bims-enlima Biomed News
on Engineered living materials
Issue of 2025–11–30
forty-six papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. Synthetic fascia for stiff and tough 4D printed multifunctional structures that detect and tolerate damage.
  2. pH-responsive synthetic cells for controlled protein synthesis and release.
  3. Strain, substrate, and matrix selection for controlled growth of wood-fungi.
  4. Light-controlled synthetic communication networks via paired connexon nanopores.
  5. Acoustic printing of conductive polymers.
  6. General-purpose mechanical computing enabled by origami circuit reconfiguration with robotic addressing and activation.
  7. Rewiring protein function through genetically encoded oxidative chemistry.
  8. Engineered orthogonal translation systems from metagenomic libraries expand the genetic code.
  9. Inverse design of stochastic, voxelated thermo-viscoelastic digital materials.
  10. Amphibious microneedles for programmable delivery of biomolecules and microorganisms in living plants.
  11. Multiplex design and discovery of proximity handles for programmable proteome editing.
  12. Encoded cell-material interactions to reroute cytokine signaling for regenerative medicine.
  13. Biomolecular condensate viscoelasticity is dictated by the interplay between single-molecule shape memory and mesh reconfigurability.
  14. Tuning viscoelasticity of dynamic covalent hydrogels for human tissue modeling.
  15. Biological semiconductors: self-assembled shell proteins as photoactive materials.
  16. Engineering a Thermally Activatable SpyCatcher/SpyTag Protein Ligation for Injectable and In Situ-Forming Hydrogels.
  17. Supramolecular Carbohydrate Assemblies with Tunable Glycan Surfaces.
  18. Liquid-in-Liquid Prints: High-Density Biochemically Encoded Information Preserved in Microdroplet Arrays.
  19. Suspended Tissue Engineering with Assemblable Microfluidics (STEAM).
  20. Modular Noncovalent Functionalization of Electrospun Piezoelectric Scaffolds with Bioactive Nanocarriers.
  21. Scalable spatial single-cell transcriptomics and translatomics in 3D thick tissue blocks.
  22. High-Throughput De Novo Protein Design Yields Novel Immunomodulatory Agonists.
  23. Engineering a CRISPR-associated IscB system for developing miniature genome-editing tools in human cells and mouse embryos.
  24. Mesh-like structure integrated core-shell-shell nanocomposites for enhanced stability and performance in carbon capture.
  25. 3D Hybrid Bioprinting for Complex Multi-Tissue Engineering.
  26. Yarns and fabrics that bend or stiffen under magnetic fields.
  27. Nuclei sense complex tissue shape and direct intestinal stem cell fate.
  28. Metabolite-responsive scaffold RNAs for dynamic CRISPR transcriptional regulation.
  29. Self-assembled cell-scale containers made from DNA origami membranes.
  30. Rigidity Sensing of Inclusions Directs Differentiated Cell Elongation and Force Generation across Phenotypes.
  31. Soft magnetic microrobots with remote sensing and communication capabilities.
  32. A membrane-driven biochemical oscillator tunable by the volume to surface area ratio.
  33. Imaging Cellular Metabolic Rewiring with SuMMIT-SRS.
  34. SubCell: Proteome-aware vision foundation models for microscopy capture single-cell biology.
  35. Engineering yeast peroxisome assembly enables the increased production of acetyl-CoA and its derived 5-deoxyflavonoids.
  36. ExoSloNano: multimodal nanogold labels for identification of macromolecules in live cells and cryo-electron tomograms.
  37. Matrix Stiffness Governs Fibroblast-Driven Immune Homeostasis in Gingival Tissues.
  38. Adapting CRISPR-associated transposons for rapid and high-throughput reverse genetics.
  39. Articular neural bioelectronics by decoupling mechanical strain from electron transport.
  40. Fabrication and Evaluation of PLGA Microsphere-Loaded Hydrogels as Potential Intraocular Lens for Sustained Release of Timolol Maleate.
  41. Reversing transgene silencing via targeted chromatin editing.
  42. Heterogeneous polymerization via two-step crosslinking for tunable microribbon hydrogels.
  43. Wireless in-body sensing through genetically engineered bacteria.
  44. Tuning collagen and collagen-alginate mechanics through extrusion bioprinting process parameters.
  45. 3D Printing of Air.
  46. Recombinant collagen in regenerative medicine: Expression strategies, structural design, and translational applications.
  1. Nat Commun. 2025 Nov 24. 16(1): 10351
    Synthetic fascia for stiff and tough 4D printed multifunctional structures that detect and tolerate damage.
    Javier M Morales Ferrer, Chloe Kekedjian, Nicole Bacca, J William Boley.
      Creating shape-morphing structures with time-responsive materials is a key goal of 4D printing, but combining high stiffness (E) and toughness (K) in a single material remains difficult. Soft materials stretch but lack strength, while stiff materials resist deformation but are brittle. Nature overcomes this trade-off in skeletal muscle by surrounding strong fibers with soft, tough tissue for protection and support. Inspired by this strategy, we develop a multi-material printing method that combines stiff synthetic muscle with a soft, stretchable adhesive to form a composite structure. Here, we show that this design greatly improves toughness without sacrificing stiffness, enables controlled actuation, and maintains function after multiple fractures. We demonstrate these properties in a damage-tolerant actuator, a lifting robot with record performance, and a lattice that detects and withstands extreme loads while remaining operational.
    DOI:  https://doi.org/10.1038/s41467-025-65279-w
  2. bioRxiv. 2025 Nov 16. pii: 2025.11.16.688650. [Epub ahead of print]
    pH-responsive synthetic cells for controlled protein synthesis and release.
    Sung-Won Hwang, Yudan Li, Alexander A Green, Allen P Liu.
      pH is a critical parameter in biological systems, with acidic environments often serving as hallmarks of pathological conditions such as cancer, infection, and metabolic disorders. Here, we developed a pH-responsive synthetic cell capable of protein synthesis and release under acidic conditions. The system was constructed by integrating three molecular modules: a proton channel for pH sensing, a pH-responsive single-stranded DNA (ssDNA) that releases a trigger ssDNA upon acidification, and a toehold switch RNA that activates translation in response to the trigger ssDNA. During integration, we discovered that adjusting the annealing length between the pH-responsive and trigger strands was critical for enabling the acid-triggered protein synthesis. Using this strategy, we successfully demonstrated acid-responsive protein expression within synthetic cells. To further explore applications, we embedded the synthetic cells in a hydrogel to endow pH-responsive behavior to materials and coupled pH-responsive protein translation with a cell-penetrating peptide technology for selective release of proteins.
    DOI:  https://doi.org/10.1101/2025.11.16.688650
  3. Soft Matter. 2025 Nov 25.
    Strain, substrate, and matrix selection for controlled growth of wood-fungi.
    Sophie Hofer, Natalie Nussbaum, Peter Fischer, Patrick A Rühs.
      Fungal fermentation offers a promising approach for the development of engineered living materials (ELMs). The design of the substrate materials to support and enhance fungal growth in both 2D and 3D is essential to realize this potential. We evaluated the mycelium of seven edible mushroom-forming fungi for growth vigor as a function of various abiotic factors. Growth assays using standard malt agar, with varying concentrations of carbohydrates and proteins, revealed that the radial expansion of the fungal is affected by the carbohydrate concentration, showing a maximum expansion rate at mid-low concentrations and a diminishing expansion rate at higher concentrations. In contrast, higher carbohydrate concentrations increased mycelium density. Different plant-based proteins also significantly influenced growth vigor, i.e. the mycelium's thickness and expansion rate. Beyond chemical substrate conditions, we modified the substrate viscoelasticity by increasing agar concentration, which resulted in higher growth proliferation. This was further confirmed using non-standard gelling agents such as guar gum, corn starch, κ-carrageenan, and bacterial cellulose. In a final step to enhance growth for practical applications, we foamed an optimized substrate material for 3D growth, achieving successful growth throughout the entire matrix. This work provides a framework to aid the selection of edible substrate materials for fungal growth, i.e. the design of engineered living materials.
    DOI:  https://doi.org/10.1039/d5sm00749f
  4. Nat Commun. 2025 Nov 22.
    Light-controlled synthetic communication networks via paired connexon nanopores.
    Ahmed Z Sihorwala, Alexander J Lin, Isabela Ramirez-Velez, Siqi Yang, Gayeon Kim, Shwetadwip Chowdhury, Jeanne C Stachowiak, Brian Belardi.
      Living cells employ dynamic networks for intercellular communication and cooperation, leading to tissue-wide activity. One emerging challenge in the field of bottom-up synthetic biology is emulating such sophisticated behaviors in liposome-based synthetic cells (SCs). Fabricating communication networks in lipid bilayer-based SCs remains a challenge, as signaling molecules must transit through two consecutive membranes to transfer information between different SCs. Here, we address this obstacle by engineering connexin channels that directly connect the lumens of adhering SC membranes. We focus on orthogonal channel-forming connexins, namely connexin 43 and connexin 32, and redesign their channel activity to be UV- and near IR-responsive, respectively. By combining engineered connexins into a single SC assembly, we demonstrate orthogonal transfer of reactive signaling molecules between SCs, giving rise to unique reaction products and network states in a wavelength-dependent manner - an important step toward synthetic communication networks.
    DOI:  https://doi.org/10.1038/s41467-025-66621-y
  5. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2509652122
    Acoustic printing of conductive polymers.
    Ethan Trepka, Lauren Cooper, Kenneth Brinson, Samuel Thompson, Marigold Gil Malinao, Nicholas J Rommelfanger, Polly Fordyce, Guosong Hong.
      Fabricating materials within optically opaque structures, such as biological tissue, is a considerable challenge. Recently, ultrasound-based printing ("sonoprinting") approaches have emerged as a promising strategy to address this challenge. However, an approach to sonoprint conductive materials has yet to be realized, limiting potential bioelectronic applications. Here, we extend sonoprinting to conductive materials by designing temperature-based and pressure-based methods to polymerize conductive polymers with focused ultrasound (FUS). Our temperature-based approach relies on the acoustic attenuation of the surrounding medium to generate heat under FUS, whereas our pressure-based approach leverages the acoustic vaporization of perfluorohexane double emulsions to trigger polymerization. We demonstrate that both approaches can be used to print the conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) through optically opaque hydrogels and biological tissue with high spatial resolution. Taken together, our results establish complementary temperature- and pressure-based methods for sonoprinting conductive polymers, paving the way for future efforts to fabricate bioelectronic interfaces in tissue.
    Keywords:  acoustic printing; bioelectronics; conductive polymers; sonoprinting
    DOI:  https://doi.org/10.1073/pnas.2509652122
  6. Nat Commun. 2025 Nov 25. 16(1): 10483
    General-purpose mechanical computing enabled by origami circuit reconfiguration with robotic addressing and activation.
    Yinghua Chen, Ting Tan, Zhimiao Yan.
      Inspired by information sensing, storage, and processing capabilities of natural systems, mechanical computing built upon intelligent matters is emerging toward directly perceiving environmental changes and making autonomous decisions. However, challenges remain in achieving general-purpose mechanical computing architecture due to the trade-off between programmability and scalability. Here, we present a mechanical programmable gate array, a scalable architecture integrating dynamic activation mechanisms for general-purpose computing. By mapping local factored Quine-McCluskey logic functions onto bistable origami switch-based logic units and embedding conductive networks, we create low-redundancy, high-stability logic modules. A robotic activation mechanism, guided by magnetic instructions, dynamically configures the logic array for all input combinations, ensuring complete programmability and scalability. The architecture also interfaces with storage units for iterative processes like function reuse and neural network weight updates. With programmability, scalability, and adaptability, this approach lays the foundation for decision-making materials with applications spanning distributed edge computing and embodied intelligent robotics.
    DOI:  https://doi.org/10.1038/s41467-025-65464-x
  7. bioRxiv. 2025 Nov 06. pii: 2025.11.06.686050. [Epub ahead of print]
    Rewiring protein function through genetically encoded oxidative chemistry.
    Hengyu Li, Alen Pavlič, Noor E Ibrahim, Di Wu, Mikhail G Shapiro.
      Oxidative chemistry underlies many natural signaling pathways but remains largely unexplored as a design strategy for synthetic control of protein function. Here we introduce genetically encoded oxidative modulation as a general mechanism for regulating protein activity in living cells. Using the genetically encodable photosensitizer miniSOG to generate reactive oxygen species (ROS), we show that controlled oxidation alters the behavior of diverse proteins. miniSOG-derived ROS increased the fluorescence of the redox reporter HyPerRed and activated redox-sensitive ion channels TRPV1 and TRPA1, with TRPA1 displaying the strongest response. The magnitude and kinetics were tunable by illumination parameters, expression ratios, and subcellular localization of miniSOG, with membrane anchoring markedly improving efficiency of activating a membrane receptor. These findings establish genetically encoded oxidative chemistry as a versatile and tunable modality for controlling protein function.
    DOI:  https://doi.org/10.1101/2025.11.06.686050
  8. bioRxiv. 2025 Oct 30. pii: 2025.10.30.685624. [Epub ahead of print]
    Engineered orthogonal translation systems from metagenomic libraries expand the genetic code.
    Kosuke Seki, Michael T A Nguyen, Petar I Penev, Jillian F Banfield, Farren J Isaacs, Michael C Jewett.
      Genetic code expansion with non-canonical amino acids (ncAAs) opens new opportunities for the function and design of proteins by broadening their chemical repertoire. Unfortunately, ncAA incorporation is limited both by a small collection of orthogonal aminoacyl-tRNA synthetases (aaRSs) and tRNAs and by low-throughput methods to discover them. Here, we report the discovery, characterization, and engineering of a UGA suppressing orthogonal translation system mined from metagenomic data. We developed an integrated computational and experimental pipeline to profile the orthogonality of >200 tRNAs, test >1,250 combinations of aaRS:tRNA pairs, and identify the AP1 TrpRS:tRNA Trp UCA as an orthogonal pair that natively encodes tryptophan at the UGA codon. We demonstrate that the AP1 TrpRS:tRNA Trp UCA is highly active in cell-free and cellular contexts. We then use Ochre , a genomically recoded Escherichia coli strain that lacks UAG and UGA codons, to engineer an AP1 TrpRS variant capable of 5-hydroxytryptophan incorporation at an open UGA codon. We anticipate that our strategy of integrating metagenomic bioprospecting with cell-free screening and cell-based engineering will accelerate the discovery and optimization of orthogonal translation systems for genetic code expansion.
    DOI:  https://doi.org/10.1101/2025.10.30.685624
  9. Nat Commun. 2025 Nov 28.
    Inverse design of stochastic, voxelated thermo-viscoelastic digital materials.
    Marc Wirth, Joël N Chapuis, Kristina Shea.
      Polymer material jetting enables the fabrication of voxelated, multi-material structures with material control at the microscale. However, current work often neglects viscoelastic effects and designing voxelated digital materials remains challenging due to the complexity of the vast design freedom and intractability of efficiently modeling macroscale voxel structures. We present an efficient representation of stochastically mixed, voxelated digital materials and develop a generalized viscoelastic temperature-dependent material model to design and simulate digital materials mixed from two constituent polymers. The material model is based on an extended percolation theory considering frequency and temperature. An artificial neural network is trained on the material model to directly estimate target material behavior given arbitrary non-linear, user requirements. The approach is validated using two case studies requiring tailored, non-linear material behavior: a personalized wrist orthosis and a machine damper. These show the newly unlocked possibilities for the design and fabrication of tuned, stochastic digital materials.
    DOI:  https://doi.org/10.1038/s41467-025-66744-2
  10. Nat Commun. 2025 Nov 24.
    Amphibious microneedles for programmable delivery of biomolecules and microorganisms in living plants.
    Di Shen, Sivamathini Rajappa, Yue Zhao, Zhihao Pang, Yuliang Li, Calvin Thenarianto, Suppanat Puangpathumanond, Cansu Sevencan, Tedrick Thomas Salim Lew.
      Efficient cargo delivery is essential for plant trait engineering, yet existing methods are often species-specific and ineffective across diverse habitats. Here, we develop core-shell microneedles for targeted delivery of biomolecular cargoes and active microorganisms into both terrestrial and aquatic plants. The microneedle architecture is rationally engineered to resist water exposure and release cargo upon contact with plant interstitial fluid, enabling controlled delivery into tissues and cells. We demonstrate that these core-shell microneedles can efficiently transport diverse cargoes, from nanoscale biomolecules such as functional nucleic acids, proteins, and plant hormones to microscale bioactive Agrobacterium, leading to strong protein expression and enhanced plant growth. Underwater delivery of salt-tolerance genes into submerged freshwater plants further demonstrates the platform's utility for engineering stress resilience in challenging environments. By facilitating the cellular uptake of diverse cargoes into intact plants across different habitats, this amphibious microneedle strategy offers a versatile cargo delivery tool to advance plant biotechnology and environmental applications.
    DOI:  https://doi.org/10.1038/s41467-025-66799-1
  11. bioRxiv. 2025 Oct 13. pii: 2025.10.13.681693. [Epub ahead of print]
    Multiplex design and discovery of proximity handles for programmable proteome editing.
    Chase C Suiter, Green Ahn, Melodie Chiu, Yi Fu, Shayan Sadre, Jessica J Simon, David S Lee, Douglas M Fowler, Dustin J Maly, David Baker, Jay Shendure.
      Although we now have a rich toolset for genome editing, an equivalent framework for manipulating the proteome with a comparable flexibility and specificity remains elusive. A promising strategy for "proteome editing" is to use bifunctional molecules (e.g. PROteolysis-Targeting Chimeras or PROTACs1) that bring a target protein into proximity with a degradation or stabilization effector, but their broader application is constrained by a limited repertoire of well-characterized target or effector "handles". We asked whether coupling de novo protein design to a multiplex screening framework could address this gap by accelerating the discovery of effector handles for intracellular protein degradation, stabilization, or relocalization. Using LABEL-seq2, a sequencing-based assay that enables multiplex, quantitative measurement of protein abundance, we screened 9,715 de novo designed candidate effector handles for their ability to recruit a target protein to components of the ubiquitin-proteasome system3 (UPS) (FBXL12, TRAF2, UCHL1, USP38) or the autophagy pathway4 (GABARAP, GABARAPL2, MAP1LC3A). In a single experiment, we discovered hundreds of de novo designed effector handles that reproducibly drove either intracellular degradation (n = 277) or stabilization (n = 204) of a reporter protein. Validation of a subset of these hits in an orthogonal assay confirmed that sequencing-based measurements from the primary screen reliably reflected changes in intracellular abundance of the target protein. Successful effector handles were discovered for both the UPS (n = 194) and autophagy (n = 287) pathways, which provide complementary routes for programmable proteome editing. Autophagy-recruiting effector handles generalized to endogenous targets, as substituting the reporter-specific target handle with a high-affinity MCL1 binder5 reduced endogenous levels of this intracellular oncoprotein6. Moreover, directing autophagy-recruiting effector handles to the outer mitochondrial membrane dramatically perturbed mitochondrial networks in a manner consistent with synthetic tethering and sequestration7,8. Beyond generating a diverse repertoire of protein abundance or localization effector handles, our results establish a scalable, low-cost platform that links deep learning-guided protein design to functional cellular readouts, and chart a course toward a general framework for programmable proteome editing.
    DOI:  https://doi.org/10.1101/2025.10.13.681693
  12. bioRxiv. 2025 Oct 25. pii: 2025.10.24.684449. [Epub ahead of print]
    Encoded cell-material interactions to reroute cytokine signaling for regenerative medicine.
    Zachary M Eidman, Jhanvi Sharma, Joanne C Lee, Nicholas F Schulze, Hannah J Brien, Kevin C Corn, Marjan Rafat, Jonathan M Brunger.
      Regenerative engineering harnesses materials science and stem cell biology to develop strategies to repair damaged and diseased tissue. Despite advances in designer materials, few techniques effectively provide auto-regulated feedback mechanisms that govern how cells sense and respond to discrete microenvironmental changes. Here, we demonstrate that the artificial, juxtacrine-like receptor synthetic Notch (synNotch) can be activated by endogenous multimeric cytokines in solution, without immobilizing materials, revealing a previously unreported activation modality and yielding up to 24-fold dynamic range. To broaden synNotch sensing to monomeric cytokines, we developed nMATRIX, a co-engineered material-cell platform that detects endogenous, soluble ligands and routes them to programmed gene circuits with spatially confined effects. nMATRIX can be tuned to recognize the interleukins IL-1β and IL-6 using synNotch receptors plus cognate biomaterials, yielding up to 68-fold dynamic range and converting these inflammatory inputs into orthogonal outputs that reprogram nearby cell phenotypes. nMATRIX functions across multiple cell types and can incorporate the synNotch-related SNIPR synthetic receptor platform. nMATRIX repurposed inflammatory signals and converted them into anti-inflammatory cues to polarize macrophages (increased CD163, CD206; decreased CD86). Thus, nMATRIX couples native soluble cues to customized cellular responses with tunable sensitivity, offering a flexible materials-based approach for self-regulating regenerative therapies.
    DOI:  https://doi.org/10.1101/2025.10.24.684449
  13. bioRxiv. 2025 Oct 07. pii: 2025.10.06.680817. [Epub ahead of print]
    Biomolecular condensate viscoelasticity is dictated by the interplay between single-molecule shape memory and mesh reconfigurability.
    Pablo L Garcia, Jerelle A Joseph.
      Biomolecular condensates are membraneless organelles that compartmentalize biological functions in living cells. Formed by the phase separation of biomolecules, condensates possess a wide range of mechanical responses. However, how condensate viscoelastic responses are encoded in the chemistries of their constituents-such as intrinsically disordered proteins (IDPs)-are not well understood. Here, we employ molecular dynamics simulations to connect measurable condensate viscoelasticity to the architectural heterogeneity and dynamic reconfigurability of associative networks formed by IDPs. Using a residue-resolution coarse-grained model, we characterize biologically relevant and synthetic condensates, demonstrating that their temperature sensitivity of elasticity is sequence dependent and modeled by exponential scaling laws. We interrogate condensate mesh heterogeneity via entanglement spacing, finding that entropy-driven structural heterogeneity and reduced IDP hydrophobicity favor condensate elasticity. Furthermore, we construct graph-theoretical representations of condensates and find that interaction network topologies with an abundance of redundant node pathways translates to more load-bearing paths for mechanical stress storage. Strikingly, we discover that elastic coupling of IDPs within condensates emerges when single-molecule shape memory timescales approach meshwork reconfiguration timescales. Akin to a condensate Deborah number, this interplay of timescales for molecular and microstructural processes dictates how restoring elastic forces propagate and are stored across IDP networks; linking condensate microstructure dynamics directly to mechanical responses. Taken together, our work provides a conceptual framework of how condensates act as stress-responsive biomaterials; helping illuminate how cells exploit condensate mechanics to sense and regulate their internal environment and opening avenues for the design of condensates with programmable material properties.
    DOI:  https://doi.org/10.1101/2025.10.06.680817
  14. bioRxiv. 2025 Oct 17. pii: 2025.10.16.682916. [Epub ahead of print]
    Tuning viscoelasticity of dynamic covalent hydrogels for human tissue modeling.
    Narelli de Paiva Narciso, Fotis Christakopoulos, Michelle S Huang, Neil J Baugh, Carla Huerta-López, Eliana X Matos, Kristine P Pashin, Andrew Spakowitz, Sarah C Heilshorn.
      The development of three-dimensional (3D) in vitro tissue culture models is critical for biomedical research. Hydrogel-based systems have become a preferred scaffold for 3D models, as they have tunable viscoelastic properties, which are well-known to influence cell morphology and function. In particular, reversible hydrogel crosslinks formed through dynamic covalent chemistry (DCC) can introduce viscoelastic behavior including stress relaxation. However, traditional strategies to increase stress-relaxation rates in DCC gels rely on faster bond kinetics, resulting in faster erosion rates that prevent their use for long-term 3D culture. As an alternative strategy, we explore the use of molecular parameters (specifically molecular weight and degree of functionalization) to independently control the stiffness and stress relaxation behavior while preventing rapid erosion. As demonstration, we develop and validate a modified theoretical model of gel viscoelasticity applied to a two-component DCC gel composed of modified hyaluronic acid and elastin-like protein. Finally, we utilize this tunable gel platform to explore the impact of scaffold viscoelasticity on encapsulated human neural progenitor cells. In summary, this work expands the molecular design space of DCC hydrogels to achieve tunable viscoelastic properties for 3D in vitro models.
    Keywords:  DCC chemistry; dynamic hydrogels; neural progenitor cells; stress-relaxation
    DOI:  https://doi.org/10.1101/2025.10.16.682916
  15. Chem Sci. 2025 Nov 13.
    Biological semiconductors: self-assembled shell proteins as photoactive materials.
    Silky Bedi, S M Rose, Sharmistha Sinha.
      Light-harvesting proteins are promising biocompatible materials for bioelectronics, yet their instability and inefficient charge transport hinder direct integration. External scaffolds offer support but introduce energy losses and delay response. Here, we identified a class of hyper-thermostable, self-assembling bacterial shell proteins that form disc-like structures with spatially organized tyrosine residues, facilitating efficient light absorption and charge transport. I-V profiling and ultraviolet photoelectron spectroscopy reveal their semiconducting behavior and low work function (<3 eV). These protein discs generate photocurrents under UV illumination without external bias and achieve external quantum efficiencies (∼0.5%) and response times (0.3 s) surpassing those of traditional photosynthetic proteins by an order of magnitude. Mutational analysis implicates a tyrosine-mediated electron transfer mechanism. These findings establish bacterial shell proteins as intrinsically stable, scaffold-free photoactive materials for next-generation bioelectronic applications.
    DOI:  https://doi.org/10.1039/d5sc05716g
  16. Angew Chem Int Ed Engl. 2025 Nov 28. e09477
    Engineering a Thermally Activatable SpyCatcher/SpyTag Protein Ligation for Injectable and In Situ-Forming Hydrogels.
    Jian Cui, Yuan Gao, Chenjing Lu, Haipeng Wu, Yu Zhang, Sheng Yin, Bin Xue, Yi Cao, Hai Lei.
      Injectable and in situ-forming hydrogels are attractive for tissue engineering and drug delivery, yet challenges remain in balancing gelation speed, mechanical strength, and cytocompatibility. Here, we report a thermally activatable SpyCatcher/SpyTag (TASpy) system that undergoes rapid chemical crosslinking at physiological temperature. Inspired by the CnaB2 domain, thermally activatable SpyCatcher (TASpyC) fuses SpyCatcher with a non-reactive SpyTag mutant, creating a single polypeptide that remains folded and minimally reactive at lower temperatures yet partially unfolds at 37 °C to expose a covalent binding site. This design enables controlled isopeptide-bond formation, facilitating the formation of robust injectable protein hydrogels. We demonstrate improved mechanical properties, enhanced cell encapsulation, and accelerated gelation upon heating-supporting high cell viability and in vivo retention. Notably, subcutaneous injections of TASpy-based precursors solidify within minutes, degrade over five weeks, and exhibit excellent biocompatibility, underscoring the potential of TASpy hydrogels for advanced biomedical applications.
    Keywords:  Cell encapsulation; Chemical crosslinking; Injectable hydrogel; SpyCatcher; Thermally activatable protein ligation
    DOI:  https://doi.org/10.1002/anie.202509477
  17. Angew Chem Int Ed Engl. 2025 Nov 23. e15926
    Supramolecular Carbohydrate Assemblies with Tunable Glycan Surfaces.
    Nives Hribernik, Marlene C S Dal Colle, Junki Fujihara, Jacobus P van Trijp, Kai Ludwig, Yu Ogawa, Katharina Ribbeck, Martina Delbianco.
      The self-assembly of molecular building blocks into ordered supramolecular structures enables the creation of nanomaterials that can display ligands on their surfaces with molecular precision. However, many of these supramolecular scaffolds face challenges in incorporating bulky or hydrophilic ligands, such as carbohydrates. This issue often requires the co-assembly of ligand-containing blocks with non-functionalized ones, diluting ligand presentation and compromising their precise spatial arrangement. Herein, we present carbohydrate oligomers that assemble into supramolecular nanomaterials featuring a molecularly controlled, dense presentation of carbohydrate ligands on their surfaces. This modular system accommodates a variety of carbohydrate ligands while maintaining consistent bulk material properties. Using this approach, we have engineered a series of supramolecular hydrogels, whose nanostructure displays specific carbohydrate residues with high density that act as biological cues to influence the morphology of Candida albicans.
    Keywords:  Candida albicans; Glycans; Hydrogels; Nanomaterials
    DOI:  https://doi.org/10.1002/anie.202515926
  18. Adv Mater. 2025 Nov 24. e16338
    Liquid-in-Liquid Prints: High-Density Biochemically Encoded Information Preserved in Microdroplet Arrays.
    Maximilian Breitfeld, Robert Strutt, Leonard Fröhlich, Claudius L Dietsche, Sebastian Bargfrede, Petra S Dittrich.
      Liquids are dense repositories of information, challenged only by how well their compositions are defined, preserved, accessed, or measured. The precise spatial patterning of solutes within a bulk liquid is challenging since diffusion disperses local concentrations and thereby attenuates functionality. Herein, a new concept is introduced for writing and preserving information in the liquid state through liquid-in-liquid microdroplet array printing. This technology produces fine resolution, 2D liquid structures, composite of indexed water-in-oil droplet pixels each with a precise composition, a high spatial resolution and a tight inter-pixel pitch. With extreme control over droplet composition and by applying standard and custom encoding schemes, various forms of information are written biochemically such as images, QR codes, text characters and words. As a composite material, reversible phase transitions between dissolved liquid and crystallized solid states control information encryption and decryption. Compared to current liquid printing and chemical encoding paradigms, ours introduces a fundamentally new precedent for deterministically programming information release, exchange or decay without stimuli or physical processing. Further computational principles such as error correction and information storage are demonstrated. These micro-liquid patterns are relevant to any application based on precise liquid handling such as information theory, materials design and biological assays.
    Keywords:  automation; chemical information; droplet microfluidics; encoding; high‐throughput assays; liquid state printing
    DOI:  https://doi.org/10.1002/adma.202516338
  19. bioRxiv. 2025 Oct 29. pii: 2025.10.28.684690. [Epub ahead of print]
    Suspended Tissue Engineering with Assemblable Microfluidics (STEAM).
    Amanda J Haack, Jamison M Whitten, Liam A Knudsen, Ella E Bouker, Asha R Viswanathan, Lauren G Brown, Dahna A Kim, Laura A Milton, Ariel Lin, Alex Georgiou, Emme A Schumacher, M Yunos Alizai, Yi-Chin Toh, Jean Berthier, Cole A DeForest, Nathan J Sniadecki, Ashleigh B Theberge, Erwin Berthier.
      Suspended tissue culture systems enable cellular responses to mechanical forces critical for tissue development and function. Tissues develop in a complex environment containing both mechanical and chemical cues that vary spatiotemporally; modeling both of these physiochemistries in vitro through integration of spatial patterning with mechanical manipulation is thus an important aspect in microphysiological tissue modeling. Here we introduce Suspended Tissue Engineering with Assemblable Microfluidics (STEAM), a modular tissue fabrication platform that allows for spatially heterogeneous suspended tissue architectures. With STEAM we achieve tissue constructs with multiple regions through the addition of capillary pinning features to control hydrogel precursor flow. STEAM tissues can easily be moved from patterning setup to well-plate to microscope slide, and enables stacking of separately generated layers. Mechanical manipulation post-fabrication is also possible via static stretching, where cell-embedded 3D tissues can be stretched farther apart to induce strain along an axis. To demonstrate this post fabrication strain ability, we induced strain in mouse myoblasts in an engineered muscle tissue model that increased alignment of myotubes. Finally, by modifying the channel geometry of the fluidic based patterning rails, we generate complex nonplanar suspended tissues. Overall, STEAM leverages microfluidic principles to generate suspended tissues that integrate patterning precision, mechanical functionality, and experimental versatility. STEAM provides a suite of tissue constructs for modeling tissue behaviors from the interplay of spatial organization and mechanical forces.
    DOI:  https://doi.org/10.1101/2025.10.28.684690
  20. bioRxiv. 2025 Oct 26. pii: 2025.10.25.684210. [Epub ahead of print]
    Modular Noncovalent Functionalization of Electrospun Piezoelectric Scaffolds with Bioactive Nanocarriers.
    Sarah Payne Bortel, Sumayia Saif Jaima Chowdhury, Jeremy Cheng, Daniella Uvaldo, Mackenzie Wright, Treena Livingston Arinzeh, Santiago Correa.
      Electrospun scaffolds offer a promising platform for immune-instructive materials, but stable and modular functionalization with bioactive signals remains a technical challenge. Here, we develop a surface coating strategy for electrospun scaffolds that consist of poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE), a piezoelectric polymer, using electrostatic adsorption of charged nanoparticles. We show that under certain conditions, these piezoelectric scaffolds are suitable substrates for electrostatic self-assembly, and that the density of nanoparticle coatings can be tuned by adjusting buffer pH, ionic strength, and nanoparticle concentration. This approach enables robust and uniform coating of both polymeric nanoparticles and soft nanocarriers such as liposomes, without requiring covalent surface modification. Liposome-coated scaffolds are cytocompatible with adherent epithelial and suspension immune cells and support lipid exchange at the cell-material interface. Using a supramolecular tethering strategy, we use liposome coatings to present interleukin-15 (IL-15) from the scaffold surface and demonstrate localized, sustained cytokine signaling. Together, these findings establish a modular approach for post-fabrication, noncovalent scaffold functionalization with bioactive nanocarriers, offering new opportunities for tissue and immune engineering.
    DOI:  https://doi.org/10.1101/2025.10.25.684210
  21. Nat Methods. 2025 Nov 24.
    Scalable spatial single-cell transcriptomics and translatomics in 3D thick tissue blocks.
    Xin Sui, Jennifer A Lo, Shuchen Luo, Yichun He, Zefang Tang, Zuwan Lin, Dániel L Barabási, Yiming Zhou, Wendy Xueyi Wang, Jia Liu, Xiao Wang.
      Characterizing the transcriptional and translational gene expression patterns at the single-cell level within their three-dimensional (3D) tissue context is essential for revealing how genes shape tissue structure and function in health and disease. However, most existing spatial profiling techniques are limited to 5-20 µm thin tissue sections. Here, we developed Deep-STARmap and Deep-RIBOmap, which enable 3D in situ quantification of thousands of gene transcripts and their corresponding translation activities, respectively, within 60-200-µm thick tissue blocks. This is achieved through scalable probe synthesis, hydrogel embedding with efficient probe anchoring and robust cDNA crosslinking. We first utilized Deep-STARmap in combination with multicolor fluorescent protein imaging for simultaneous molecular cell typing and 3D neuron morphology tracing in the mouse brain. We also demonstrate that 3D spatial profiling facilitates comprehensive and quantitative analysis of tumor-immune interactions in human skin cancer.
    DOI:  https://doi.org/10.1038/s41592-025-02867-0
  22. bioRxiv. 2025 Oct 13. pii: 2025.10.12.681920. [Epub ahead of print]
    High-Throughput De Novo Protein Design Yields Novel Immunomodulatory Agonists.
    Mohamad Abedi, Marc Expòsit, Brian Coventry, Divij Mathew, Shruti Jain, Aditya Krishnakumar, Inna Goreshnik, Sophie L Gray-Gaillard, Margaret Lunn-Halbert, Ta-Yi Yu, Matthias Glögl, Uma Mitchell, Riya Keshri, Jung Ho Chun, Hannele Ruohola-Baker, E John Wherry, David Baker.
      Cytokines regulate cell behavior by bringing together specific receptor subunits to trigger downstream signaling. Designed molecules that bring together non-natural receptor pairs could have novel signaling responses and cell specificities. We present a high-throughput de-novo design approach to create novel cytokines by generating and fusing pairs of computationally designed binders. By combining 33 designed receptor-binding domains, we generated over a thousand potential de novo designed "Novokines", of which 75 activated pSTAT signaling in peripheral blood mononuclear cells. We characterized 18 of these, including new pairings of established common receptors, cross-family pairings such as TrkA-γcommon, and a series of pairings with interferon receptor-1 (IFNAR1), revealing that IFNAR1 can function as a versatile common receptor similar to γcommon or βcommon. We identify novokines that drive monocyte proliferation, T cell survival and CD4+ T cell-specific proliferation. Our framework provides a blueprint for expanding the understanding of cytokine signaling and generating novel therapeutic proteins.
    Keywords:  Cell Signaling; Computational Protein Design; Cytokine; Synthetic Biology
    DOI:  https://doi.org/10.1101/2025.10.12.681920
  23. Nat Commun. 2025 Nov 27. 16(1): 10693
    Engineering a CRISPR-associated IscB system for developing miniature genome-editing tools in human cells and mouse embryos.
    Fei Zhang, Yuxin Peng, Dongdong Fan, Guoxu Song, Xing Gao, Yong Tian.
      IscB, as the putative ancestor of Cas9, possesses a compact size, making it suitable for in vivo delivery. OgeuIscB is the first IscB protein known to function in eukaryotic cells but requires a complex TAM (NWRRNA). Here, we characterize a CRISPR-associated IscB system, named DelIscB, which recognizes a flexible TAM (NAC). Through systematically engineering its protein and sgRNA, we obtain enDelIscB with an average 48.9-fold increase in activity. By fusing enDelIscB with T5 exonuclease (T5E), we find that enDelIscB-T5E displays robust efficiency comparable to that of enIscB-T5E in human cells. Moreover, by fusing cytosine or adenosine deaminase with enDelIscB nickase, we establish efficient miniature base editors (ICBE and IABE). Finally, we efficiently generate mouse models by microinjecting mRNA/sgRNA of enDelIscB and enDelIscB-T5E into mouse embryos. Collectively, our work presents a set of enDelIscB-based miniature genome-editing tools with great potential for diverse applications in vivo.
    DOI:  https://doi.org/10.1038/s41467-025-65724-w
  24. Nat Commun. 2025 Nov 26. 16(1): 10526
    Mesh-like structure integrated core-shell-shell nanocomposites for enhanced stability and performance in carbon capture.
    Sizhuo Yang, Haiyan Mao, Chaochao Dun, Jianfang Liu, Kaipeng Hou, Angela Cai, Jing Wang, Jane K J Lee, Donglin Li, Hao Lyu, Zhouyi Chen, Xudong Lv, Hao Zhuang, Xueer Xu, Xueli Zheng, Gang Ren, Jeffrey A Reimer, Yi Cui, Jeffrey J Urban.
      Carbon capture is essential for mitigating climate change, yet most sorbents struggle to combine high capacity with chemical stability. Here we report core-shell-shell (CSS) nanocomposites that integrate adsorption efficiency with exceptional robustness. The design couples a metal-organic framework (MOF) core, which enriches local CO2 concentration, with a polyamine shell that is reorganized into a porous, ordered network through entanglement with an outer covalent organic framework (COF) shell. This hierarchical architecture enables dual amine functionalization via sequential "click" and Schiff-base reactions, achieving a CO2 uptake of 3.4 mmol g-1 at 1 bar. The COF outer layer also acts as a protective barrier, suppressing humidity interference and doubling cycling stability under simulated flue gas. Remarkably, the nanocomposites maintain structural integrity after one week in strongly acidic (3 M HNO3) or basic (NaOH, pH=14) environments, underscoring their chemical resilience. By uniting high capacity, cycling durability, and environmental tolerance, this CSS strategy offers a versatile platform for next-generation carbon capture materials.
    DOI:  https://doi.org/10.1038/s41467-025-65531-3
  25. bioRxiv. 2025 Nov 07. pii: 2025.11.06.682452. [Epub ahead of print]
    3D Hybrid Bioprinting for Complex Multi-Tissue Engineering.
    Hossein Vahid Alizadeh, Andrea S Flores Pérez, Tomohiro Uno, Richard Sammy Muniz, Sun Hyung Kwon, Anjana Balachandar, Nicholas Riley, Chantal Aivan Le, Jiannan Li, Peng Zhao, Elaine Lui, Carolyn Kim, Seyedsina Moeinzadeh, Chi-Chun Pan, Nidhi Bhutani, Constance Chu, Sungwoo Kim, Yunzhi P Yang.
      3D bioprinting has revolutionized tissue engineering, enabling intricate, physiologically relevant constructs unattainable with conventional techniques, yet it remains limited in integrating soft and rigid multifunctional components for complex multi-tissue applications. In this study, we introduce a 3D hybrid bioprinting approach implementing the Hybprinter platform, which integrates multiple 3D printing modules under optimized conditions for a continuous bioprinting process with multiple soft and hard biomaterials. This approach demonstrates robust biocompatibility and broad tissue engineering potential for modeling and therapeutic applications. The capacity to fabricate multi-hydrogel hybrid constructs is illustrated by representative examples highlighting vascularization, multifunctionality, mechanical robustness, and implant suturability. Notably, compared with commonly fabricated hydrogel-only constructs, the resulting hybrid constructs achieve over a 1000-fold increase in mechanical strength, and demonstrated enhanced osteogenic differentiation, underscoring their suitability for load-bearing musculoskeletal and orthopedic tissue engineering. Additionally, cell-laden hydrogel constructs demonstrated robust chondrogenic differentiation, highlighting the capacity for lineage-specific tissue development in vitro. Beyond these outcomes, the presented hybrid bioprinting approach integrates essential tissue engineering attributes that unites mechanical robustness and suturable capacity with multi-material integration, gradient property design, incorporation of bioactive agents, and support for multi-cell loading. This versatile platform advances complex tissue engineering and holds promise for patient specific, organ-on-demand applications.
    DOI:  https://doi.org/10.1101/2025.11.06.682452
  26. Nature. 2025 Nov 26.
    Yarns and fabrics that bend or stiffen under magnetic fields.
      
    Keywords:  Materials science
    DOI:  https://doi.org/10.1038/d41586-025-03745-7
  27. bioRxiv. 2025 Oct 24. pii: 2025.10.23.684219. [Epub ahead of print]
    Nuclei sense complex tissue shape and direct intestinal stem cell fate.
    Kaustav Bera, Delaney L McNally, Bruce E Kirkpatrick, Nolan R Petrich, F Max Yavitt, Marilyne Coulombe, Michaela Quintero, Nathaniel P Skillin, Alex Khang, Patrick S McGrath, Linda C Samuelson, Tanmay P Lele, Peter J Dempsey, Kristi S Anseth.
      Tissue architecture and function are influenced by mechanical cues. Yet, how cell nuclei sense forces within 3D tissues and dictate differentiation remains unknown as prior studies focused on isolated mesenchymal cells, which fail to fully predict tissue-level mechanical properties. We fill this knowledge gap utilizing live reporters and material-based organoid models. We posit the nucleus as an active mechanosensor of tissue shape, with levels of the nuclear scaffolding protein lamin-A varying across intestinal stem cell differentiation trajectory. Elevated forces on differentiated Paneth cell nuclei, in both organoids and tissue explants, increase lamin-A and nuclear wrinkling. Enhancing nuclear mechanotransduction primes cell differentiation, in otherwise stem promoting conditions, revealing that nuclear mechanics can direct stem cell fate. By engineering spatiotemporally controlled de novo tissue curvature with photo-degradable hydrogels, we direct spatially patterned lamin-A levels across mouse and human organoids of healthy and diseased origin, uncovering conserved nuclear mechanosensing pathway in epithelial tissues.
    DOI:  https://doi.org/10.1101/2025.10.23.684219
  28. Nucleic Acids Res. 2025 Nov 13. pii: gkaf1290. [Epub ahead of print]53(21):
    Metabolite-responsive scaffold RNAs for dynamic CRISPR transcriptional regulation.
    Anthony M Stohr, Helena Hansen, Blake Richards, Hayeon Park, Antonio G Goncalves, Ayushi Agrawal, Mark Blenner, Wilfred Chen.
      CRISPR activation is a powerful tool to upregulate a vast array of genes in many different contexts. However, there are few dynamic CRISPR transcriptional programs, which limit its usage in the creation of living biosensors, self-regulating microbial factories, or conditional therapeutics. Here, we address this limitation by embedding a molecular switch directly into a guide RNA to create a combined sensor-actuator called a metabolite-responsive scaffold RNA (MR-scRNA). We demonstrate the regulatory potential for MR-scRNAs by conditionally activating genes in three different kingdoms of life. We create MR-scRNAs responsive to two distinct metabolites, theophylline and tryptophan, by swapping the molecular switch used. MR-scRNAs respond quickly in a dose-dependent manner specifically to their target metabolite and enhance biochemical production when used as a dynamic regulator of pathway enzyme expression. The broad functionality and ease of design of the MR-scRNAs offer a promising tool for dynamic cellular regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf1290
  29. Nat Mater. 2025 Nov 28.
    Self-assembled cell-scale containers made from DNA origami membranes.
    Christoph Karfusehr, Markus Eder, Hao Yuan Yang, Brice Beinsteiner, Marion Jasnin, Friedrich C Simmel.
      Biological compartmentalization creates and controls localized environments to ensure that chemical processes are efficient, thus enabling life's complexity and functionality. Biological systems use crystalline protein cages for nanoscale compartments, whereas larger, dynamic structures, such as vesicles and cell membranes, are formed from lipid bilayers. Although membrane-based approaches have prevailed in bottom-up synthetic biology, DNA and protein nanotechnology has focused on designing rigid cage assemblies. Here we report on the self-assembly of radially symmetric DNA origami subunits that are inspired by the structure and interactions of lipids. The formed DNA origami monolayer membranes can be readily programmed to form vesicles or hollow tubes with diameters ranging from 100 nm to over 1 μm. These DNA origami membranes represent an approach for compartmentalization that opens possibilities in bottom-up biology and cell-scale soft robotics.
    DOI:  https://doi.org/10.1038/s41563-025-02418-0
  30. ACS Biomater Sci Eng. 2025 Nov 27.
    Rigidity Sensing of Inclusions Directs Differentiated Cell Elongation and Force Generation across Phenotypes.
    Yuxin Luo, Yimin Luo.
      Fibrosis is driven in part by the transition of healthy fibroblasts to a contractile phenotype called myofibroblasts. The mechanics of the extracellular matrix play a crucial role in regulating cell fates and behaviors during this transition. However, most studies to date focus on cells grown on 2D surfaces and matrices with homogeneous properties. This leaves open how local rigidity differentially regulates the behaviors of both phenotypes in 3D environments, including polarization, contraction, and maintenance of phenotypes, during remodeling. Here, we engineer 3D microgel-in-collagen composites by embedding low-volume fractions of cell-scale microgels with two levels of rigidity, mimicking healthy and pathological tissues that are stiffer than the surrounding collagen but do not significantly change the bulk modulus. We find that microgels serve as mechanical centers: both phenotypes polarize toward microgel inclusions. The polarization response decays as a power-law with distance ∼r-n, decreasing more slowly for myofibroblasts (n ≈ 0.35) than fibroblasts (n ≈ 0.81), indicating that myofibroblasts are more sensitive to small mechanical variations. In situ measurements finds that forces are highest for myofibroblasts near stiff microgels and lowest for fibroblasts near soft microgels. Local rigidity also stabilizes the myofibroblast phenotype: Both the ordering of the proinflammatory marker α-smooth muscle actin and nuclear Yes-associated protein localization persist for cells cultured with stiff microgels over several days but diminish quickly for those cultured with soft microgels and in pure collagen. Together, these results reveal a rigidity- and phenotype-dependent feedback loop: stiff inclusions induce cell polarization and collagen remodeling via a contractile force, which in turn maintain the myofibroblast phenotype. Our study positions mechanical heterogeneity as a useful and sensitive handle to probe and potentially modulate early fibrotic progressions.
    Keywords:  biomaterials; hydrogels; mechanotransduction; myofibroblasts; polarization; remodeling
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c01611
  31. Nat Commun. 2025 Nov 25. 16(1): 10489
    Soft magnetic microrobots with remote sensing and communication capabilities.
    Quan Gao, Minsoo Kim, Denis von Arx, Elric Zhang, Xinzhi Zhang, Hao Ye, Christian Vogt, Claas Ehmke, Dianne Corsino, Federica Catania, Niko Münzenrieder, Michele Magno, Giuseppe Cantarella, Bradley J Nelson, Salvador Pané.
      Remote communication in small-scale robotics offers a powerful way to enhance their capabilities, introducing options for state monitoring, multi-agent collaboration, and autonomous operation. Integrating common remote communication tools, such as antennas, into microrobots is challenging with conventional design and manufacturing techniques. We propose a concept that integrates shape-reconfigurable soft microrobots with flexible electronics, leveraging their elastic mechanical properties to enable remote communication. This approach, based on photolithography processes, is scalable and adaptable to various sensing applications. As a proof of concept, we present a microrobot, which integrates a thermoresponsive magnetic hydrogel, an anisotropic support structure, and a flexible dipole antenna into a cohesive three-layered design. The microrobot can morph from a helical shape at low-temperatures to a planar shape at high-temperatures. This shape transformation can be remotely detected by external radio communication receivers, enabling shape-state recognition and environmental temperature sensing. Furthermore, we show that the collective behavior of multiple microrobots enhances the recognition performance by amplifying the signal. The concept represents a significant advancement in co-engineering smart materials and flexible electronics, illustrating an approach of microrobotic embodied intelligence by integrating environmental monitoring, magnetic navigation, and remote signaling.
    DOI:  https://doi.org/10.1038/s41467-025-65459-8
  32. bioRxiv. 2025 Nov 16. pii: 2025.11.14.688573. [Epub ahead of print]
    A membrane-driven biochemical oscillator tunable by the volume to surface area ratio.
    Jonathan Fischer, Ezra Greenberg, Yue Moon Ying, Sho S Takeshita, Samuel L Foley, Margaret E Johnson.
      Oscillations are ubiquitous features of biological organisms, playing crucial roles in processes from circadian rhythms to developmental patterning. Protein-based biochemical oscillators have particular applications in synthetic biology because they can access fast and slow timescales that are independent from the transcription-translation machinery required of genetic oscillators. Here, we introduce and model such a mass-conserving biochemical oscillator using mass-action reaction kinetics that exploits dynamic changes to membrane phospholipid concentrations to drive proteins on and off the membrane in robust, tunable rhythms. Importantly, the oscillations rely on amplification of reactions on the membrane via dimensional reduction, and they are therefore tunable by variations in the volume-to-surface area ratio (V/A) of the system. With components inspired by the endocytic machinery, we show that a wide range of physiologically relevant biochemical rates can produce oscillations in part due to this independent geometric control. A broad computational screen of the high-dimensional parameter space reveals that oscillations require relatively strict enzyme kinetic design rules for low V/A but much more permissive kinetics for larger V/A. We validate that oscillations persist with more realistic reaction-diffusion simulations that captures explicit diffusion and stochastic, integer valued copy numbers, in overall good agreement with the period and amplitude of the deterministic oscillators. Because the oscillations rely on time-dependent changes to the surface properties and not post-translational modifications to the protein subunits, we demonstrate that it can be coupled to a self-assembling trimer, driving not only changes in localization but trimer yield. Our analysis establishes this membrane-localization oscillator as a new, geometry tunable and programmable timing module and suggests a potential for geometry sensing in engineered or cell-free systems.
    DOI:  https://doi.org/10.1101/2025.11.14.688573
  33. bioRxiv. 2025 Oct 13. pii: 2025.10.10.681769. [Epub ahead of print]
    Imaging Cellular Metabolic Rewiring with SuMMIT-SRS.
    Yajuan Li, Zhi Li, Yuhan Li, Kevin Rhine, Sural Ranamukhaarachchi, Shuo Qin, Hongje Jang, Jorge Villazon, Zhiliang Bai, Stephanie I Fraley, Gene W Yeo, Rong Fan, Lingyan Shi.
      Cells dynamically rewire their metabolic pathways in response to physiological and pathological cues. Such plasticity is particularly critical in neurons, stem cells, cancer cells, and immune cells, where biosynthetic demands can shift rapidly. However, current metabolic imaging techniques using isotope labeling typically track only one metabolite at a time, limiting their ability to capture the rapid dynamics of complex metabolic networks including coordinated precursor utilization, crosstalk, and turnover. Here, we present Subcellular Multiplexed Metabolic Isotope Tracing Stimulated Raman Scattering microscopy (SuMMIT-SRS), a platform that enables simultaneous visualization of multiple metabolic dynamics at subcellular resolution. By exploiting the distinct vibrational signatures of carbon-deuterium bonds derived from multiple deuterated amino acids, lipids, and monosaccharide tracers, SuMMIT-SRS maps co-regulated DNA, RNA, protein, and lipid synthesis at the same time and resolves various individual amino acid-mediated metabolic pathways within intact cells and tissues. We demonstrate SuMMIT's broad utility across Drosophila fat body tissue and developing brain, tumor organoids, aged human neurons, and mouse liver, capturing cell type-specific metabolic rewiring under genetic and pathological perturbations. This approach extends SRS to multiplexed isotope tracing, offering a powerful tool to uncover dynamic and complex biosynthesis programs in development, health, and disease.
    Keywords:  Metabolic rewiring; SRS; lipid; metabolism; multiplex; optical imaging; protein
    DOI:  https://doi.org/10.1101/2025.10.10.681769
  34. bioRxiv. 2025 Oct 30. pii: 2024.12.06.627299. [Epub ahead of print]
    SubCell: Proteome-aware vision foundation models for microscopy capture single-cell biology.
    Ankit Gupta, Zoe Wefers, Konstantin Kahnert, Jan N Hansen, Mohini K Misra, Will Leineweber, Anthony Cesnik, Dan Lu, Ulrika Axelsson, Frederic Ballllosera, Russ B Altman, Theofanis Karaletsos, Emma Lundberg.
      Cell morphology and subcellular protein organization provide important insights into cellular function and behavior. These features of cells can be studied using large-scale protein fluorescence microscopy, and machine learning has become a powerful tool to interpret the resulting images for biological insights. Here, we introduce SubCell, a suite of self-supervised deep learning models for fluorescence microscopy designed to accurately capture cellular morphology, protein localization, cellular organization, and biological function beyond what humans can readily perceive. These models were trained on the proteome-wide image collection from the Human Protein Atlas with a novel proteome-aware learning objective. SubCell outperforms state-of-the-art methods across a variety of tasks relevant to single-cell biology and generalizes to other fluorescence microscopy datasets without any fine-tuning. Additionally, we construct the first proteome-wide hierarchical map of proteome organization that is directly learned from image data. This vision-based multiscale cell map defines cellular subsystems with high resolution of protein complexes, reveals proteins with similar functions, and distinguishes dynamic and stable behaviors within cellular compartments. Finally, Subcell enables a rich multimodal protein representation when integrated with a protein sequence model, allowing for a more comprehensive capture of gene function than either vision-only or sequence-only models alone. In conclusion, SubCell creates deep, image-driven representations of cellular architecture that are applicable across diverse biological contexts and datasets.
    DOI:  https://doi.org/10.1101/2024.12.06.627299
  35. Nat Commun. 2025 Nov 25. 16(1): 10468
    Engineering yeast peroxisome assembly enables the increased production of acetyl-CoA and its derived 5-deoxyflavonoids.
    Yongxing Li, Bingjie Du, Chun Li, Xudong Feng.
      Acetyl-CoA serves as a foundational precursor and energy source for various biosynthesis pathways. The insufficient supply of acetyl-CoA in cytosol is usually a bottleneck for exogenous chemical synthesis in engineered microbes such as yeast. Exportation of acetyl-CoA from peroxisome, an exclusive organelle for fatty acids β-oxidation, may be an effective way to solve this problem. In this study, we develop a peroxin (PEX) engineering strategy to modulate peroxisome assembly in S. cerevisiae. Then, robust peroxisomes are constructed with improved acetyl-CoA supply by up to 98%, which further leads to the increased liquiritigenin titer (1102.4 mg/L). We also demonstrate that the PEX-mediated peroxisome engineering strategy can be extended across yeast species. Hybrid peroxisomes with tailored function are constructed in S. cerevisiae by transplanting selected PEXs from Y. lipolytica. Our study provides mechanistic insights into the "PEXs-peroxisome assembly-acetyl-CoA synthesis" relationship.
    DOI:  https://doi.org/10.1038/s41467-025-65444-1
  36. Nat Methods. 2025 Nov 28.
    ExoSloNano: multimodal nanogold labels for identification of macromolecules in live cells and cryo-electron tomograms.
    Lindsey N Young, Alice Sherrard, Huabin Zhou, Farhaz Shaikh, Joshua Hutchings, Margot Riggi, Mythreyi Narasimhan, W Alexander Flaherty, Eric J Bennett, Michael K Rosen, Antonio J Giraldez, Elizabeth Villa.
      In situ cryo-electron microscopy (cryo-EM) enables the direct interrogation of structure-function relationships by resolving macromolecular structures in their native cellular environment. Recent progress in sample preparation, imaging and data processing has enabled the identification and determination of large biomolecular complexes. However, the majority of proteins are of a size that still eludes identification in cellular cryo-EM data, and most proteins exist in low copy numbers. Therefore, novel tools are needed for cryo-EM to identify macromolecules across multiple size scales (from microns to nanometers). Here we introduce nanogold probes for detecting specific proteins using correlative light and electron microscopy, cryo-electron tomography (cryo-ET) and resin-embedded electron microscopy. These nanogold probes can be introduced into live cells, in a manner that preserves intact molecular networks and cell viability. We use this ExoSloNano system to identify both cytoplasmic and nuclear proteins by room-temperature electron microscopy, and resolve associated structures by cryo-ET. By providing high-efficiency protein labeling in live cells and molecular specificity within cryo-ET tomograms, ExoSloNano expands the proteome available to electron microscopy.
    DOI:  https://doi.org/10.1038/s41592-025-02928-4
  37. bioRxiv. 2025 Oct 21. pii: 2025.10.20.683155. [Epub ahead of print]
    Matrix Stiffness Governs Fibroblast-Driven Immune Homeostasis in Gingival Tissues.
    Hardik Makkar, Nghi Tran, Yu-Chang Chen, Kang I Ko, Rebecca G Wells, Kyle H Vining.
      Periodontal disease is associated with inflamed gingival tissues and degradation of the gingival extracellular matrix (ECM), yet the role of mechanical cues is poorly understood. Gingival ECM in periodontal disease showed a loss of fibrillar collagen compared to healthy samples. We hypothesized that ECM softening in periodontal disease contributes to inflammation due to dysregulated gingival fibroblasts (GFs). A mechanically tunable hydrogel model of the gingival ECM was developed to investigate the mechano-immune crosstalk. Stiff collagen-alginate hydrogels matched the rheological properties of gingival biopsies. Human donor GFs encapsulated in these stiff hydrogels showed significantly suppressed toll-like receptor inflammatory responses compared to soft. Stiffness-dependent inflammatory responses of GFs were directed by the non-canonical NFκB pathway and epigenetic nuclear organization. The direct impact of mechanical cues on immune responses was investigated with human donor cells ex vivo by co-culture of human GFs with myeloid cells and in human gingival explants. Myeloid progenitors co-cultured with GFs in stiff hydrogels differentiated into immunomodulatory dendritic cells. Ex vivo crosslinking of human gingival tissue increased stiffness and reduced inflammatory cytokines. Gingival mechano-immune regulation provides a new avenue for biomaterials-based treatments in periodontitis.
    Keywords:  Epigenetic regulation; Fibroblast–immune crosstalk; Gingival extracellular matrix; Matrix stiffness; Mechanotransduction; Nuclear organization; Periodontal Disease
    DOI:  https://doi.org/10.1101/2025.10.20.683155
  38. bioRxiv. 2025 Nov 01. pii: 2025.10.31.685825. [Epub ahead of print]
    Adapting CRISPR-associated transposons for rapid and high-throughput reverse genetics.
    David W Basta, Franz G Zingl, Yiyan Yang, Kaylee T Nguyen, Yang-Yu Liu, Matthew K Waldor.
      CRISPR-associated transposons (CAST) use guide RNAs to direct their transposition and are being harnessed as tools for programmable genome engineering across diverse bacterial species. However, CAST systems have not been adapted for high-throughput genetic screening. Here, we present MultiCAST, a streamlined platform for rapid and scalable guide RNA-directed transposon insertion in bacteria. MultiCAST generates targeted insertions in a single step through conjugative delivery of conditionally replicative plasmids encoding the CAST enzymatic machinery and a selectable mini-transposon expressing the guide RNA. By leveraging the inserted guide sequence as a molecular barcode, MultiCAST enables pooled, high-throughput genetic screens using only amplicon sequencing. We identified factors that influence transposition efficiency and the accuracy of insertion frequency measurements derived from guide sequencing. Adjusting the ratio of donor and recipient strain during conjugation mitigates guide-transposon "crosstalk", in which a single recipient cell acquires multiple donor plasmids containing distinct guides. Furthermore, we developed a machine learning-based predictive model for selecting highly active guides based on target sequence features that strongly correlate with activity. The nucleoid-associated protein H-NS was also found to inhibit CAST activity, providing a mechanistic explanation for variable insertion frequencies among non-essential genes. To demonstrate the scalability of MultiCAST, we screened a pooled mutant population created from >5,200 guides targeting 88 genes in E. coli across twelve nutrient conditions, accurately identifying genes with condition-specific fitness effects. The simplicity, speed, and throughput of MultiCAST make genome-scale functional screens more accessible across a wide range of bacterial species.
    Significance: Efficient gene disruption is essential for understanding bacterial gene function, but traditional genetic approaches are labor-intensive and generally not well-suited for high-throughput studies. We developed MultiCAST, a simple and scalable method that harnesses guide RNA-directed CRISPR-associated transposons for targeted bacterial gene disruption. MultiCAST enables single and pooled transposon mutagenesis in a single step and eliminates the need for complex sequencing library preparation protocols by using the guide sequence as a quantifiable surrogate for mutant abundance. This approach allows thousands of mutants to be generated and screened simultaneously across multiple conditions using only amplicon sequencing. By dramatically reducing the time, cost, and complexity of reverse genetics, MultiCAST opens new possibilities for genome-scale functional studies, accelerating the discovery of bacterial gene functions.
    DOI:  https://doi.org/10.1101/2025.10.31.685825
  39. Sci Adv. 2025 Nov 28. 11(48): eaea3345
    Articular neural bioelectronics by decoupling mechanical strain from electron transport.
    Tong Li, Fei Jin, Lisha Hua, Juan Ma, Fuyi Wang, Zhidong Wei, Ting Wang, Steven Wang, Zhang-Qi Feng.
      Implantable bioelectronics for dynamic articular nerves require interfaces that harmonize extreme mechanical compliance at extreme strains exceeding 120%, stable conductivity, and metabolic permeability-a triad unattained by current stretchable devices. Here, we introduce liquid metal-based ultraelastic fibrous bioelectronics for articular nerves that overcome interfacial and mechanical limitations through molecular engineering and structural design. Thiol-functionalized self-assembled monolayers on liquid metal nanoparticles enhance interfacial adhesion with neural tissues, eliminating fibrous encapsulation, while anisotropic silver nanowire networks decouple mechanical strain from electron transport, achieving negligible resistance variation under 150% repetitive strain. The porous mesh structure enables fluid permeability five orders of magnitude higher than conventional materials, ensuring physiological nutrient exchange in synovial joints. In vivo integration with rat ulnar nerves demonstrated chronic neuromodulation over 6 weeks without disruption of functional behavior. This work redefines biomechanically adaptive neuroelectronics, offering a universal framework for interfacing dynamic biological systems, from prosthetic sensory feedback to treating neurodegenerative pathologies.
    DOI:  https://doi.org/10.1126/sciadv.aea3345
  40. Mol Pharm. 2025 Nov 26.
    Fabrication and Evaluation of PLGA Microsphere-Loaded Hydrogels as Potential Intraocular Lens for Sustained Release of Timolol Maleate.
    Shahid Iqbal Mir, Yethmini Senadheera, Debrupa Lahiri, Prateek K Jha.
      Eye drops suffer from challenges primarily associated with fast tear clearance, resulting in poor drug bioavailability. We developed a drug-eluting intraocular lens (IOL) that ensures a sustained release of timolol (maleate) as an antiglaucoma agent, for extended periods. Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres encapsulated with timolol are first synthesized using the water-in-oil-in-water (w/o/w) double emulsion method. These drug-loaded microspheres are incorporated into poly(acrylamide-sodium acrylate) hydrogel (PAH) IOL cast from a 3D-printed mold, which is then monitored for sustained drug release for an extended period. Developed drug-loaded IOLs are transparent and flexible and demonstrate sustained release of timolol for over 7 weeks. This release duration is drastically higher than direct drug loading in the PAH film, i.e., the degradation control of drug release is much more efficient than drug transport by diffusion alone. Moreover, the incorporation of PLGA microspheres into the PAH film slows PLGA degradation, resulting in a 3-fold increase in release duration when compared to that of standalone microspheres. The resulting system ensures a long-term, patient-friendly approach to glaucoma treatment.
    Keywords:  3D printing; biodegradable; cataract; glaucoma; hydrogel; intraocular lens (IOL); ocular drug delivery; sustained drug release; timolol
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01161
  41. bioRxiv. 2025 Nov 05. pii: 2025.10.28.685244. [Epub ahead of print]
    Reversing transgene silencing via targeted chromatin editing.
    Sebastian Palacios, Elia Salibi, Eric Lu, Ron Weiss, Thorsten M Schlaeger, James J Collins, Domitilla Del Vecchio.
      Mammalian cell engineering offers the opportunity to uncover biological principles and develop next-generation biotechnologies. However, epigenetic silencing of transgenes hinders the control of gene expression in mammalian cells. Here, we use chromatin editing of an integrated reporter in CHO-K1 and human induced pluripotent stem cells to study the molecular interactions driving silencing and its reversal. After transient induction of either DNA methylation or H3K9me3, stable silencing was exclusively observed with both marks. Due to the positive feedback between DNA methylation and H3K9me3 and the relative low stability of H3K9me3, our model predicts that removing DNA methylation is sufficient for transgene reactivation. Accordingly, targeted DNA demethylation reactivated the reporter irrespective of whether silencing was achieved by inducing DNA methylation, H3K9me3, or by the endogenous cellular machinery. These results shed light on molecular mechanisms at play during silencing and provide engineering tools for potent and specific transgene reactivation in mammalian cells.
    DOI:  https://doi.org/10.1101/2025.10.28.685244
  42. Biofabrication. 2025 Nov 24.
    Heterogeneous polymerization via two-step crosslinking for tunable microribbon hydrogels.
    Mahsa Karimi, Fereshteh Ahadi, Niloofar Esmati, Mingyue Fan, Lin Han, Christopher Y Li, Li-Hsin Han.
      Hydrogels are widely used in tissue engineering but conventional homogeneous polymerization often creates dense matrices that hinder cell migration and restrict extracellular matrix production. The motivation of this project was to overcome these limitations by developing a heterogeneously crosslinkable hydrogel platform that enables both cell migration and matrix deposition. We present a two-step heterogeneous polymerization approach that introduces spatial variations in matrix density, producing tunable, cell-sized pores that promote migration, proliferation, and matrix synthesis. As an implementation, gelatin was pre-assembled into microribbon-like building blocks using a Dynamic Molding process, methacrylated to introduce crosslinkable groups, chemically modified, washed, and freeze-dried. Upon rehydration, the ribbons formed a moldable paste that could be mixed with cells and photo-crosslinked into scaffolds with in situ-formed, cell-sized pores. The main novelty of this method is the introduction of chemical modifications with methacrylic anhydride (MAA), acetic anhydride (AceA), and succinic anhydride (SucA), which enable a controlled two-step heterogeneous polymerization and allow independent tuning of scaffold microstructure, mechanics, and degradation. AceA reduced crosslink density and accelerated degradation, whereas SucA promoted swelling, enhanced mechanical strength, and slowed degradation. Cell studies revealed that SucA-modified scaffolds supported superior adhesion and proliferation compared to AceA-modified and unmodified controls. Such work may significantly impact the design of next-generation scaffolds by providing a versatile platform that integrates structural, mechanical, and biochemical control for regenerative medicine applications.
    Keywords:  Building blocks; Heterogeneous hydrogel; Hydrogel polymerization; Multi-step crosslinking; Porous hydrogel; Tissue engineering
    DOI:  https://doi.org/10.1088/1758-5090/ae235a
  43. Nat Commun. 2025 Nov 25. 16(1): 10432
    Wireless in-body sensing through genetically engineered bacteria.
    Ahmet Bilir, Merve Yavuz, Urartu Ozgur Safak Seker, Sema Dumanli.
      This paper introduces a class of wireless implantable sensors that integrate genetically engineered cells capable of detecting specific molecules for continuous monitoring. While synthetic biology enables cells to sense molecular targets, wireless communication of this information remains a challenge. Electromagnetic (EM) waves at cellular-scale wavelengths are strongly attenuated in tissue, necessitating centimeter-scale wavelengths for in-body links. Aligning cellular responses with these longer EM wavelengths enables effective interaction. In this work, the response of Escherichia coli is harnessed to trigger the controlled degradation of a passive microwave antenna, which is then monitored via backscatter communication. This approach converts cellular activity into detectable EM signals, eliminating the need for batteries or circuits. We demonstrate a wireless link between a passive, cell-based sensor in a human body phantom and an external receiver, achieving molecular-level sensing at 25 mm implant depth. Future implementations could couple bacterial responses to diverse molecular targets.
    DOI:  https://doi.org/10.1038/s41467-025-65416-5
  44. RSC Adv. 2025 Nov 24. 15(54): 46591-46601
    Tuning collagen and collagen-alginate mechanics through extrusion bioprinting process parameters.
    Grace Hu, Karla Gutierrez Cebrero, Nandita Venkataraman, Dharneedar Ravichandran, Yunzhi Lin, Zeqing Jin, Zev J Gartner, Grace X Gu.
      Bioprinting allows the fabrication of biopolymers into complex and hierarchical structures reminiscent of their organization in vivo. As the main structural protein found in connective tissues, type I collagen is of particular interest as a biomaterial due to its biochemical activity and ease of physical or chemical crosslinking. However, several limitations of collagen-based constructs include poor mechanical strength and inability to bear loads in dynamic conditions. Towards overcoming these challenges, this study explores the impact of higher concentration collagen bioinks (35 and 70 mg mL-1) and the incorporation of an alginate hydrogel during synthesis to create designs with shape fidelity and tunable mechanical properties. Using bioprinting processes, we quantify the relationship between bioink composition, printing parameters, and post-processing on printability and mechanical behavior. Results show that both pure collagen bioinks and low-concentration collagen to alginate volume ratios of 1 : 1, 1 : 5, and 1 : 10 exhibited good printability, but increasing the alginate concentration led to greater shrinkage of scaffolds after thermo-ionic crosslinking. Uniaxial compression results indicated a directly increased modulus and compressive strength after 24 hours of crosslinking, which was also seen in tensile modulus after 12 hours of crosslinking. Notably, blend composition demonstrated the greatest influence on material stiffness, with crosslinking duration serving as a secondary factor. Scanning electron microscopy used to visualize the cross-section of these collagen constructs reveals a dense fibrous microstructure that may help reinforce mechanical properties and promote cell adhesion. Ultimately, designing collagen-based biomaterials that can be mechanically tailored through printing process parameters will inform customizable extrusion of soft tissues for regenerative medicine.
    DOI:  https://doi.org/10.1039/d5ra03922c
  45. Res Sq. 2025 Oct 28. pii: rs.3.rs-7762382. [Epub ahead of print]
    3D Printing of Air.
    Ibrahim Ozbolat, Deepak Gupta, Henrique Piva, Vaibhav Pal, Suihong Liu, Syed Rizvi, Mecit Alioglu, Yasar Yilmaz, Annie Smith, Logan Haugh, Joao Robazzi, Jade Sency, Myoung Kim, Thomas Neuberger, Francesco Costanzo.
      Historically, three-dimensional (3D) printing involved depositing tangible materials onto a substrate or within a supporting medium to create solid and porous architectures. Here, we unveil 3D printing of air, an intangible and invisible ink having ~10^9 times less viscosity than conventional inks, to spatially pattern bubbles and fabricate freeform air channels in 3D within diverse materials. This study delves into air bubble dynamics, encompassing formation, deformation, spatiotemporal stability in non-spherical configurations, and interaction within yield stress materials. We integrate machine learning algorithms to predict air printability based on material properties, providing a framework for rational material selection. The interplay between yield stress, viscosity, and nozzle diameter facilitates the formation of stable air channels with extremely high aspect ratios (~ 4×10^4). These insights establish a foundation for harnessing air as a printable medium and as a functional ink in applications spanning biology, optics, material science, engineering, and medicine.
    DOI:  https://doi.org/10.21203/rs.3.rs-7762382/v1
  46. Mater Today Bio. 2025 Dec;35 102452
    Recombinant collagen in regenerative medicine: Expression strategies, structural design, and translational applications.
    Huixia He, Mingzhu Ye, Guoqi Cui, Jianxi Xiao.
      Recombinant collagen represents a new generation of biomaterials that integrate molecular precision, functional tunability, and scalable biomanufacturing. While animal-derived collagens remain clinically established, their inherent biological variability, limited controllability, and potential pathogen risks have spurred the development of recombinant systems capable of producing collagen with defined sequences and consistent quality. Advances in synthetic biology have enabled expression across diverse hosts-including E. coli, yeast, plants, mammalian cells, and transgenic organisms-each offering distinct advantages in yield, post-translational modification, and triple-helix assembly. Emerging molecular architectures, encompassing triple-helical recombinant collagens, non-helical gelatin-like proteins, and multifunctional fusion constructs, collectively expand the structural repertoire and functional landscape of recombinant collagen-based biomaterials. These engineered materials show strong promise in bone and cartilage regeneration, skin reconstruction, and corneal repair. Nonetheless, challenges remain in achieving complete hydroxylation, cost-effective large-scale manufacturing, and harmonized regulatory standards. The integration of AI-assisted sequence design, programmable molecular engineering, and GMP-compliant production is expected to accelerate clinical translation. By bridging molecular innovation with clinical application, recombinant collagen is poised to redefine the landscape of regenerative medicine and usher in a new era of precision-engineered biomaterials.
    Keywords:  Expression systems; Protein engineering; Recombinant collagen; Tissue regeneration; Triple helix stabilization
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102452
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