bims-enlima Biomed News
on Engineered living materials
Issue of 2025–03–30
forty-one papers selected by
Rahul Kumar, Tallinna Tehnikaülikool



  1. Small. 2025 Mar 27. e2502199
      Engineered Living Materials (ELMs) combine synthetic biology with artificial materials to create biohybrid living systems capable of replicating, self-repairing, and responding to external stimuli. Due to their self-optimization abilities, these systems hold great potential for biotechnological applications. This study is a first step toward ELMs based on DNA hydrogels, focusing on the production of biohybrid materials using the exoelectrogenic bacterium Shewanella oneidensis. To equip the bacterium with the functionality needed for building DNA hydrogels, inducible cell surface anchors are developed, which can bind exogenous polymerase via the SpyCatcher/SpyTag (SC/ST) technology. The process parameters for in situ production of DNA hydrogels are established, enabling the development of these materials in the context of living bacteria for the first time. Using an extracellular nuclease-deficient S. oneidensis strain, stable biohybrid biofilms are generated directly on the surface of bioelectrochemical systems, showing the current generation. Given the high programmability and functionalization potential of DNA hydrogels, it is believed that this study represents a significant step toward establishing dynamic biohybrid material systems that exhibit both conductivity and metabolic activity.
    Keywords:  BES; DNA materials; S. oneidensis; biofilms; engineered living materials
    DOI:  https://doi.org/10.1002/smll.202502199
  2. J Biomed Mater Res A. 2025 Apr;113(4): e37897
      Hydrogels are an important class of biomaterials that permit cells to be cultured and studied within engineered microenvironments of user-defined physical and chemical properties. Though conventional 3D extrusion and stereolithographic (SLA) printing readily enable homogeneous and multimaterial hydrogels to be formed with specific macroscopic geometries, strategies that further afford spatiotemporal customization of the underlying gel physicochemistry in a non-discrete manner would be profoundly useful toward recapitulating the complexity of native tissue in vitro. Here, we demonstrate that grayscale control over local biomaterial biochemistry and mechanics can be rapidly achieved across large constructs using an inexpensive (~$300) and commercially available liquid crystal display (LCD)-based printer. Template grayscale images are first processed into a "height-extruded" 3D object, which is then printed on a standard LCD printer with an immobile build head. As the local height of the 3D object corresponds to the final light dosage delivered at the corresponding xy-coordinate, this method provides a route toward spatially specifying the extent of various dosage-dependent and biomaterial, forming/modifying photochemistries. Demonstrating the utility of this approach, we photopattern the grayscale polymerization of poly(ethylene glycol) (PEG) diacrylate gels, biochemical functionalization of agarose- and PEG-based gels via oxime ligation, and the controlled 2D adhesion and 3D growth of cells in response to a de novo-designed α5β1-modulating protein via thiol-norbornene click chemistry. Owing to the method's low cost, simple implementation, and high compatibility with many biomaterial photochemistries, we expect this strategy will prove useful toward fundamental biological studies and functional tissue engineering alike.
    Keywords:  3D printing; additive manufacturing; grayscale; hydrogel; light; photopatterning
    DOI:  https://doi.org/10.1002/jbm.a.37897
  3. J Biomed Mater Res A. 2025 Apr;113(4): e37900
      Establishing a robust, functional microvascular network remains a critical challenge for both the revascularization of damaged or diseased tissues and the development of engineered biological materials. Vascularizing microgels may aid in efforts to develop complex, multiphasic tissues by providing discrete, vascularized tissue modules that can be distributed throughout engineered constructs to vascularize large volumes. Here, we fabricated poly(ethylene glycol)-norbornene (PEGNB) microgels containing endothelial and stromal cells via flow-focusing microfluidic droplet generation. When embedded in bulk fibrin hydrogels, these cell-laden microgels initiated the formation and development of robust microvascular networks. Furthermore, extended preculture of cell-laden PEGNB microgels enabled the formation of vessel-like structures supported by basement membrane within the matrix without aggregation. Our findings highlight the suitability of PEG-based matrices for the development of vascularizing microgels capable of forming well-distributed, robust microvascular networks.
    Keywords:  microfluidics; microgels; poly(ethylene glycol); prevascularization
    DOI:  https://doi.org/10.1002/jbm.a.37900
  4. Small. 2025 Mar 26. e2500740
      Low-carbon building materials are urgently needed due to the tremendous carbon emissions and energy consumption associated with traditional concrete building materials. However, limited mechanical performance usually restricts the practical applications of current low-carbon building materials, and the massive adhesive utilization can cause their high embodied CO2. Here, the tough and sustainable bioinspired low-carbon building materials are fabricated by binding sand grains and glass fibers with a small amount of natural-based adhesive (below 3.2 wt.%) at low-temperature and atmospheric pressure. These bioinspired low-carbon building materials possess ultra-low embodied CO2 of 0.031-0.064 kgCO2eq kg-1 and embodied energy of 0.29-0.59 MJ kg-1, over one order of magnitude lower than concrete building materials. Additionally, the bioinspired low-carbon building materials are versatile with various grains, such as sand grains, mineral residues etc., and exhibit good mechanical performance that can meet the cement mortar standard. This study provides a promising strategy to design the low-carbon building materials for practical application in next-generation constructions.
    Keywords:  bioinspired; building materials; glass fibers; low‐carbon
    DOI:  https://doi.org/10.1002/smll.202500740
  5. Nat Water. 2025 ;3(3): 319-333
      Membrane-based separation processes hold great promise for sustainable extraction of lithium from brines for the rapidly expanding electric vehicle industry and renewable energy storage. However, it remains challenging to develop high-selectivity membranes that can be upscaled for industrial processes. Here we report solution-processable polymer membranes with subnanometre pores with excellent ion separation selectivity in electrodialysis processes for lithium extraction. Polymers of intrinsic microporosity incorporated with hydrophilic functional groups enable fast transport of monovalent alkali cations (Li+, Na+ and K+) while rejecting relatively larger divalent ions such as Mg2+. The polymer of intrinsic microporosity membranes surpasses the performance of most existing membrane materials. Furthermore, the membranes were scaled up and integrated into an electrodialysis stack, demonstrating excellent selectivity in simulated salt-lake brines. This work will inspire the development of selective membranes for a wide range of sustainable separation processes critical for resource recovery and a global circular economy.
    Keywords:  Chemical engineering; Materials chemistry; Polymer chemistry; Polymers; Porous materials
    DOI:  https://doi.org/10.1038/s44221-025-00398-8
  6. Cell Rep Methods. 2025 Mar 24. pii: S2667-2375(25)00045-1. [Epub ahead of print]5(3): 101009
      We demonstrate a cybernetic approach to control the composition of a P. putida and E. coli co-culture that does not rely on genetic engineering to interface cells with computers. We first show how composition information can be extracted from different bioreactor measurements and then combined with a system model using an extended Kalman filter to generate accurate estimates of a noisy system. We then demonstrate that adjusting the culture temperature can drive the composition due to the species' different optimal temperatures. Using a proportional-integral control algorithm, we are able to track dynamic references with real-time noise rejection and independence from starting conditions such as inoculation ratio. We stabilize the co-culture for 7 days (∼250 generations) with the experiment ending before the cells could adapt out of the control. This cybernetic framework is broadly applicable, with different microbes' unique characteristics enabling robust control over diverse co-cultures.
    Keywords:  CP: biotechnology; CP: microbiology; PI control; biofilm; bioreactor; co-culture; control; cybergenetic; cybernetic; systems biology
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101009
  7. ACS Nano. 2025 Mar 27.
      Cells are diverse systems with unique molecular profiles that support vital functions, such as energy production and nutrient absorption. Advances in omics have provided valuable insights into these cellular processes, but many of these tools rely on cell lysis, limiting the ability to track dynamic changes over time. To overcome this, methods for longitudinal profiling of living cells have emerged; however, challenges such as low throughput and genetic manipulation still need to be addressed. Nanomaterials, particularly nanowires, offer a promising solution due to their size, high aspect ratios, low cost, simplicity, and potential for high-throughput manufacturing. Here, we present a nanowire-based platform for longitudinal mRNA profiling in living cells using vertically aligned nickel nanowire arrays for efficient mRNA extraction with minimal cellular disruption. We demonstrate its ability to track enhanced green fluorescent protein expression and transcriptomic changes from drug responses in the same cells over time, showcasing the platform's potential for dynamic cellular analysis.
    Keywords:  intracellular sampling; longitudinal profiling; nanowires; temporal; transcriptomics
    DOI:  https://doi.org/10.1021/acsnano.4c18297
  8. Nat Commun. 2025 Mar 26. 16(1): 2946
      Magnetically responsive soft materials with spatially-encoded magnetic and material properties enable versatile shape morphing for applications ranging from soft medical robots to biointerfaces. Although high-resolution encoding of 3D magnetic and material properties create a vast design space, their intrinsic coupling makes trial-and-error based design exploration infeasible. Here, we introduce a data-driven strategy that uses stochastic design alterations guided by a predictive neural network, combined with cost-efficient simulations, to optimize distributed magnetization profile and morphology of magnetic soft materials for desired shape-morphing and robotic behaviors. Our approach uncovers non-intuitive 2D designs that morph into complex 2D/3D structures and optimizes morphological behaviors, such as maximizing rotation or minimizing volume. We further demonstrate enhanced jumping performance over an intuitive reference design and showcase fabrication- and scale-agnostic, inherently 3D, multi-material soft structures for robotic tasks including traversing and jumping. This generic, data-driven framework enables efficient exploration of design space of stimuli-responsive soft materials, providing functional shape morphing and behavior for the next generation of soft robots and devices.
    DOI:  https://doi.org/10.1038/s41467-025-58091-z
  9. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2416771122
      In native extracellular matrices (ECM), cells utilize matrix metalloproteinases (MMPs) to degrade and remodel their microenvironment. Accordingly, synthetic matrices have been engineered to permit MMP-mediated cleavage, facilitating cell spreading, migration, and interactions. However, the interplay between matrix degradability and mechanical properties remains underexplored. We hypothesized that MMP activity induces immediate mechanical alterations in the ECM, which are subsequently detected by cells. We observed that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation following MMP exposure. Cells responded to these variations in relaxation by modulating their spreading and focal adhesions. Furthermore, we demonstrated that stress relaxation and cell spreading can be precisely controlled through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, with potential implications for a broad spectrum of biological applications.
    Keywords:  collagen; degradability; extracellular matrix; matrix metalloproteinase; stress relaxation
    DOI:  https://doi.org/10.1073/pnas.2416771122
  10. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2419507122
      Liquid-liquid phase separation (LLPS) has been achieved in various cytomimetic (protocell) models, but controlling molecular condensation using noninert crowders to systematically alter protocell function remains challenging. Intracellular ATP levels influence protein-protein interactions, and dysregulation of ATP can alter cellular crowding dynamics, thereby disrupting the normal formation or dissolution of condensates. Here, we develop a membranized protocell model capable of endogenous LLPS and liquid-gel-like phase separation through precise manipulation of intermolecular interactions within semipermeable polysaccharide-based microcapsules (polysaccharidosomes, P-somes), prepared using microtemplate-guided assembly. We demonstrate that intraprotocellular diffusion-mediated LLPS can be extended into the liquid-gel-like domain by the uptake of the biologically active crowder ATP, resulting in a range of modalities dependent on the fine-tuning of molecular condensation. Endogenous enzyme activity in these crowded polysaccharidosomes is enhanced compared to free enzymes in solution, though this enhancement diminishes at higher levels of intraprotocellular condensation. Additionally, increased molecular crowding inhibits intraprotocell DNA strand displacement reactions. Our findings introduce an expedient and optimized approach to the batch construction of membranized protocell models with controllable molecular crowding and functional diversity. Our mix-incubate-wash protocol for inducing endogenous LLPS in membranized protocells offers potential applications in microreactor technology, environmental sensing, and the delivery and sustained release of therapeutics.
    Keywords:  ATP; liquid–liquid phase separation; membraneless organelles; molecular condensation; polysaccharidosome
    DOI:  https://doi.org/10.1073/pnas.2419507122
  11. Angew Chem Int Ed Engl. 2025 Mar 28. e202502053
      Supramolecular gels assembled from low-molecular-weight gelators (LMWGs) are fascinating soft materials for use in synthesis, combining aspects of hetero- and homogeneous systems. The unique combination of environments within a gel offers the ability to control reactivity in new ways. For example, self-assembly into a gel network can modify the reactivity of catalytic sites on the LMWG. Controlling the assembly of multiple LMWGs can result in integrated gels with orthogonal activities that could not normally co-exist. Enzymes encapsulated within self-assembled gels can exhibit superactivity, extending their use into solvent media more appropriate for organic synthesis. Highly reactive species, such as ligand-free nanoparticles or moisture/air-sensitive organometallics can be protected within the unique environment of a supramolecular gel, facilitating their use in ambient conditions, potentially opening up the use of such species to non-specialist researchers. Beyond fundamental chemistry, performing reactions in gels leads to the emerging concept of gels as 'nanoreactors'. Smart chemical engineering methods are enabling the fabrication of materials and devices for use in a variety of synthetic workflows, potentially transforming the way synthesis is done. In summary, this review provides an overview of key concepts and signposts the way towards future developments of gels as active tools for reaction engineering.
    Keywords:  Self-assembly; catalysis; gels; nanoreactors; supramolecular
    DOI:  https://doi.org/10.1002/anie.202502053
  12. J Am Chem Soc. 2025 Mar 26.
      Here, we present an efficient synthetic route to biobased alternating copolymers via the living radical copolymerization of naturally occurring levoglucosenone (LGO) and dienes. By employing reversible addition-fragmentation chain transfer (RAFT) polymerization, well-defined LGO-derived copolymers were readily synthesized featuring high degrees of alternation, well-controlled molecular weights, and excellent end-group fidelity. Additionally, the alternating copolymers exhibited thermal and mechanical properties comparable to those of the commodity polystyrene. Furthermore, an on-demand metathesis degradation was identified, highlighting their potential as degradable materials.
    DOI:  https://doi.org/10.1021/jacs.5c02397
  13. J Control Release. 2025 Mar 20. pii: S0168-3659(25)00271-8. [Epub ahead of print]381 113651
      The majority of cellular functions are regulated by intracellular proteins, and regulating their interactions can unlock fundamental insights in biology and open new avenues for drug discovery. Because the vast majority of intracellular targets remain undruggable, there is significant current interest in developing protein-based agents especially monoclonal antibodies due to their specificity, availability, and established screening/engineering methods. However, efficient delivery of proteins into the cytoplasm has been a major challenge in biological engineering and drug discovery. We previously reported a platform technology based on a Coomassie blue-cholesterol conjugate (CB-tag) capable of delivering small proteins directly into the cytoplasm. Here, we report a new generation of CB-tag that can bring proteins with a wide size range into the cytoplasm, bypassing endosomal sequestration. Remarkably, intracellular targets with distinct structures were visualized. Overall, the new CB-tag demonstrated a robust ability in protein delivery with broad applications ranging from live-cell immunofluorescence to protein-based therapeutic development.
    Keywords:  Antibody; Cytosolic delivery; Drug discovery; Live-cell imaging; Protein; Small molecule
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113651
  14. iScience. 2025 Mar 21. 28(3): 112012
      The protein universe is the collection of all proteins on earth from all organisms both extant and extinct. Classical studies on protein folding suggested that proteins exist as a unique three-dimensional conformation that is dictated by the genetic code and is critical for function. In this perspective, we discuss ideas and developments that emerged over the past three decades regarding the protein structure-function paradigm. It is now clear that ordered (active/functional) and disordered/denatured (and hence inactive/non-functional) represent a continuum of states rather than binary states. Some proteins can switch folds without sequence change. Others exist as conformational ensembles lacking defined structure yet play critical roles in many biological processes, including forming membrane-less organelles driven by liquid-liquid phase separation. Numerous diverse proteins harbor segments with the potential to form amyloid fibrils, many of which are functional, and some possess prion-like properties enabling conformation-based transfer of heritable information. Taken together, these developments reveal the remarkable complexity of the protein universe.
    Keywords:  Biochemistry; Biological sciences; Protein; Structural biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112012
  15. Nat Mater. 2025 Mar 24.
      Mechanical factors such as stress in the extracellular environment affect the phenotypic commitment of cells. Stress fields experienced by cells in tissues are multiaxial, but how cells integrate such information is largely unknown. Here we report that the anisotropy of stress fields is a critical factor triggering a phenotypic transition in fibroblast cells, outweighing the role of stress amplitude, a factor previously described to modulate such a transition. Combining experimental and computational approaches, we identified a self-reinforcing mechanism in which cellular protrusions interact with collagen fibres to establish tension anisotropy. This anisotropy, in turn, stabilizes the protrusions and enhances their contractile forces. Disruption of this self-reinforcing process, either by reducing tension anisotropy or by inhibiting contractile protrusions, prevents the phenotypic conversion of fibroblasts to contractile myofibroblasts. Overall, our findings support stress anisotropy as a factor modulating cellular responses, expanding our understanding of the role of mechanical forces in biological processes.
    DOI:  https://doi.org/10.1038/s41563-025-02162-5
  16. Chem Soc Rev. 2025 Mar 28.
      Protein-derived cofactors, formed through posttranslational modification of a single amino acid or covalent crosslinking of amino acid side chains, represent a rapidly expanding class of catalytic moieties that redefine enzyme functionality. Once considered rare, these cofactors are recognized across all domains of life, with their repertoire growing from 17 to 38 types in two decades in our survey. Their biosynthesis proceeds via diverse pathways, including oxidation, metal-assisted rearrangements, and enzymatic modifications, yielding intricate motifs that underpin distinctive catalytic strategies. These cofactors span paramagnetic and non-radical states, including both mono-radical and crosslinked radical forms, sometimes accompanied by additional modifications. While their discovery has accelerated, mechanistic understanding lags, as conventional mutagenesis disrupts cofactor assembly. Emerging approaches, such as site-specific incorporation of non-canonical amino acids, now enable precise interrogation of cofactor biogenesis and function, offering a viable and increasingly rigorous means to gain mechanistic insights. Beyond redox chemistry and electron transfer, these cofactors confer enzymes with expanded functionalities. Recent studies have unveiled new paradigms, such as long-range remote catalysis and redox-regulated crosslinks as molecular switches. Advances in structural biology, mass spectrometry, and biophysical spectroscopy continue to elucidate their mechanisms. Moreover, synthetic biology and biomimetic chemistry are increasingly leveraging these natural designs to engineer enzyme-inspired catalysts. This review integrates recent advances in cofactor biogenesis, reactivity, metabolic regulation, and synthetic applications, highlighting the expanding chemical landscape and growing diversity of protein-derived cofactors and their far-reaching implications for enzymology, biocatalysis, and biotechnology.
    DOI:  https://doi.org/10.1039/d4cs00981a
  17. Chem Rev. 2025 Mar 26.
      Skeletal muscle's elegant protein-based architecture powers motion throughout the animal kingdom, with its constituent actomyosin complexes driving intra- and extra-cellular motion. Classical motors and recently developed soft actuators cannot match the packing density and contractility of individual muscle fibers that scale to power the motion of ants and elephants alike. Accordingly, the interdisciplinary fields of robotics and tissue engineering have combined efforts to build living muscle actuators that can power a new class of robots to be more energy-efficient, dexterous, and safe than existing motor-powered and hydraulic paradigms. Doing so ethically and at scale─creating meter-scale tissue constructs from sustainable muscle progenitor cell lines─has inspired innovations in biomaterials and tissue culture methodology. We weave discussions of muscle cell biology, materials chemistry, tissue engineering, and biohybrid design to review the state of the art in soft actuator biofabrication. Looking forward, we outline a vision for meter-scale biohybrid robotic systems and tie discussions of recent progress to long-term research goals.
    DOI:  https://doi.org/10.1021/acs.chemrev.4c00785
  18. J Cell Sci. 2025 Mar 15. pii: jcs263834. [Epub ahead of print]138(6):
      The organization and mechanics of extracellular matrix (ECM) protein polymers determine tissue structure and function. Secreted ECM components are assembled into polymers via a cell-mediated process. The specific mechanisms that cells use for assembly are crucial for generating tissue-appropriate matrices. Fibronectin (FN) is a ubiquitous and abundant ECM protein that is assembled into a fibrillar matrix by a receptor-mediated process, and the FN matrix provides a foundation for incorporation of many other proteins into the ECM. In this Cell Science at a Glance article and the accompanying poster, we describe the domain organization of FN and the events that initiate and propagate a stable insoluble network of FN fibrils. We also discuss intracellular pathways that regulate FN assembly and the impact of changes in assembly on disease progression.
    Keywords:  Assembly; Extracellular matrix; Fibrillogenesis; Fibronectin
    DOI:  https://doi.org/10.1242/jcs.263834
  19. Microb Cell Fact. 2025 Mar 28. 24(1): 74
       BACKGROUND: The regulation of multiple gene expression is pivotal for metabolic engineering. Although CRISPR interference (CRISPRi) has been extensively utilized for multi-gene regulation, the construction of numerous single-guide RNA (sgRNA) expression plasmids for combinatorial regulation remains a significant challenge.
    RESULTS: In this study, we developed a combinatorial repression system for multiple genes by optimizing the expression of multi-sgRNA with various inducible promoters in Escherichia coli. We designed a modified Golden Gate Assembly method to rapidly construct the sgRNA expression plasmid p3gRNA-LTA. By optimizing both the promoter and the sgRNA handle sequence, we substantially mitigated undesired repression caused by the leaky expression of sgRNA. This method facilitates the rapid assessment of the effects of various inhibitory combinations on three genes by simply adding different inducers. Using the biosynthesis of N-acetylneuraminic acid (NeuAc) as an example, we found that the optimal combinatorial inhibition of the pta, ptsI, and pykA genes resulted in a 2.4-fold increase in NeuAc yield compared to the control.
    CONCLUSION: We anticipate that our combinatorial repression system will greatly simplify the regulation of multiple genes and facilitate the fine-tuning of metabolic flow in the engineered strains.
    Keywords:  CRISPRi; Combinatorial repression; Inducible promoters; Metabolic flow; Multiple genes
    DOI:  https://doi.org/10.1186/s12934-025-02697-x
  20. Nat Mater. 2025 Mar 24.
      The power and energy consumption of resistive switching devices can be lowered by reducing the dimensions of their active layers. Efforts to push this low-energy switching property to its limits have led to the investigation of active regions made with two-dimensional (2D) layered materials. Despite their small dimensions, 2D layered materials exhibit a rich variety of switching mechanisms, each involving different types of atomic structure reconfiguration. In this Review, we highlight and classify the mechanisms of resistive switching in monolayer and bulk 2D layered materials, with a subsequent focus on those occurring in a monolayer and/or localized to point defects in the crystalline sheet. We discuss the complex energetics involved in these fundamentally defect-assisted processes, including the coexistence of multiple mechanisms and the effects of the contacts used. Examining the highly localized 'atomristor'-type switching, we provide insights into atomic motions and electronic transport across the metal-2D interfaces underlying their operation. Finally, we discuss progress and our perspective on the challenges associated with the development of 2D resistive switching devices. Promising application areas and material systems are identified and suggested for further research.
    DOI:  https://doi.org/10.1038/s41563-025-02170-5
  21. Nat Commun. 2025 Mar 21. 16(1): 2784
      Starch is a primary food ingredient and industrial feedstock. Low-carbon microbial manufacturing offers a carbon-neutral/negative arable land-independent strategy for starch production. Here, we reconfigure the oleaginous yeast as a starch-rich micro-grain producer by rewiring the starch biosynthesis and gluconeogenesis pathways and regulating cell morphology. With the CO2 electro-synthesized acetate as the substrate, the strain accumulates starch 47.18% of dry cell weight. The optimized system renders spatial-temporal starch productivity (243.7 g/m2/d) approximately 50-fold higher than crop cultivation and volumetric productivity (160.83 mg/L/h) over other microbial systems by an order of magnitude. We demonstrate tunable starch composition and starch-protein ratios via strain and process engineering. The engineered artificial strains adopt a cellular resources reallocation strategy to ensure high-level starch production in micro-grain and could facilitate a highly efficient straw/cellulose-to-starch conversion. This work elucidates starch biosynthesis machinery and establishes a superior-to-nature platform for customizable starch synthesis, advancing low-carbon nutritional manufacturing.
    DOI:  https://doi.org/10.1038/s41467-025-58067-z
  22. Mater Horiz. 2025 Mar 24.
      Polycarbonate is an advanced engineering plastic widely used in aerospace, high-speed rail and 5G communications. However, it remains a huge challenge to synthesize polycarbonate materials using a strategy that simultaneously integrates green-preparation, service-stage advanced-performance and end-of-life easy-recyclability. Herein, we propose an ultrahigh-efficiency and green halogen/phosphorus-free strategy to prepare a mechanically robust, highly transparent, super-fire-resistant and chemically easily recyclable polycarbonate plastic. By chemical copolymerization of only catalytic amounts of sodium sulfonate-naphthol (0.3-0.5 mol%, namely 3400-5600 ppm), the corresponding polycarbonates exhibit >85 MPa tensile strength, >67 kJ m-2 notched impact strength, >90% transparency, >36% ultra-high limiting oxygen index and 1.6 mm thin-wall UL-94 V-0 rating during the service-stage. Especially, at the end-of-life, these polycarbonates can be easily depolymerized back to the raw monomer bisphenol A and high-value 2-oxazolidinone under mild conditions (50 °C for 4 h), achieving ultra-high atom-economic chemical recycling. Starting from the source of a chemical structure, this work opens up a new perspective for constructing life cycle-managed plastic materials with advanced high-performance and full-recyclability, contributing to the global circular economy through sustainable material design.
    DOI:  https://doi.org/10.1039/d5mh00260e
  23. Nat Commun. 2025 Mar 21. 16(1): 2788
      By converting light into mechanical strain, photostrictive materials are expected to define a revolutionary solution to the wireless micro-electromechanical devices. However, the photoinduced strain (photostriction) of most inorganic materials are unsatisfactory as compared to the electric-field-induced strain of ferro/piezoelectric materials. Here, we demonstrate the effective optimization of the photostriction of inorganic materials by constructing polymorphic phase boundary (PPB) in Pb3V2-xPxO8 compounds. Large photostriction over 0.3% and excellent photostrictive efficiency in the level of 10-10 m3/W are realized in Pb3V2-xPxO8 compositions at the PPB region, which perform better than most of the existing inorganic photostrictive materials. Besides, photostriction over 0.1% (same level of piezoelectric strain) can be achieved with light intensity as low as 200 mW/cm2. We theoretically reveal that enhanced photostriction arises from photoinduced phase transition driven by Pb-O-V collinearity and V-V dimer formation, and P-doping can facilitate the transition, enabling large deformation at low photoexcitation. This work will accelerate the development of high-performance inorganic photostrictive materials and their applications for optomechanical devices.
    DOI:  https://doi.org/10.1038/s41467-025-58100-1
  24. Mater Today Bio. 2025 Apr;31 101644
      Nature offers a boundless source of inspiration for designing bio-inspired technologies and advanced materials. Cephalopods, including octopuses, squids, and cuttlefish, exhibit remarkable biological adaptations, such as dynamic camouflage for predator evasion and communication, as well as robust prey-capturing tools, including beaks and sucker-ring teeth that operate under extreme mechanical stresses in aqueous environments. Central to these remarkable traits are structural proteins that serve as versatile polymeric materials. From a materials science perspective, proteins present unique opportunities due to their genetically encoded sequences, enabling access to a diversity of sequences and precise control over polymer composition and properties. This intrinsic programmability allows scalable, environmentally sustainable production through recombinant biotechnology, in contrast to petroleum-derived polymers. This review highlights recent advances in understanding cephalopod-specific proteins, emphasizing their potential for creating next-generation bioengineered materials and driving sustainable innovation in biomaterials science.
    Keywords:  Cephalopods; Histidine-binding proteins; Protein-based materials; Reflectins; Suckerins
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101644
  25. Nat Biotechnol. 2025 Mar 26.
      Molecular proximity is a governing principle of biology that is essential to normal and disease-related biochemical pathways. At the cell surface, protein-protein proximity regulates receptor activation, inhibition and protein recycling and degradation. Induced proximity is a molecular engineering principle in which bifunctional molecules are designed to bring two protein targets into close contact, inducing a desired biological outcome. Researchers use this engineering principle for therapeutic purposes and to interrogate fundamental biological mechanisms. This Review focuses on the use of induced proximity at the cell surface for diverse applications, such as targeted protein degradation, receptor inhibition and activating intracellular signaling cascades. We see a rich future for proximity-based modulation of cell surface protein activity both in basic and translational science.
    DOI:  https://doi.org/10.1038/s41587-025-02592-1
  26. J Mater Chem B. 2025 Mar 24.
      Recently, digital light processing (DLP) 3D printing has garnered significant interest for fabricating high-fidelity hydrogels. However, the intrinsic weak and loose network of hydrogels, coupled with uncontrollable light projection, leads to low printing resolution and restricts their broader applications. Herein, we propose a straightforward DLP 3D printing strategy utilizing in situ phase separation to produce high-fidelity, high-modulus, and biocompatible hydrogels. By selecting acrylamide monomers with poor compatibility within a polyvinyl pyrrolidone (PVP) network during polymerization, we create phase-separated domains within polyacrylamide (PAM) that effectively inhibit ultraviolet (UV) light transmission. This regulation of UV light distribution results in anhydrous inks with exceptional properties: ultra-high resolution (1.5 μm), ultra-high modulus (1043 MPa), and high strength (70.0 MPa). Upon hydration, the modulus and strength of the hydrogels decrease to approximately 4000 times those of the anhydrous gels, exhibiting high mechano-moisture sensitivity suitable for actuator applications. Additionally, the DLP 3D-printed hydrogels, featuring micro-scale structures, demonstrate good biocompatibility and facilitate nutrient transport for cell proliferation. This versatile DLP 3D printing strategy paves the way for the fabrication of high-fidelity and multifunctional hydrogels.
    DOI:  https://doi.org/10.1039/d5tb00106d
  27. Nat Chem Biol. 2025 Mar 26.
      The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTMs). For instance, starvation and low-carbohydrate diets lead to the accumulation of β-hydroxybutyrate (BHB), whose blood concentrations can reach millimolar levels, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. Here we report that class I histone deacetylases (HDACs) unexpectedly catalyze the formation of Kbhb. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and noncanonical HDAC-catalyzed β-hydroxybutyrylation. On the basis of these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and the BHB carboxylic acid, thereby generating an amide bond. This reversible HDAC activity is not limited to BHB and extends to multiple short-chain fatty acids, representing a novel mechanism of PTM deposition relevant to metabolically sensitive proteome modifications.
    DOI:  https://doi.org/10.1038/s41589-025-01869-5
  28. Nat Commun. 2025 Mar 26. 16(1): 2939
      The sequence specificity and programmability of DNA binding and cleavage have enabled widespread applications of CRISPR-Cas12a in genetic engineering. As an RNA-guided CRISPR endonuclease, Cas12a engages a 20-base pair (bp) DNA segment by forming a three-stranded R-loop structure in which the guide RNA hybridizes to the DNA target. Here we use single-molecule torque spectroscopy to investigate the dynamics and mechanics of R-loop formation of two widely used Cas12a orthologs at base-pair resolution. We directly observe kinetic intermediates corresponding to a ~5 bp initial RNA-DNA hybridization and a ~17 bp intermediate preceding R-loop completion, followed by transient DNA unwinding that extends beyond the 20 bp R-loop. The complex multistate landscape of R-loop formation is ortholog-dependent and shaped by target sequence, mismatches, and DNA supercoiling. A four-state kinetic model captures essential features of Cas12a R-loop dynamics and provides a biophysical framework for understanding Cas12a activity and specificity.
    DOI:  https://doi.org/10.1038/s41467-025-57703-y
  29. ACS Appl Mater Interfaces. 2025 Mar 26. 17(12): 17655-17656
      
    DOI:  https://doi.org/10.1021/acsami.5c05040
  30. J Vis Exp. 2025 Mar 07.
      Granular hydrogel scaffolds hold significant potential in regenerative medicine, functioning either as carriers for cell delivery or as interfaces for tissue integration. This article introduces two novel approaches for quantifying cell migration within and into granular hydrogels, highlighting the distinct applications of these scaffolds. First, a cell monolayer interface assay that simulates tissue growth into granular hydrogels for integration purposes is presented. Second, a spheroid-based assay is described, designed to track cell movement within the hydrogel matrix, specifically suited for applications involving cell delivery. Both methods enable precise and controlled measurements of cell migration, providing a comprehensive toolkit for researchers utilizing granular hydrogel scaffolds. The motivation for these methods stems from the need for tailored control over cell migration within the scaffold to align with specific applications. By optimizing and standardizing these quantification techniques, researchers can iteratively refine granular hydrogel properties, ensuring their effectiveness in diverse regenerative medicine contexts. This robust set of quantitative tools offers new opportunities to enhance granular hydrogel scaffolds, advancing their use in both cell delivery and tissue integration applications.
    DOI:  https://doi.org/10.3791/67627
  31. Nat Commun. 2025 Mar 22. 16(1): 2838
      Here, we present StimExo as a rational design strategy allowing various user-defined control signals to trigger calcium-dependent exocytosis and mediate on-demand protein secretion in cell-therapy settings. Using a modular framework incorporating inducible protein-protein interactions into an engineered bipartite activator of calcium release-activated calcium (CRAC) channels, Ca2+ influx mediated by the STIM/Orai1 machinery was flexibly adjusted to depend on different user-defined input signals. Application of StimExo to various endocrine cells enables instant secretion of therapeutic hormones upon administration of safe and patient-compliant trigger compounds. StimExo also mediated insulin exocytosis using a cell-based gene delivery strategy in vivo, accounting for real-time control of blood glucose homeostasis in male diabetic mice in response to the FDA-approved drug grazoprevir. This study achieves true "sense-and-respond" cell-based therapies and provides a platform for remote control of in vivo transgene activities using various trigger signals of interest.
    DOI:  https://doi.org/10.1038/s41467-025-58184-9
  32. Biomaterials. 2025 Mar 22. pii: S0142-9612(25)00189-9. [Epub ahead of print]320 123270
      Recapitulating the biophysical and biochemical complexity of the extracellular matrix (ECM) remains a major challenge in tissue engineering. Hydrogels derived from decellularized ECM provide a unique opportunity to replicate the architecture and bioactivity of native ECM, however, they exhibit limited long-term stability and mechanical integrity. In turn, materials assembled through supramolecular interactions have achieved considerable success in replicating the dynamic biophysical properties of the ECM. Here, we merge both methodologies by promoting the supramolecular assembly of decellularized human amniotic membrane (hAM), mediated by host-guest interactions between hAM proteins and acryloyl-β-cyclodextrin (AcβCD). Photopolymerization of the cyclodextrins results in the formation of soft hydrogels that exhibit tunable stress relaxation and strain-stiffening. Disaggregation of bulk hydrogels yields an injectable granular material that self-reconstitutes into shape-adaptable bulk hydrogels, supporting cell delivery and promoting neovascularization. Additionally, cells encapsulated within bulk hydrogels sense and respond to the biophysical properties of the surrounding matrix, as early cell spreading is favored in hydrogels that exhibit greater susceptibility to applied stress, evidencing proper cell-matrix interplay. Thus, this system is shown to be a promising substitute for native ECM in tissue repair and modelling.
    Keywords:  Decellularized extracellular matrix; Human derived materials; Mechanoreciprocity; Self-healing materials; Supramolecular interactions
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123270
  33. PNAS Nexus. 2025 Mar;4(3): pgaf080
      The over-representation of motifs was previously considered a viable definition of building blocks in biological networks. Here, we construct an alternative definition based on invariance properties of enzymes in metabolic networks of Escherichia coli. In particular, we consider input trees of each enzyme that bundle all metabolic reactions where information is transmitted. Isomorphisms of such input trees point to symmetric enzymes grouped in "fibers" of the metabolic network that process equivalent dynamics. Such groups of enzymes constitute an alternative concept of building blocks which can be systematically classified into topological types of input trees according to their complexity. In contrast to motifs and modules, enzymes in such fibers are not necessarily mutually connected but still can be functionally related. Our analysis finds novel varieties of building blocks that capture such symmetries in hitherto unknown "composite Fibonacci" fibers. Lending credence to their significance as fundamental building blocks, we observe that enzymes in fibers are functionally more homogeneous than their network motif and module counterparts, suggesting that fibers point to a novel way of building blocks that capture metabolic functionality on a topological level.
    Keywords:  Fibonacci structures; fibrations; metabolic networks; symmetries
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf080
  34. ACS Synth Biol. 2025 Mar 24.
      Efficient methods for diversifying genes of interest (GOIs) are essential in protein engineering. For example, OrthoRep, a yeast-based orthogonal DNA replication system that achieves the rapid in vivo diversification of GOIs encoded on a cytosolic plasmid (p1), has been successfully used to drive numerous protein engineering campaigns. However, OrthoRep-based GOI evolution has almost always started from single GOI sequences, limiting the number of locations on a fitness landscape from where evolutionary search begins. Here, we present a simple approach for the high-efficiency integration of GOI libraries onto OrthoRep. By leveraging integrases, we demonstrate recombination of donor DNA onto the cytosolic p1 plasmid at exceptionally high transformation efficiencies, even surpassing the transformation efficiency of standard circular plasmids and linearized plasmid fragments into yeast. We demonstrate our method's utility through the straightforward construction of mock nanobody libraries encoded on OrthoRep, from which rare binders were reliably enriched. Overall, integrase-assisted manipulation of yeast cytosolic plasmids should enhance the versatility of OrthoRep in continuous evolution experiments and support the routine construction of large GOI libraries in yeast, in general.
    Keywords:  Continuous Evolution; Gene Libraries; Integrase; OrthoRep; Protein Engineering; Yeast Transformation
    DOI:  https://doi.org/10.1021/acssynbio.4c00786
  35. Protein Sci. 2025 Apr;34(4): e70106
      Expression and purification of recombinant proteins in Escherichia coli is a bedrock technique in biochemistry and molecular biology. Expression optimization requires testing different combinations of solubility tags, affinity purification techniques, and site-specific proteases. This optimization is laborious and time-consuming as these features are spread across different vector series and require different cloning strategies with varying efficiencies. Modular cloning kits based on the Golden Gate system exist, but they are not optimized for protein biochemistry and are overly complicated for many applications, such as undergraduate research or simple screening of protein purification features. An ideal solution is for a single gene synthesis or PCR product to be compatible with a large series of pre-assembled Golden Gate vectors containing a broad array of purification features at either the N or C terminus. To our knowledge, no such system exists. To fulfill this unmet need, we Golden Gate domesticated the pET28b vector and developed a suite of 21 vectors with different combinations of purification tags, solubility domains, visualization/labeling tags, and protease sites. We also developed a vector series with nine different N-terminal tags and no C-terminal cloning scar. The system is modular, allowing users to easily customize the vectors with their preferred combinations of features. To allow for easy visual screening of cloned vectors, we optimized constitutive expression of the fluorescent protein mScarlet3 in the reverse strand, resulting in a red to white color change upon successful cloning. Testing with the model protein sfGFP shows the ease of visual screening, high efficiency of cloning, and robust protein expression. These vectors provide versatile, high-throughput solutions for protein engineering and functional studies in E. coli.
    Keywords:  Golden Gate; cloning; protein engineering; protein expression
    DOI:  https://doi.org/10.1002/pro.70106
  36. Nature. 2025 Mar 26.
      Although quantum computers can perform a wide range of practically important tasks beyond the abilities of classical computers1,2, realizing this potential remains a challenge. An example is to use an untrusted remote device to generate random bits that can be certified to contain a certain amount of entropy3. Certified randomness has many applications but is impossible to achieve solely by classical computation. Here we demonstrate the generation of certifiably random bits using the 56-qubit Quantinuum H2-1 trapped-ion quantum computer accessed over the Internet. Our protocol leverages the classical hardness of recent random circuit sampling demonstrations4,5: a client generates quantum 'challenge' circuits using a small randomness seed, sends them to an untrusted quantum server to execute and verifies the results of the server. We analyse the security of our protocol against a restricted class of realistic near-term adversaries. Using classical verification with measured combined sustained performance of 1.1 × 1018 floating-point operations per second across multiple supercomputers, we certify 71,313 bits of entropy under this restricted adversary and additional assumptions. Our results demonstrate a step towards the practical applicability of present-day quantum computers.
    DOI:  https://doi.org/10.1038/s41586-025-08737-1
  37. Macromol Rapid Commun. 2025 Mar 27. e2401099
      Selectively targeting diseases with therapeutics remains a crucial yet still unsatisfied challenge in (nano)medicine. In recent years, a large body of biologically based drug carrier systems are produced which have proven to be suitable for the efficient transport of active compounds such as biopharmaceuticals and biotechnological drugs. However, those naturally occurring materials often entail risks, for example, due to accessible, functional groups created by uncontrolled protein denaturation processes of enzymes (e.g., proteases) which can lead to unwanted side effects in the body. To deal with this issue, designing bio-inspired synthetic copolymers offers a suitable alternative compared to systems based on materials derived from natural sources. Owing to the variety of electrostatically interacting motifs abundant in nature, synthetic statistical copolymers are developed with different polarity and zwitterionic arginine-derived units. To achieve the required physicochemical demands, a simple one-step synthesis approach is applied, the so-called xanthate-supported photo-iniferter reversible-addition-fragmentation chain-transfer (XPI-RAFT) polymerization. The cellular association of these polymers is compared to a fully non-ionic polymer. The results highlight new findings in the design of zwitterionic macromolecule structures for medical applications and further progress the understanding of the driving forces of the cell specificity of polyzwitterions.
    Keywords:  XPI RAFT polymerization; arginine; cell association; polyelectrolyte; zwitterionic polymer
    DOI:  https://doi.org/10.1002/marc.202401099
  38. FEMS Yeast Res. 2025 Mar 22. pii: foaf014. [Epub ahead of print]
      Saccharomyces cerevisiae is a promising microbial cell factory. However, the overflow metabolism, known as the Crabtree effect, directs the majority of the carbon source toward ethanol production, in many cases, resulting in low yields of other target chemicals and byproducts accumulation. To construct Crabtree-negative S. cerevisiae, the deletion of pyruvate decarboxylases and/or ethanol dehydrogenases is required. However, these modifications compromises the growth of the strains on glucose. This review discusses the metabolic engineering approaches used to eliminate ethanol production, the efforts to alleviate growth defect of Crabtree-negative strains, and the underlying mechanisms of the growth rescue. In addition, it summarizes the applications of Crabtree-negative S. cerevisiae in the synthesis of various chemicals such as lactic acid, 2,3-butanediol, malic acid, succinic acid, isobutanol, and others.
    Keywords:   Saccharomyces cerevisiae ; Crabtree effect; Ethanol; Metabolic engineering; Pyruvate decarboxylase deficient strains
    DOI:  https://doi.org/10.1093/femsyr/foaf014
  39. Nat Chem Eng. 2025 ;2(3): 209-219
      Injectable drug depots have transformed our capacity to enhance medication adherence through dose simplification. Central to patient adoption of injectables is the acceptability of needle injections, with needle gauge as a key factor informing patient discomfort. Maximizing drug loading in injectables supports longer drug release while reducing injection volume and discomfort. Here, to address these requirements, we developed self-aggregating long-acting injectable microcrystals (SLIM), an injectable formulation containing drug microcrystals that self-aggregate in the subcutaneous space to form a monolithic implant with a low ratio of polymer excipient to drug (0.0625:1 w/w). By minimizing polymer content, SLIM supports injection through low-profile needles (<25 G) with high drug loading (293 mg ml-1). We demonstrate in vitro and in vivo that self-aggregation is driven by solvent exchange at the injection site and that slower-exchanging solvents result in increased microcrystal compaction and reduced implant porosity. We further show that self-aggregation enhances long-term drug release in rodents. We anticipate that SLIM could enable low-cost interventions for contraceptives.
    Keywords:  Drug delivery; Materials for devices
    DOI:  https://doi.org/10.1038/s44286-025-00194-x
  40. Nat Protoc. 2025 Mar 21.
      The epigenome of a cell is tightly correlated with gene transcription, which controls cell identity and diverse biological activities. Recent advances in spatial technologies have improved our understanding of tissue heterogeneity by analyzing transcriptomics or epigenomics with spatial information preserved, but have been mainly restricted to one molecular layer at a time. Here we present procedures for two spatially resolved sequencing methods, spatial-ATAC-RNA-seq and spatial-CUT&Tag-RNA-seq, that co-profile transcriptome and epigenome genome wide. In both methods, transcriptomic readouts are generated through tissue fixation, permeabilization and in situ reverse transcription. In spatial-ATAC-RNA-seq, Tn5 transposase is used to probe accessible chromatin, and in spatial-CUT&Tag-RNA-seq, the tissue is incubated with primary antibodies that target histone modifications, followed by Protein A-fused Tn5-induced tagmentation. Both methods leverage a microfluidic device that delivers two sets of oligonucleotide barcodes to generate a two-dimensional mosaic of tissue pixels at near single-cell resolution. A spatial-ATAC-RNA-seq or spatial-CUT&Tag-RNA-seq library can be generated in 3-5 d, allowing researchers to simultaneously investigate the transcriptomic landscape and epigenomic landscape of an intact tissue section. This protocol is an extension of our previous spatially resolved epigenome sequencing protocol and provides opportunities in multimodal profiling.
    DOI:  https://doi.org/10.1038/s41596-025-01145-9