi.org/10.1021/acsnano.5c11267
  37. Adv Healthc Mater. 2025 Oct 21. e04630
    Multiscale 3D Printing of Nanoporous Scaffolds with Surface Topography for Guiding 3D Cell Alignment.
    Rao Fu, Evan Jones, Ni Chen, Boyuan Sun, Biao Si, Zhenglun Alan Wei, Guillermo Ameer, Cheng Sun, Yonghui Ding.
      Engineering biomaterial scaffolds with hierarchical structures that integrate macroscale architecture with micro/nanoscale features is essential for directing cellular organization and tissue regeneration. However, fabricating such multiscale scaffolds remains a challenge due to the limitations of conventional techniques and the speed-resolution trade-off in current 3D printing methods. Here, a multiscale micro-continuous liquid interface production (MµCLIP) method is presented, combined with polymerization-induced phase separation, to enable rapid, one-step 3D printing of centimeter-scale scaffolds featuring microscale surface topography and nanoscale porosity. MµCLIP achieves unprecedented structural resolution across five orders of magnitude (20 nm-1 cm) at high printing speed of up to 1.85 mm min-1. As a proof of concept, a 1cm-long tubular scaffold with interconnected nanopores (20-260 nm) and dual surface topographies: 15 µm circumferential rings on outer surface and 20 µm longitudinal grooves on luminal surface is fabricated. These topographies directed orthogonal alignment of vascular smooth muscle cells and endothelial cells, closely recapitulating the architecture of native arteries. Additionally, surface grooves significantly enhanced endothelial cell migration within scaffolds, suggesting a promising approach for accelerating re-endothelialization. This study establishes MµCLIP as a versatile platform for integrating distinct topographies into 3D scaffolds, opening new opportunities for regenerative implants and biomimetic tissue models.
    Keywords:  3D printing; cell alignment; multiscale fabrication; surface topography
    DOI:  https://doi.org/10.1002/adhm.202504630
  38. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2505807122
    Proteolytically activated antibacterial toxins inhibit the growth of diverse gram-positive bacteria.
    Jake Colautti, Stephen R Garrett, John C Whitney.
      Many species of bacteria produce small-molecule antibiotics that enter and kill a wide range of competitor microbes. However, diffusible antibacterial proteins (ABPs) that share this broad-spectrum activity are not known to exist. Here, we report a family of proteins widespread in gram-positive bacteria that display potent antibacterial activity against a diverse range of target organisms. Upon entering susceptible cells, these ABPs enzymatically degrade essential cellular components including DNA, transfer ribonucleic acid (tRNA), and ribosomal ribonucleic acid (rRNA). Unlike previously characterized bactericidal proteins, which require a specific cell surface receptor and therefore display a narrow spectrum of activity, we find that ABPs act in a receptor-independent manner and consequently kill bacteria spanning multiple phyla. Target cell entry by ABPs requires proteolytic activation by a cognate, coexported serine protease, and the liberated toxin component of the cleaved ABP is driven across the target cell membrane by the proton motive force. By examining representative ABPs from diverse pathogenic, commensal, and environmental bacteria, we show that broad-spectrum antibacterial activity is a conserved property of this protein family. Collectively, our work demonstrates that secreted proteins can act as broad-spectrum antibiotics, suggesting that ABPs represent one of potentially many such families produced in nature.
    Keywords:  antibacterial toxins; bacterial protein export; ribonucleases
    DOI:  https://doi.org/10.1073/pnas.2505807122
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