bims-enlima 2025-08-03 papers

bims-enlima

Biomed News

on Engineered living materials

Issue of 2025–08–03
forty-four papers selected by
Rahul Kumar, Tallinna Tehnikaülikool

Organoid bioprinting to pattern the matrix microenvironment.
Supramolecular Materials and Strategies for Bioorthogonal Chemical Transformations.
Microbial production of creatine using growth-coupled selection systems.
Bond-centric modular design of protein assemblies.
Engineering Escherichia coli Pyruvate Metabolism to Generate Noncanonical Reducing Power.
Programmable protein ligation on cell surfaces.
Microbial Production of Fuels, Commodity Chemicals, and Materials from Sustainable Sources of Carbon and Energy.
Mechanoresponsive Hydrogels Emerging from Dynamic and Non-Covalent Interactions.
Integrating DNA-Based Memory in Water-Resistant Electrospun Polymer Fibers for Nondestructive Data Retrieval.
Centrifugal microfluidic chip with an air gap for oil-free production of enhanced adipogenic multicellular microspheres.
Chirality Makes or Breaks Chemically Driven Self-Assembly.
Thermodynamically consistent, reduced models of gene regulatory networks.
Integration of Bayesian optimization and solution thermodynamics to optimize media design for mammalian biomanufacturing.
Future Frontiers in Bioinspired Implanted Biomaterials.
Polymer design of microwell hydrogels influences epithelial-mesenchymal interactions during human bronchosphere formation.
Self-adaptable mechanical ceramic fibrous aerogels from prestressed topology and multistable constraints.
How many plasmids can bacteria carry? A synthetic biology perspective.
Next-generation stimuli-responsive polymers for a sustainable tomorrow.
Translation efficiency covariation identifies conserved coordination patterns across cell types.
Life Engineering of Materials: Artificial Materials as Plugins for Biological Regulations.
A framework for complex signal processing via synthetic biological operational amplifiers.
Self-Driving Laboratories: Translating Materials Science from Laboratory to Factory.
Mammalian cells measure the extracellular matrix area and respond through switching the adhesion state.
Characterizing the hyperuniformity of disordered network metamaterials.
Identification of conserved RNA regulatory switches in living cells using RNA secondary structure ensemble mapping and covariation analysis.
Engineering of photo-inducible binary interaction tools for biomedical applications.
SMART tool builds proteins on cell surfaces.
Exploring the intersection of natural sciences and information technology via entropy and randomness.
Multichannel bioelectronic sensing using engineered Escherichia coli.
Evolution and evolvability of rifampicin resistance across the bacterial tree of life.
Directed evolution of LaccID for cell surface proximity labeling and electron microscopy.
Sustainable production through spatial niche partitioning in engineered light-driven microbial community.
Color and fluorescence switchable 2D and 3D printed hybrid materials.
Trigger factor accelerates nascent chain compaction and folding.
Improving Recombinant Antibody Production Using FcBAR: An In Situ Approach to Detect and Amplify Protein-Protein Interactions.
pH-modulated soluble expression of alcohol dehydrogenases in Escherichia coli using adaptive laboratory evolution.
An on-chip phased array for non-classical light.
Cholesterol modulates membrane elasticity via unified biophysical laws.
Dynamic landscapes and statistical limits on growth during cell fate specification.
GFP-on mouse model for interrogation of in vivo gene editing.
Computational design of bifaceted protein nanomaterials.
Advancing engineering design strategies for targeted cancer nanomedicine.
Comment on "Viscoelastic mechanics of living cells" by Hui Zhou, Ruye Liu, Yizhou Xu, Jierui Fan, Xinyue Liu, Longquan Chen, Qiang Wei.
Cas13d-mediated isoform-specific RNA knockdown with a unified computational and experimental toolbox.

Curr Opin Biomed Eng. 2025 Sep;pii: 100607. [Epub ahead of print]35

Organoid bioprinting to pattern the matrix microenvironment.

Daiyao Zhang, Carla Huerta-López, Sarah C Heilshorn.

The development of organoid cultures has propelled the fields of cell biology, tissue engineering, and regenerative medicine forward. These cultures better mimic in vivo tissue structure and function compared to 2D cell culture; however, organoids are limited in size and do not inherently allow precise control over tissue architecture and cell heterogeneity. Hand-wrought organoid biofabrication approaches enable the production of larger and more complex tissues, but they still lack reproducible control of spatiotemporal tissue patterns. In contrast, bioprinting is a collection of machine-wrought technologies that are emerging as powerful tools in tissue engineering and disease modeling, but have not yet been widely applied to organoids. When combined with advances in biomaterials science, bioprinting offers the possibility to control spatiotemporal cellular and microenvironmental features. The interactions between biomaterial inks, support baths, and embedded cells provide the opportunity to guide the maturation and functionality of engineered tissues. This review describes how recent advances in organoid technology, bioprinting, and biomaterials science can be integrated to achieve spatiotemporal patterning of four aspects of the microenvironment: matrix structure and mechanics, matrix ligands and morphogens, co-culture of multiple cell types, and incorporation of vasculature. These insights underscore the potential for organoid bioprinting to advance the fabrication of in vitro tissue mimics for applications in drug screening, disease modeling, and regenerative medicine.

DOI: https://doi.org/10.1016/j.cobme.2025.100607
Chem Rev. 2025 Aug 01.

Supramolecular Materials and Strategies for Bioorthogonal Chemical Transformations.

Annechien A H Laporte, Joost N H Reek.

Bioorthogonal reactions play a key role in controlled chemical transformations in living systems and are therefore applied to a diverse area of biological and medical applications. However, these applications can be limited by poor selectivity, slow kinetics under biological conditions, and intrinsic incompatibility between the introduced materials and the cellular environment. An emerging strategy for greater functional control over bioorthogonal transformations is the employment of supramolecular strategies or constructs. Herein, we focus on synthetic supramolecular systems that (i) improve biocompatibility by shielding reactive species within protective supramolecular constructs from harsh biological environments; (ii) allow for integration of subcellular targeting moieties; (iii) reduce toxicity; (iv) accelerate reaction rates through molecular preorganization; (v) explore entirely new tools, such as catalysis regulated by controlled stimuli at a functionalized surface. Through rational integration of these supramolecular strategies, bioorthogonal reactions could achieve enhanced precision, faster kinetics, and targeted reactivity within specific tissues, cells, or organelles, subsequently paving the way for further applications in chemical biology and therapeutic interventions.

DOI: https://doi.org/10.1021/acs.chemrev.5c00047
Metab Eng. 2025 Jul 23. pii: S1096-7176(25)00112-0. [Epub ahead of print]

Microbial production of creatine using growth-coupled selection systems.

Jinbei Li, Simon R Krarup, Pascal Pieters, Tobias B Alter, Paul Jacottin, Josefin Johnsen, Elsayed T Mohamed, Thomas Harris, Linda Ahonen, Khem Bahadur Adhikari, Bernhard O Palsson, Adam M Feist, Lei Yang.

Creatine is an important energy storage molecule produced exclusively in vertebrates and is crucial for muscle development. It is particularly valuable as a food supplement, especially for plant-based diets. Here, we present an alternative to chemical synthesis by developing a biosynthetic process using an Escherichia coli cell factory expressing a heterologous pathway. We employed a model-driven growth-coupled selection approach combined with adaptive laboratory evolution to overcome metabolic bottlenecks in the heterologous synthesis of creatine. We developed a novel growth-coupling strategy to optimize an important glycine amidinotransferase step guided by genome-scale modeling. We also improved creatine tolerance of E. coli by adaptive evolution. Several design-build-test-learn cycles of evolution and selection resulted in a 58% increase in titer over the baseline strain from glycine and arginine. This study highlights the advantage of combining production with growth for efficient cell factory generation driven by evolutionary engineering and computational biology.

DOI: https://doi.org/10.1016/j.ymben.2025.07.009
Nat Mater. 2025 Jul 31.

Bond-centric modular design of protein assemblies.

Shunzhi Wang, Andrew Favor, Ryan D Kibler, Joshua M Lubner, Andrew J Borst, Nicolas Coudray, Rachel L Redler, Huat Thart Chiang, William Sheffler, Yang Hsia, Neville P Bethel, Zhe Li, Damian C Ekiert, Gira Bhabha, Lilo D Pozzo, David Baker.

Directional interactions that generate regular coordination geometries are a powerful means of guiding molecular and colloidal self-assembly, but implementing such high-level interactions with proteins remains challenging due to their complex shapes and intricate interface properties. Here we describe a modular approach to protein nanomaterial design inspired by the rich chemical diversity that can be generated from the small number of atomic valencies. We design protein building blocks using deep learning-based generative tools, incorporating regular coordination geometries and tailorable bonding interactions that enable the assembly of diverse closed and open architectures guided by simple geometric principles. Experimental characterization confirms the successful formation of more than 20 multicomponent polyhedral protein cages, two-dimensional arrays and three-dimensional protein lattices, with a high (10%-50%) success rate and electron microscopy data closely matching the corresponding design models. Due to modularity, individual building blocks can assemble with different partners to generate distinct regular assemblies, resulting in an economy of parts and enabling the construction of reconfigurable networks for designer nanomaterials.

DOI: https://doi.org/10.1038/s41563-025-02297-5
ACS Catal. 2024 Jul 05. 14(13): 9776-9784

Engineering Escherichia coli Pyruvate Metabolism to Generate Noncanonical Reducing Power.

Derek Aspacio, Emma Luu, Suphanida Worakaensai, Youtian Cui, Sarah Maxel, Edward King, Raine Hagerty, Alexander Chu, Derek Minn, Justin B Siegel, Han Li.

  The future of biomanufacturing is dependent on rewiring biological systems to establish an alternative approach to our current chemical industries. However, a key limitation in biomanufacturing is that desired processes must rely on the same two redox cofactors as natural metabolism, nicotinamide adenine dinucleotide (phosphate) NAD(P)+, to shuttle electrons energy. Thus, competition of resources with natural reactions within host cells is nearly unavoidable. One strategy to overcome redox cofactor resource competition is the implementation of a third, noncanonical redox cofactor, such as nicotinamide mononucleotide (NMN+), which supports specific electron delivery to desired reactions. Here, we redesign the Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc) to specially utilize NMN+ by engineering its E3 subunit (Lpd). Through rational design, we discover a cofactor promiscuous variant Lpd Penta (G182R-I186T-M206E-E205W-I271L) with an ~2500-fold improvement in NMN+ apparent turnover number. We tailor the enzyme to exclusively use NMN+ through computational design and construct Lpd Ortho (Penta-R292E-Q317L) with a 2.4 × 105-fold cofactor specificity improvement toward NMN+ compared to the wild type. Molecular simulation allowed tracking of the cofactor's alternative binding poses that emerge as the enzyme evolves, which was crucial to precisely guide engineering. We demonstrate that the engineered NMN+-specific PDHc functions in E. coli cells to sustain the life-essential pyruvate metabolism, in an NMN+-dependent manner. These results expand the available NMN+ toolkit to include the high flux and nearly irreversible reaction of PDHc as an insulated electron source.

Keywords:  biomimetic cofactor; dihydrolipoamide dehydrogenase; nicotinamide mononucleotide; noncanonical redox cofactor; orthogonal pathway engineering; pyruvate dehydrogenase complex; rational protein design

DOI:  https://doi.org/10.1021/acscatal.4c02131
Nature. 2025 Jul 30.

Programmable protein ligation on cell surfaces.

Christian Kofoed, Girum Erkalo, Nicholas E S Tay, Xuanjia Ye, Yutong Lin, Tom W Muir.

The surface landscapes of cells differ as a function of cell type and are frequently altered in disease contexts1-3. Exploiting such differences is key to many therapeutic strategies and is the basis for developing diagnostic and basic-science tools. State-of-the-art strategies typically target single surface antigens, but each individual receptor rarely defines the specific cell type4,5. The development of programmable molecular systems that integrate multiple cell-surface features to convert on-target inputs to user-defined outputs is therefore highly desirable. Here we describe an autonomous decision-making device driven by proximity-gated protein trans-splicing that allows local generation of an active protein from two otherwise inactive polypeptide fragments. We show that this protein-actuator platform can perform convergent protein ligation on designated cell surfaces, allowing highly selective generation of active proteins, which can either remain physically associated with the cell surface on which they were manufactured or be released into the surrounding milieu. Because of its intrinsic modularity and tunability, we demonstrate that the technology is compatible with different types of input, targeting modality and functional output, allowing for the localized interrogation or manipulation of cellular systems.

DOI: https://doi.org/10.1038/s41586-025-09287-2
Curr Opin Syst Biol. 2023 Dec;pii: 100482. [Epub ahead of print]36

Microbial Production of Fuels, Commodity Chemicals, and Materials from Sustainable Sources of Carbon and Energy.

Aidan E Cowan, Sarah H Klass, Peter H Winegar, Jay D Keasling.

  Anthropogenic carbon emissions are driving rapid changes to the earth's climate, disrupting whole ecosystems and endangering the stability of human society. Innovations in engineered microbial fermentation enable the fossil resource-free production of fuels, commodity chemicals, and materials, thereby reducing the carbon emissions associated with these products. Microorganisms have been engineered to catabolize sustainable sources of carbon and energy (i.e., plant biomass, plastic waste, and one-carbon feedstocks) and biosynthesize carbon-neutral or carbon-negative products. These engineering efforts exploit and optimize natural biological pathways or generate unnatural pathways which can biosynthesize chemicals that have not yet been accessed using synthetic chemistry. Recent advances in microbial fermentation seek not only to maximize the titer, rate, and yield of desired products, but also to tailor microbial catabolism to utilize inexpensive feedstocks. Ultimately, these advances aim to lower the cost of bioproduction so that microorganism-derived chemicals can be economically competitive with fossil-derived chemicals.

Keywords:  Biofuels; Biomaterials; Biopolymers; C1 Feedstocks; Engineered Microorganisms; Metabolic Engineering; Microbial Fermentation; Plant Biomass; Plastic Waste; Synthetic Biology

DOI:  https://doi.org/10.1016/j.coisb.2023.100482
Adv Mater. 2025 Jul 29. e2507397

Mechanoresponsive Hydrogels Emerging from Dynamic and Non-Covalent Interactions.

Rachel C Ollier, Matthew J Webber.

  Mechanoresponsive hydrogels undergo changes in their physical and chemical properties in response to mechanical stimuli such as strain, force, or shear stress. These responses are often mediated by dynamic or non-covalent intermolecular interactions. Unlike covalent bonds, which confer desirable mechanical strength but result in static networks, dynamic crosslinking motifs introduce reversibility that enables mechanically actuatable behaviors such as self-healing, shear-thinning or -thickening, and strain-stiffening. This review highlights these four distinct mechanoresponsive behaviors in dynamic hydrogels, examining their underlying mechanisms, characterization methods, and emerging applications, with a focus on the critical role of dynamic interactions in enabling their mechanoresponsive properties.

Keywords:  dynamic networks; mechanical adaptability; polymer science; responsive materials; rheology

DOI:  https://doi.org/10.1002/adma.202507397
ACS Appl Mater Interfaces. 2025 Jul 30.

Integrating DNA-Based Memory in Water-Resistant Electrospun Polymer Fibers for Nondestructive Data Retrieval.

Cecilia Wetzl, Diana Soukarie, Jokin Yeregui Elosua, Ibon Santiago.

  DNA is a digital memory storage medium with advantageous properties, including longevity and high information density. Embedding information-bearing oligonucleotides into materials for long-term storage has gained traction by leveraging modern coding, DNA synthesis, and sequencing technologies. Here, we present a versatile way to store digital information in synthetic DNA embedded in polymer fibers. These composite fibers are made of hydrophilic (poly(vinyl alcohol) and poly(ethylene oxide)) and hydrophobic (polycaprolactone and cellulose acetate) polymers synthesized by solution electrospinning and followed by cross-linking to enhance water resistance. We demonstrate the on-demand retrieval from all fiber compositions of short and long messages encoded in a single oligonucleotide and a pool of oligonucleotides, respectively. DNA/cellulose acetate fiber composites are true nondestructive readout memory: repeated access to messages stored in fibers is afforded without damaging the integrity of fibers or DNA. We envisage that our simple and robust manufacturing approach will contribute to the development of scalable and accessible DNA data storage solutions.

Keywords:  DNA data storage; DNA preservation; electrospinning; fibers; water-resistant

DOI:  https://doi.org/10.1021/acsami.5c06554
Lab Chip. 2025 Aug 01.

Centrifugal microfluidic chip with an air gap for oil-free production of enhanced adipogenic multicellular microspheres.

Xueqing Ren, Xin Wang, Xiaolu Cai, Yi Zou, Peng Chen, Bi-Feng Liu, Yiwei Li.

Hydrogel microspheres, derived from natural or synthetic materials, serve as crucial platforms for three-dimensional (3D) cell culture and tissue engineering. While traditional production methods like emulsification and microfluidics are widely used, they often involve complex processes and oil phases that can compromise biocompatibility. Here, we present a novel centrifugal microfluidic device with an air gap for producing hydrogel microspheres. Centrifugal force provides a driving force for uniform parallel channels, enabling high-throughput microsphere generation while ensuring size uniformity. The system enables precise size control through centrifugal speed modulation, producing microspheres with diameters ranging from 140.6 ± 17.3 μm to 417.1 ± 34.4 μm with a coefficient of variation below 4.8%. The air gap within the microchannel establishes a step-structure that enables oil-free microsphere generation while ensuring biocompatibility. Moreover, by blending a collagen solution into sodium alginate as the matrix, oil-free microspheres with an interpenetrating polymer network (IPN) can be fabricated, which exhibit excellent biocompatibility to support the culture and adipogenic differentiation of mesenchymal stem cells (MSCs). When cells are cultured with a microsphere-formed scaffold, they exhibit aggregation behavior for enhanced cell-cell communication, which further elevated their adipogenic differentiation potential. Overall, this simplified, high-throughput approach offers a unique platform for applications in cell delivery, drug screening, and tissue engineering.

DOI: https://doi.org/10.1039/d5lc00467e
Angew Chem Int Ed Engl. 2025 Jul 31. e202508481

Chirality Makes or Breaks Chemically Driven Self-Assembly.

Lenard Saile, Kun Dai, Mahesh D Pol, Thejus Pramod, Ralf Thomann, Charalampos G Pappas.

  Nature has consistently selected homochiral building blocks from millions of possible diastereomers across diverse biomolecular structures to drive molecular recognition, catalysis and self-assembly. Despite its central role in biology, chirality's influence on chemically driven reaction networks remains unexplored. Here, we demonstrate that chiral aminoacyl phosphate esters, synthetic analogs of biological acylating intermediates, drive self-assembly and reaction pathways, that are modulated purely by their configuration, without the need for changes in functional groups. Using enantiopure aminoacyl phosphate esters, we show that these left- and right-handed acylating agents generate transient epimeric (thio)-esters from homochiral peptide substrates, leading to supramolecular architectures with distinct lifetimes and self-assembly dynamics. Moreover, chirality regulates downstream reactivity in cascade reactions, where stereochemical control over an intermediate propagates into subsequent transformations. Finally, chiral acylating agents differentiate between two reaction cycles, selectively modulating one pathway while keeping another invariant - a level of control that remains difficult to achieve with conventional chemical strategies. Stereochemical programming enables control over reactivity and self-assembly, offering new opportunities to encode chirality in reaction networks and modulate their function through a single molecular parameter.

Keywords:  Acylation; Aminoacyl phosphates; Chirality; Non‐equilibrium self‐assembly; Peptides

DOI:  https://doi.org/10.1002/anie.202508481
R Soc Open Sci. 2025 Jul;12(7): 241725

Thermodynamically consistent, reduced models of gene regulatory networks.

Michael Pan, Peter J Gawthrop, Matthew Faria, Stuart T Johnston.

  Synthetic biology aims to engineer novel functionalities into biological systems. While the approach has been predominantly applied to single cells, a richer set of biological phenomena can be engineered by applying synthetic biology to cell populations. To rationally design cell populations, we require mathematical models that link between intracellular biochemistry and intercellular interactions. In this study, we develop a kinetic model of gene expression that is suitable for incorporation into agent-based models of cell populations. To be scalable to large cell populations, models of gene expression should be both computationally efficient and compliant with the laws of physics. We satisfy the first requirement by applying a model reduction scheme to translation and the second requirement by formulating models using bond graphs, a modelling approach that ensures thermodynamic consistency. Our reduced model is significantly faster to simulate than the full model and reproduces important behaviours of the full model. We couple separate models of gene expression to build models of the toggle switch and repressilator. With these models, we explore the effects of resource availability and cell-to-cell heterogeneity on circuit behaviour. The modelling approaches developed here are a bridge towards engineering collective cell behaviours such as synchronization and division of labour.

Keywords:  bond graph; gene regulatory networks; thermodynamics

DOI:  https://doi.org/10.1098/rsos.241725
iScience. 2025 Aug 15. 28(8): 112944

Integration of Bayesian optimization and solution thermodynamics to optimize media design for mammalian biomanufacturing.

Nelson Ndahiro, Edward Ma, Tom Bertalan, Marc Donohue, Yannis Kevrekidis, Michael Betenbaugh.

  Rapid, cost-effective biomanufacturing of products like therapeutics, materials, and lab-grown foods depends on optimizing cell culture media, a complex and expensive task due to the combination of components and processing variables. This is especially important for therapeutic production using mammalian systems like Chinese Hamster Ovary (CHO) cells, where long development timelines contribute to high drug costs. Using Bayesian optimization (BO), adapted for bioprocess applications, our method supports multiple parallel experiments and incorporates thermodynamics-based constraints on media solubility to ensure feasible medium formulations. The approach is validated both in-silico and in experimental bioreactor settings, showing improved product titers compared to classical design of experiments (DOE) methods. This work bridges machine learning and physical modeling to create a more data-efficient process optimization strategy. The integration of this method into biomanufacturing pipelines together with robotics-assisted bioreactors paves the way for automated bioprocess optimization and more rapidly available and affordable biotherapeutics.

Keywords:  Biological sciences; Engineering; Materials science

DOI:  https://doi.org/10.1016/j.isci.2025.112944
Adv Mater. 2025 Jul 30. e06323

Future Frontiers in Bioinspired Implanted Biomaterials.

Qi Gu, Rui Yuan, Dadi Sun, Gordon Wallace.

  Bioinspired materials draw design inspiration from nature's principles and integrate them with engineering requirements to construct highly functional and complex systems across multiple length scales. Bioinspired implanted biomaterials are highly promising in regenerative medicine, being designed to integrate customized materials with biological functions to replicate the complexity of living tissues. Organs are dynamic, multi-interface architectures with intricate mechanical, biochemical, and physiological properties, posing a major challenge for accurate replication. This perspective explores recent advancements in the design of natural and synthetic biomaterials, focusing on strategies like cell-laden scaffolds and cell-free constructs, which interact dynamically with the body's microenvironments to promote tissue regeneration. How smart biomaterials that respond to biological stimuli are reshaping material functionalization, offering long-term therapeutic solutions is examined. Additionally, how innovations in 3D printing, nanotechnology, and personalized medicine are overcoming current barriers and improving clinical use. Overcoming the challenges associated with replicating complex tissue structures, along with technological advancements, will be crucial to unlocking the full clinical potential of bioinspired implanted biomaterials.

Keywords:  bioinspired materials; implantation; tissue engineering

DOI:  https://doi.org/10.1002/adma.202506323
Adv Nanobiomed Res. 2025 Jan;pii: 2300110. [Epub ahead of print]5(1):

Polymer design of microwell hydrogels influences epithelial-mesenchymal interactions during human bronchosphere formation.

Madeline K Eiken, Justin E Levine, Shinyeong Lee, Samantha Lukpat, Eleanor M Plaster, Vikram Bala, Jason R Spence, Claudia Loebel.

  Bronchospheres have emerged as a promising in vitro model towards probing questions on organ development and disease. Several organoid models, including from airway (e.g., bronchial, tracheal) cells, require 3D Matrigel, a complex mouse tumor-derived matrix that typically leads to heterogenous size and structures. Synthetic and naturally-derived polymeric hydrogels show increased opportunities as an alternative to Matrigel culture. In addition, recent advances in hydrogel-based microcavities (i.e., microwells) have shown improved control over organoid size, structure, and composition. Here, we build upon this approach and describe the fabrication and characterization of microwell hydrogels based on other polymers, including diacrylated poly(ethylene glycol), agarose, methacrylated gelatin, and norbornene-modified hyaluronic acid. Using these microwell hydrogels, human bronchial epithelial cells and lung fibroblasts readily assemble into viable cyst-like bronchospheres. Our study shows that the cellular composition regulates the formation and structure of the bronchosphere which is also regulated by the type and adhesiveness of the hydrogel. Furthermore, both hydrogel type and cellular composition influence the amount and composition of deposited ECM within the microwells. This hydrogel fabrication platform provides an accessible in vitro culture platform for the formation and growth of bronchospheres which can be extended to the culture of other stem/progenitor and tissue-derived organoids.

Keywords:  bronchospheres; hydrogels for cell culture; microwells

DOI:  https://doi.org/10.1002/anbr.202300110
Nat Commun. 2025 Jul 25. 16(1): 6885

Self-adaptable mechanical ceramic fibrous aerogels from prestressed topology and multistable constraints.

Hongxing Wang, Longdi Cheng, Jianyong Yu, Yang Si.

Ceramic aerogels, widely used as thermal insulation materials, are renowned for their remarkable characteristics, including ultralight weight and ultralow thermal conductivity. However, their application is often limited by susceptibility to damage under repeated dynamic thermal shocks-a challenge that remains inadequately addressed. Herein, we present a multicomponent structural engineering approach that integrates ceramic nanofibers with traditional textile knitting topology to fabricate mechanically adaptable ceramic fibrous aerogels. Benefiting from the porous nanofibrous network and the synchronized motion of the prestressed knitted topological framework, which can be readily activated to accommodate deformation while efficiently dissipating energy, the resulting aerogels exhibit exceptional mechanical properties. Specifically, our aerogels demonstrate a high tensile strength of 356.6 kPa, a compressive strength of 109.1 kPa, and remarkable mechanical adaptability in response to external stimuli. Moreover, these aerogels achieve a high fracture energy of 117.26 kJ m-3 and display exceptional recovery from deformation after 1000 cycles of compression or 500 cycles of tension. This study elucidates the structural-property interdependence in aerogel materials through multiscale analysis and advances the rational design of the next-generation impact-absorbing systems and metamaterials.

DOI: https://doi.org/10.1038/s41467-025-62164-4
Open Biol. 2025 Jul;15(7): 240378

How many plasmids can bacteria carry? A synthetic biology perspective.

Cholpisit Kiattisewee.

  Plasmids are pinnacle tools in synthetic biology and other biotechnological applications. They serve as the simplest approach to introduce recombinant DNA, which is then transcribed into RNA that functions as is or is translated into a protein of interest. Despite their widespread utility, the question 'how many plasmids can be used in this bacterium?' remains underexplored in the existing literature. In this article, I discuss the maintenance of multiple unique plasmids in bacteria through a microbial synthetic biology perspective, both in theoretical and practical aspects. I delve into the existing evidence of multi-plasmid systems, aiming to pinpoint the possible maximum number of unique plasmids a single microbe can carry. Finally, I highlight how the existing applications of multi-plasmid systems drive novel discovery and development in metabolic engineering, synthetic biology and other relevant areas in comparison to other non-plasmid strategies.

Keywords:  bacteria; plasmids; synthetic biology

DOI:  https://doi.org/10.1098/rsob.240378
Chem Commun (Camb). 2025 Jul 28.

Next-generation stimuli-responsive polymers for a sustainable tomorrow.

Bhanendra Sahu, Swarup Maity, Amul Jain, Sanjib Banerjee.

Stimuli-responsive polymers (SRPs) represent an emerging class of intelligent materials that can undergo controlled, often reversible, variations in their chemical structures or functions in response to single/multiple external stimuli such as pH, temperature, magnetic fields, and mechanical forces. Thus, these materials have gained significant use in various applications, including targeted drug delivery, environmental remediation, soft actuators, and adaptive devices. With the global shift toward a circular economy, the demand for smart polymeric materials that are not only functional but also sustainable has intensified. Recent research has emphasized the design of SRPs that are biodegradable, biocompatible, recyclable, and synthesized in green solvents such as ionic liquids (ILs) using renewable/bio-derived feedstocks. This feature article presents a comprehensive overview of the recent advances in the evolution, properties, and sustainability-driven design strategies of next-generation SRPs. We discuss recent innovations in their synthesis and applications, particularly in 3D printing, energy dissipation, biomedical diagnostics, and environmental engineering. Additionally, this review highlights key challenges, such as scalability, durability, and environmental safety, that must be addressed to fully recognise the potential of SRPs. Through this exploration, we aim to demonstrate how SRPs are emerging not only as versatile functional materials but also as transformative enablers of sustainable technological solutions.

DOI: https://doi.org/10.1039/d5cc02729b
Nat Biotechnol. 2025 Jul 25.

Translation efficiency covariation identifies conserved coordination patterns across cell types.

Yue Liu, Shilpa Rao, Ian Hoskins, Michael Geng, Qiuxia Zhao, Jonathan Chacko, Vighnesh Ghatpande, Kangsheng Qi, Logan Persyn, Jun Wang, Dinghai Zheng, Yochen Zhong, Dayea Park, Elif Sarinay Cenik, Vikram Agarwal, Hakan Ozadam, Can Cenik.

Characterizing shared patterns of RNA expression between genes across conditions has led to the discovery of regulatory networks and biological functions. However, it is unclear if such coordination extends to translation. In this study, we uniformly analyze 3,819 ribosome profiling datasets from 117 human and 94 mouse tissues and cell lines. We introduce the concept of translation efficiency covariation (TEC), identifying coordinated translation patterns across cell types. We nominate candidate mechanisms driving shared patterns of translation regulation. TEC is conserved across human and mouse cells and uncovers gene functions that are not evident from RNA or protein co-expression. Moreover, our observations indicate that proteins that physically interact are highly enriched for positive covariation at both translational and transcriptional levels. Our findings establish TEC as a conserved organizing principle of mammalian transcriptomes. TEC has potential as a predictive marker for gene function and may offer a framework for designing gene expression systems in synthetic biology and biotechnological applications.

DOI: https://doi.org/10.1038/s41587-025-02718-5
Adv Mater. 2025 Jul 28. e05767

Life Engineering of Materials: Artificial Materials as Plugins for Biological Regulations.

Jiake Lin, Lishan Hu, Xiaoyu Wang, Ruikang Tang.

  Biomineralization is nature's precision engineering system, creating functional biomaterials with exceptional performance through orchestrated organic-inorganic synergistic interactions. Beyond fundamental investigations into biomineralization processes and mechanisms, research has evolved from structural biomimetics toward creating interdependent material-organism hybrids through mineralization-inspired design. Breakthroughs in technologies such as inorganic ion polymerization have significantly advanced strategies for fusing artificial materials with hard tissue regeneration (teeth/bones). Through material-biological integration strategies such as extracellular assembly, artificial organelle transplantation, and artificial functional tissue construction, the creation of artificial life plugins with enhanced nongenetic biological functions (not directly encoded by the DNA) has been achieved. A key pathway to achieving mineralization-inspired design lies in the development of a material-engineered bio-plugin, the material unit with interfaces characterized by chemically tailored compatibility and programmable bio-interactions. Materials that can serve as bio-plugins confer organisms with emergent functionalities such as cell protection, vaccine enhancement, and disease treatment. This review systematically summarizes recent advancements in artificial material-biological fusion technologies, highlights their critical role in the life engineering of materials, and envisions their potential to catalyze new paradigms in biomedical applications.

Keywords:  biomimetic materials; biomineralization; bio‐plugin; life engineering; organism–materials integration

DOI:  https://doi.org/10.1002/adma.202505767
Nat Commun. 2025 Jul 31. 16(1): 7037

A framework for complex signal processing via synthetic biological operational amplifiers.

Wenjun Cao, Lili Liu, Qingxu Sun, Yang Shan, Ye Chen.

Engineering genetic circuits to process complex biological signals remains a significant challenge due to non-orthogonal signal responses that limit precise control. In this study, we introduce a framework that integrates orthogonal operational amplifiers (OAs) into standardized biological processes to enable efficient signal decomposition and amplification. By engineering σ/anti-σ pairs, varying ribosome binding site (RBS) strengths, and utilizing both open-loop and closed-loop configurations, we design scalable OAs that enhance the precision, adaptability, and signal-to-noise ratio of genetic circuits. Additionally, we present a prototype whole-cell biosensor capable of detecting transcriptional changes in response to growth conditions, enabling growth-state-responsive induction systems. These systems provide dynamic gene expression control without external inducers, offering significant advantages for metabolic engineering applications. We also apply our framework to mitigate crosstalk in multi-signal systems, ensuring independent control over each signal channel within complex biological networks. Our approach enhances synthetic biology systems by robust signal processing and precise dynamic regulation.

DOI: https://doi.org/10.1038/s41467-025-62464-9
ACS Omega. 2025 Jul 22. 10(28): 29902-29908

Self-Driving Laboratories: Translating Materials Science from Laboratory to Factory.

Andre K Y Low, Jayce J W Cheng, Kedar Hippalgaonkar, Leonard W T Ng.

The field of materials science stands at a critical inflection point. While laboratory innovations continue to emerge at an unprecedented pace, the traditional timeline from discovery to market in 10-20 years has become an unacceptable bottleneck in addressing urgent technological challenges. We argue that self-driving laboratories (SDLs) represent not merely another step in automation, but a fundamental reimagining of the materials development pipeline. By integrating manufacturing constraints and scalability considerations from the earliest stages of discovery, SDLs can collapse the laboratory-to-factory timeline while improving reproducibility and success rates. This requires abandoning the traditional sequential approach of materials screening, device optimization and manufacturing scale-up; in favor of concurrent cross-scale development. Here, we critically examine current SDL implementations, challenge prevailing assumptions about automation in materials science, and propose a roadmap for truly integrated materials development platforms that could revolutionize how we translate laboratory discoveries into commercial products.

DOI: https://doi.org/10.1021/acsomega.5c02197
Nat Commun. 2025 Jul 25. 16(1): 6870

Mammalian cells measure the extracellular matrix area and respond through switching the adhesion state.

Xiaole Wang, Pengli Wang, Lihang Zhang, Tianyu Xu, Seungkuk Ahn, Upnishad Sharma, Han Yu, Nico Strohmeyer, Daniel J Müller.

Mammalian cells adjust integrin-mediated adhesion based on the composition and structure of the extracellular matrix (ECM). However, how spatially confined ECM ligands regulate cell adhesion initiation remains unclear. Here, we investigate how cells adapt early adhesion to different ECM protein areas. Through combining microcontact printing with single-cell force spectroscopy we measure cell adhesion initiation and strengthening to defined areas of ECM proteins. HeLa cells and mouse embryonic fibroblasts gradually increase adhesion with collagen I or fibronectin area, while reaching maximum adhesion force to ECM patterns having areas above certain thresholds. On much smaller patterns, both cell types switch to a different state and considerably increase the adhesion force per ECM protein area, which they strengthen much faster. This spatially enhanced adhesion state does not require talin or kindlin, indicating a fundamentally different adhesion mechanism. Mechanotransduction seems to play integrin and cell type-specific roles in the spatially enhanced adhesion state.

DOI: https://doi.org/10.1038/s41467-025-62153-7
Phys Rev E. 2025 Jun;111(6-2): 065420

Characterizing the hyperuniformity of disordered network metamaterials.

Charles Emmett Maher, Katherine A Newhall.

Advancements in materials design and manufacturing have allowed for the production of ordered and disordered metamaterials with diverse properties. Hyperuniform two-phase heterogeneous materials, which anomalously suppress density fluctuations on large length scales compared to typical disordered systems, and network materials are two classes of metamaterials that have desirable physical properties. Recent focus has been placed on the design of disordered hyperuniform network metamaterials that inherit the desirable properties of both of these metamaterial classes. In this work, we focus on determining the extent to which network structures derived from the spatial tessellations of hyperuniform point patterns inherit the hyperuniformity of the progenitor point patterns. In particular, we examine the Delaunay, Voronoi, Delaunay-centroidal, and Gabriel tessellations of nonhyperuniform and hyperuniform point patterns in two- and three-dimensional Euclidean space. We use the spectral density to characterize the density fluctuations of two-phase media created by thickening the edges of these tessellations in two dimensions and introduce a variance-based measurement to characterize the network structures directly in two and three dimensions. We find that, while none of the tessellations completely inherit the hyperuniformity of the progenitor point pattern, the degree to which the hyperuniformity is inherited is sensitive to the tessellation scheme and the short- and long-range translational disorder in the point pattern, but not to the choice of beam shape when mapping the networks into two-phase media.

DOI: https://doi.org/10.1103/l5hk-kwyn
Nat Biotechnol. 2025 Jul 25.

Identification of conserved RNA regulatory switches in living cells using RNA secondary structure ensemble mapping and covariation analysis.

Ivana Borovská, Chundan Zhang, Sarah-Luisa J Dülk, Edoardo Morandi, Marta F S Cardoso, Billal M Bourkia, Daphne A L van den Homberg, Michael T Wolfinger, Willem A Velema, Danny Incarnato.

RNA molecules can populate ensembles of alternative structural conformations; however, comprehensively mapping RNA conformational landscapes within living cells presents notable challenges and has, as such, so far remained elusive. Here, we generate transcriptome-scale maps of RNA secondary structure ensembles in both Escherichia coli and human cells, uncovering features of structurally heterogeneous regions. By combining ensemble deconvolution and covariation analyses, we report the discovery of several bacterial RNA thermometers in the 5' untranslated regions (UTRs) of the cspG, cspI, cpxP and lpxP mRNAs of Escherichia coli. We mechanistically characterize how these thermometers switch structure in response to cold shock and reveal the CspE chaperone-mediated regulation of lpxP. Furthermore, we introduce a method for the transcriptome-scale mapping of 5' UTR structures in eukaryotes and leverage it to uncover RNA structural switches regulating the differential usage of open reading frames in the 5' UTRs of the CKS2 and TXNL4A mRNAs in HEK293 cells. Collectively, this work reveals the complexity of RNA structural dynamics in living cells and provides a resource to accelerate the discovery of regulatory RNA switches.

DOI: https://doi.org/10.1038/s41587-025-02739-0
Nat Commun. 2025 Jul 28. 16(1): 6940

Engineering of photo-inducible binary interaction tools for biomedical applications.

Yi-Tsang Lee, Lei Guo, Tien-Hung Lan, Tatsuki Nonomura, Gan Liu, Guolin Ma, Rui Wang, Yun Huang, Yubin Zhou.

The ssrA-sspB dimerization system, derived from the bacterial degradation machinery, comprises a 7-residue ssrA peptide and its binding partner sspB. The compact size of ssrA makes it ideal for insertion into proteins of interest to manipulate host protein function by engineered light-responsive sspB. In contrast to the LOV2 caging strategy employed to develop optical dimerizers, we present herein two distinct photo-inducible binary interaction tools (PhoBITs) systems: PhoBIT1, a light-OFF switch generated by integrating LOV2 into sspB, and PhoBIT2, a light-ON switch building upon an evolved ssrA/CRY2-sspB pair with minimal basal interaction. These tools enable mechanistic dissection and optogenetic modulation of GPCRs, ion channels, necroptosis, and innate immune signaling. When incorporated into a monobody, PhoBIT2 allows photo-switchable inhibition of an oncogenic fusion protein to curtail leukemogenesis in vivo. Collectively, through targeted ssrA insertions, PhoBITs offer versatile control over diverse protein functions, thereby expanding possibilities for optogenetic engineering and potential therapeutic applications.

DOI: https://doi.org/10.1038/s41467-025-61710-4
Nature. 2025 Jul 30.

SMART tool builds proteins on cell surfaces.

Gemma Conroy.



Keywords:  Biological techniques; Molecular biology; Proteomics; Technology

DOI:  https://doi.org/10.1038/d41586-025-02411-2
Nat Commun. 2025 Jul 29. 16(1): 6969

Exploring the intersection of natural sciences and information technology via entropy and randomness.

Anne M Luescher, Reinhard Heckel, Robert N Grass.

Physical sources of randomness are indispensable for information technology and cryptography. Yet, the usefulness of random processes seems to be ignored by many natural science researchers, who are exposed to the downsides of randomness, which adds noise and uncertainty to experiments. Here, we look at experimental science through the lens of information theory, with entropy as a key concept that bridges multiple fields. By examining physical unclonable functions and molecular information technology, we highlight interdisciplinary research leveraging these synergies. With this perspective, we hope to inspire the fascination of randomness and entropy in science, encouraging new research directions across different disciplines.

DOI: https://doi.org/10.1038/s41467-025-62353-1
Nat Commun. 2025 Jul 29. 16(1): 6953

Multichannel bioelectronic sensing using engineered Escherichia coli.

Xu Zhang, Marimikel Charrier, Caroline M Ajo-Franklin.

To advance environmental health and hazard detection, researchers have developed whole-cell bioelectronic sensors by engineering extracellular electron transfer to be dependent on an analyte1. However, these sensors regulate a single electron transfer pathway as an electrochemical channel, limiting the sensing information to a single analyte. We have developed a multichannel bioelectronic sensor where different chemicals regulate distinct extracellular electron transfer pathways within a single Escherichia coli cell. One channel utilizes the flavin synthesis pathway from Bacillus subtilis2 and is controlled by a cadmium-responsive promoter. Another channel, the CymA-Mtr pathway from Shewanella oneidensis3, is controlled by an arsenite-responsive promoter and activates cytochrome CymA expression4,5. We exploit the differing redox potentials of the two extracellular electron transfer pathways6 to develop a redox-potential-dependent algorithm that efficiently converts biological signals into 2-bit binary outputs. This enables our bioelectronic sensor to detect and differentiate heavy metals at EPA limits. When deployed in complex environmental water samples, our sensor effectively and accurately encodes 2-bit binary signals across various analyte conditions. Thus, our multichannel bioelectronic sensor advances the field through simultaneous detection of different chemicals by a single cell, significantly expanding information transmission and helping to safeguard human and environmental health.

DOI: https://doi.org/10.1038/s41467-025-62256-1
Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2424307122

Evolution and evolvability of rifampicin resistance across the bacterial tree of life.

Negin Bolourchi, Christopher R P Brown, Andrew D Letten, Jan Engelstädter.

  Predicting the ability of bacteria to develop antibiotic resistance is challenging, especially for the vast majority of species for which no experimental data are available. Here, we investigated the evolvability and intrinsic presence of rifampicin resistance across the bacterial tree of life. We compiled a comprehensive panel of known rifampicin resistance mutations, comprising 57 amino acid substitutions within the gene rpoB. We then screened more than 18,000 genomes from all major bacterial groups for the presence of those mutations and determined which mutations can evolve through point mutations. Our results demonstrate that although the evolvability of individual mutations varies considerably across species, overall predicted evolvability is high and relatively homogeneous across bacterial taxa. Rifampicin resistance mutations are present intrinsically in 8% of species that tend to be phylogenetically clustered. Our analysis provides a global picture of the mutational landscape of rifampicin resistance, affording insight into existing observations and informing future discoveries such as the identification of probiotics.

Keywords:  antibiotic resistance; evolvability; intrinsic resistance; mutational spectrum; rifampicin

DOI:  https://doi.org/10.1073/pnas.2424307122
Nat Chem Biol. 2025 Aug 01.

Directed evolution of LaccID for cell surface proximity labeling and electron microscopy.

Song-Yi Lee, Heegwang Roh, David Gonzalez-Perez, Mason R Mackey, Daniel Hoces, Colleen N McLaughlin, Chang Lin, Stephen R Adams, Khanh Nguyen, Keun-Young Kim, David J Luginbuhl, Liqun Luo, Namrata D Udeshi, Steven A Carr, Rogelio A Hernández-López, Mark H Ellisman, Miguel Alcalde, Alice Y Ting.

Enzymes that oxidize aromatic substrates have been harnessed for cell-based technologies including proximity labeling and electron microscopy; however, they are associated with drawbacks such as the need for toxic H2O2. Here, we explore multicopper oxidases (laccases) as a new enzyme class for proximity labeling and electron microscopy in mammalian cells. LaccID was generated through 11 rounds of directed evolution from an ancestral fungal laccase and catalyzes one-electron oxidation of diverse aromatic substrates using O2 instead of toxic H2O2. Surprisingly, we found that LaccID is selectively active at the surface plasma membrane of both living and fixed cells. We use LaccID proximity labeling and mass spectrometry to map the changing surface proteome of T cells that engage with tumor cells through antigen-specific T cell receptors. In addition, we use LaccID as a genetically encodable tag for EM visualization of cell surface features in mammalian cell culture and in the fly brain. Our study paves the way for future cell-based applications of LaccID.

DOI: https://doi.org/10.1038/s41589-025-01973-6
Metab Eng. 2025 Jul 28. pii: S1096-7176(25)00116-8. [Epub ahead of print]92 90-101

Sustainable production through spatial niche partitioning in engineered light-driven microbial community.

Hao Gao, Yifan Song, Yujia Jiang, Wankui Jiang, Feng Guo, Ziyi Yu, Minjiao Chen, Guodong Luan, Jee Loon Foo, Wenming Zhang, Matthew Wook Chang, Fengxue Xin, Min Jiang.

  Light-driven microbial communities consisting of phototrophs and heterotrophs represent an emerging frontier for biochemicals production from carbon dioxide (CO2). However, the construction of stable and robust light-driven artificial microbial communities remains challenging because the dominant strain wins the competition for nutrient and leads to the instability of subpopulations. Inspired by natural ecosystems, one promising approach to assemble stable consortia is to construct spatial niches partitioning subpopulations-that is, physically separating different microbial members into distinct microenvironments to reduce competition and enable stable coexistence. Herein, a light-driven microbial community containing an autotrophic Synechococcus elongatus FL130 strain and a heterotrophic Meyerozyma guilliermondii strain was first constructed. Then, we developed spatially arranged core-shell microgels, enabling the precise control of subpopulations of different microbial members. Next, these microgels were integrated into macroscopic living material scaffold using extrusion bioprinting to advance bioprocessing applications, obtaining a well-coupled, robust and reusable light-driven microbial community. This resulted in a light-driven microbial communities with spatially compartmentalized distribution that can efficiently convert CO2 into valuable chemical products of 2-phenylethanol and tyrosol, representing a pioneering approach for sustainable high-value biochemical production.

Keywords:  Light-driven microbial community; Phototrophs and heterotrophs; Spatial niches; Sustainable biochemical production

DOI:  https://doi.org/10.1016/j.ymben.2025.07.012
Mater Horiz. 2025 Jul 28.

Color and fluorescence switchable 2D and 3D printed hybrid materials.

Matthias Steurer, Xingyu Wu, Agnes C Morrissey, Konstantin Faershteyn, Magdalena Fladung, Paul Somers, Florian Feist, Martin Bastmeyer, Martin Wegener, Claus Feldmann, Christopher Barner-Kowollik.

We introduce an ink system for light-driven 3D printing that consists of electrostatically stabilized inorganic-organic hybrid nanoparticles (IOH-NPs), a crosslinking monomer and a photoinitiator, enabling the printing of color- and fluorescence-switchable 3D objects. Nanoparticles (NPs) are often prone to aggregation in photoresins, causing significant light scattering that hinders the printing process. Furthermore, the particles may degrade upon exposure, resulting in the loss of their properties. These issues result in poor printing quality or a loss of functionality. By carefully selecting NPs and resin composition, we successfully incorporate IOH-NPs into a soft-matter 3D network, enabling a fast pH-dependent color and fluorescence change over a wide pH range. In-depth characterization of the printed structures via imaging, spectroscopic and spectrometric techniques reveals that the IOH-NPs remain intact after printing, exhibiting repeatable color and fluorescence switching. We further demonstrate that multi-material objects can be fabricated entailing both color-switchable and non-switchable structural elements. The hybrid materials for 3D printing introduced here enable tunable optical properties and hold promise for applications in sensors or optical devices.

DOI: https://doi.org/10.1039/d5mh00564g
Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2422678122

Trigger factor accelerates nascent chain compaction and folding.

Katharina Till, Anne-Bart Seinen, Florian Wruck, Vanda Sunderlikova, Carla V Galmozzi, Alexandros Katranidis, Bernd Bukau, Günter Kramer, Sander J Tans.

  Conformational control of nascent chains is poorly understood. Chaperones are known to stabilize, unfold, and disaggregate polypeptides away from the ribosome. In comparison, much less is known about the elementary conformational control mechanisms at the ribosome. Yet, proteins encounter major folding and aggregation challenges during translation. Here, using selective ribosome profiling and optical tweezers with correlated single-molecule fluorescence, with dihydrofolate reductase (DHFR) as a model system, we show that the Escherichia coli chaperone trigger factor (TF) accelerates nascent chain folding. TF scans nascent chains by transient binding events, and then locks into a stable binding mode as the chain collapses and folds. This interplay is reciprocal: TF binding collapses nascent chains and stabilizes partial folds, while nascent chain compaction prolongs TF binding. Ongoing translation controls these cooperative effects, with TF-accelerated folding depending on the emergence of a peptide segment that is central to the core DHFR beta-sheet. The folding acceleration we report here impacts processes that depend on folding occurring cotranslationally, including cotranslational protein assembly, protein aggregation, and translational pausing, and may be relevant to other domains of life.

Keywords:  chaperones; optical tweezers; protein folding; ribosomes

DOI:  https://doi.org/10.1073/pnas.2422678122
Metab Eng. 2025 Jul 23. pii: S1096-7176(25)00110-7. [Epub ahead of print]

Improving Recombinant Antibody Production Using FcBAR: An In Situ Approach to Detect and Amplify Protein-Protein Interactions.

Mina Ying Min Wu, Frances Rocamora, Mojtaba Samoudi, Caressa M Robinson, Chih-Chung Kuo, Nuša Pristovšek, Lise Marie Grav, Helene Faustrup Kildegaard, Gyun Min Lee, Alexandre Rosa Campos, Nathan E Lewis.

Recombinant proteins, in particular monoclonal antibodies and related molecules, have become dominant therapeutics. As they are produced in mammalian cells, they require the concerted function of hundreds of host cell proteins in the protein secretion pathway. However, the comprehensive set of host cell machinery involved remains unclear. Thus, it is often unknown why some recombinant proteins fail to express well. Here we present and deploy an approach called Fc-targeting Biotinylation by Antibody Recognition (FcBAR), which allows for the in situ detection of protein-protein interactions for any recombinant protein with Fc domain. Briefly, cells are permeabilized and incubated with an anti-Fc antibody, conjugated with horseradish peroxidase. All proteins interacting with Fc-bearing proteins are then biotinylated, pulled down and identified via mass spectrometry. We applied this method on a panel of rituximab-producing CHO-S clones with a range of productivity levels. Through analysis of FcBAR protein-protein interactions and RNA-Seq, we identified protein interactions positively correlated with rituximab secretion, and tested 7 of these targets. We found overexpression of AGPAT4, EPHX1, and NSDHL significantly increased rituximab production. Thus, FcBAR provides an unbiased approach to measure PPIs supporting recombinant antibody production in situ, and can guide efforts to boost production of biotherapeutics and biosimilars by addressing production bottlenecks.

DOI: https://doi.org/10.1016/j.ymben.2025.07.006
Trends Biotechnol. 2025 Jul 31. pii: S0167-7799(25)00274-4. [Epub ahead of print]

pH-modulated soluble expression of alcohol dehydrogenases in Escherichia coli using adaptive laboratory evolution.

Suraj Mital, Graham Christie, Annette Alcasabas, Ryan Mellor, Duygu Dikicioglu.

  Industrial production of alcohol dehydrogenases (ADHs) is severely hampered by their propensity to form insoluble inclusion bodies during recombinant expression. This work achieves soluble expression of such historically aggregate-prone enzymes in Escherichia coli by addressing the fundamental physicochemical incompatibilities between recombinant proteins and their host environment. Elevating the expression medium to pH 9 and engineering E. coli to adapt to high- pH improved catalytically active soluble yields for industrially significant Rhodococcus ADH-A and ADH-G by 18.55-fold and 26.59-fold, respectively. The evolved E. coli overcame alkaline stress by optimizing energy-intensive metabolic pathways for cytoplasmic pH homeostasis rather than by modulating ribosomal machinery and translation. Seven key mutations acquired during adaptive evolution conferred strategic modifications to cell envelope stress responses, metabolism, and genomic regulation, collectively enhancing fitness. This robust framework proposed for matching the biochemical requirements of heterologous enzymes with host physiology offers a powerful solution for the high-yield production of challenging industrial biocatalysts.

Keywords:  Escherichia coli; adaptive laboratory evolution; alcohol dehydrogenase; enzymes; inclusion bodies; pH; protein solubility

DOI:  https://doi.org/10.1016/j.tibtech.2025.07.013
Nat Commun. 2025 Jul 29. 16(1): 6849

An on-chip phased array for non-classical light.

Volkan Gurses, Samantha I Davis, Raju Valivarthi, Neil Sinclair, Maria Spiropulu, Ali Hajimiri.

Quantum science and technology can offer fundamental enhancements in sensing, communications and computing. The expansion from wired to wireless links is an exciting prospect for quantum technologies. For classical technologies, the advent of phased arrays enabled directional and adaptive wireless links by manipulating electromagnetic waves over free space. Here we demonstrate a phased array system on a chip that can receive, image and manipulate non-classical light over free space. We use an integrated photonic-electronic system with more than 1000 functional components on-chip to detect squeezed light. By integrating an array of 32 sub-wavelength engineered metamaterial antennas, we demonstrate a direct free-space-to-chip interface for reconfigurable quantum links. On the same chip, we implement a large-scale array of quantum-limited coherent receivers that can resolve non-classical signals simultaneously across 32 channels. With coherent readout and manipulation of these signals, we demonstrate 32-pixel imaging and spatially configurable reception of squeezed light over free space. Our work advances wireless quantum technologies that could enable practical applications in quantum communications and sensing.

DOI: https://doi.org/10.1038/s41467-025-61886-9
Nat Commun. 2025 Jul 31. 16(1): 7024

Cholesterol modulates membrane elasticity via unified biophysical laws.

Teshani Kumarage, Sudipta Gupta, Nicholas B Morris, Fathima T Doole, Haden L Scott, Laura-Roxana Stingaciu, Sai Venkatesh Pingali, John Katsaras, George Khelashvili, Milka Doktorova, Michael F Brown, Rana Ashkar.

Cholesterol and lipid unsaturation underlie a balance of opposing forces that features prominently in adaptive cell responses to diet and environmental cues. These competing factors have resulted in contradictory observations of membrane elasticity across different measurement scales, requiring chemical specificity to explain incompatible structural and elastic effects. Here, we demonstrate that - unlike macroscopic observations - lipid membranes exhibit a unified elastic behavior in the mesoscopic regime between molecular and macroscopic dimensions. Using nuclear spin techniques and computational analysis, we find that mesoscopic bending moduli follow a universal dependence on the lipid packing density regardless of cholesterol content, lipid unsaturation, or temperature. Our observations reveal that compositional complexity can be explained by simple biophysical laws that directly map membrane elasticity to molecular packing associated with biological function, curvature transformations, and protein interactions. The obtained scaling laws closely align with theoretical predictions based on conformational chain entropy and elastic stress fields. These findings provide unique insights into the membrane design rules optimized by nature and unlock predictive capabilities for guiding the functional performance of lipid-based materials in synthetic biology and real-world applications.

DOI: https://doi.org/10.1038/s41467-025-62106-0
Phys Rev E. 2025 Jun;111(6-1): 064418

Dynamic landscapes and statistical limits on growth during cell fate specification.

Gautam Reddy.

The complexity of gene regulatory networks in multicellular organisms makes interpretable low-dimensional models highly desirable. An attractive geometric picture, attributed to Waddington, visualizes the differentiation of a cell into diverse functional types as gradient flow on a dynamic potential landscape. However, it is unclear under what constraints this metaphor is mathematically precise. Here, we consider the controlled growth of a single cell into a population with a target distribution over cell states. Expanding on a connection between stochastic control and optimal transport, we show that growth-maximizing regulatory strategies are described by time-dependent potential landscapes under certain generic growth-control trade-offs. Our analysis leads to a sharp bound on the time it takes for a population to grow to a target distribution with a certain size. We show how the framework can be used to compute regulatory strategies and growth curves in an illustrative model of growth and differentiation. The theory suggests a conceptual link between nonequilibrium thermodynamics, cellular decision-making during fate specification, and transport-based sampling methods from machine learning.

DOI: https://doi.org/10.1103/63d2-4wq6
Nat Commun. 2025 Jul 31. 16(1): 7017

GFP-on mouse model for interrogation of in vivo gene editing.

Carla Dib, Jack A Queenan, Leah Swartzrock, Hana Willner, Morgane Denis, Nouraiz Ahmed, Fareha Moulana Zada, Beltran Borges, Carsten T Charlesworth, Tony Lum, Bradley P Yates, Caleb Y Kwon, Augustino V Scorzo, Scott C Davis, Jessie R Davis, Ran He, Jun Xie, Guangping Gao, Tippi C MacKenzie, David R Liu, Gregory A Newby, Agnieszka D Czechowicz.

Gene editing technologies have revolutionized therapies for numerous genetic diseases. However, in vivo gene editing hinges on identifying efficient delivery vehicles for editing in targeted cell types, a significant hurdle in fully realizing its therapeutic potential. A model system to rapidly evaluate systemic gene editing would advance the field. Here, we develop the GFP-on reporter mouse, which harbors a nonsense mutation in a genomic EGFP sequence correctable by adenine base editor (ABE) among other genome editors. The GFP-on system was validated using single and dual adeno-associated virus (AAV9) encoding ABE8e and sgRNA. Intravenous administration of AAV9-ABE8e-sgRNA into adult GFP-on mice results in EGFP expression consistent with the tropism of AAV9. Intrahepatic delivery of AAV9-ABE8e-sgRNA into GFP-on fetal mice restores EGFP expression in AAV9-targeted organs lasting at least six months post-treatment. The GFP-on model provides an ideal platform for high-throughput evaluation of emerging gene editing tools and delivery modalities.

DOI: https://doi.org/10.1038/s41467-025-61449-y
Nat Mater. 2025 Jul 31.

Computational design of bifaceted protein nanomaterials.

Sanela Rankovic, Kenneth D Carr, Justin Decarreau, Rebecca Skotheim, Ryan D Kibler, Sebastian Ols, Sangmin Lee, Jung-Ho Chun, Marti R Tooley, Justas Dauparas, Helen E Eisenach, Matthias Glögl, Connor Weidle, Andrew J Borst, David Baker, Neil P King.

Advances in computational methods have led to considerable progress in the design of protein nanomaterials. However, nearly all nanoparticles designed so far exhibit strict point group symmetry, which limits structural diversity and precludes anisotropic functionalization. Here we describe a computational strategy for designing multicomponent bifaceted protein nanomaterials with two distinctly addressable sides. The method centres on docking pseudosymmetric hetero-oligomeric building blocks in architectures with dihedral symmetry and designing an asymmetric protein-protein interface between them. We obtain an initial 30-subunit assembly with pseudo-D5 symmetry and generate variants in which we alter the size and morphology of the bifaceted nanoparticles by designing extensions to one of the subunits. Functionalization of the two nanoparticle faces with protein minibinders enables the specific colocalization of two populations of polystyrene microparticles coated with the target protein receptors. The ability to accurately design anisotropic protein nanoparticles could be broadly useful in applications requiring the colocalization of distinct target moieties.

DOI: https://doi.org/10.1038/s41563-025-02295-7
Nat Rev Cancer. 2025 Aug 01.

Advancing engineering design strategies for targeted cancer nanomedicine.

Victoria F Gomerdinger, Namita Nabar, Paula T Hammond.

Engineered nanoparticles have greatly expanded cancer treatment by encapsulating and delivering therapeutic and diagnostic agents, otherwise limited by poor pharmacokinetics and toxicity, to target tumour cells. Leveraging our increased understanding of the tumour microenvironment, nanomedicine has expanded to additionally target key tissues and cells implicated in tumorigenesis, such as immune and stromal cells, to improve potency and further mitigate off-target toxicities. To design nanocarriers that overcome the body's physiological barriers to access tumours, the field has explored broader routes of administration and nanoparticle design principles, beyond the enhanced permeation and retention effect. This Review explores the advantages of non-covalent surface modifications of nanoparticles, along with other surface modifications, to modulate nanoparticle trafficking from the injection site, into tumour and lymphoid tissues, to the target cell, and ultimately its subcellular fate. Using electrostatic or other non-covalent techniques, nanoparticle surfaces can be decorated with native and synthetic macromolecules that confer highly precise cell and tissue trafficking. Rational design can additionally minimize detection and clearance by the immune system and prolong half-life - key to maximizing efficacy of therapeutic cargos. Finally, we outline how cancer nanomedicine continues to evolve by incorporating learnings from novel screening technologies, computational approaches and patient-level data to design efficacious targeted therapies.

DOI: https://doi.org/10.1038/s41568-025-00847-2
Phys Life Rev. 2025 Jul 28. pii: S1571-0645(25)00116-2. [Epub ahead of print]54 205-206

Comment on "Viscoelastic mechanics of living cells" by Hui Zhou, Ruye Liu, Yizhou Xu, Jierui Fan, Xinyue Liu, Longquan Chen, Qiang Wei.

Guang-Kui Xu.



Keywords:  Cell mechanics; Viscoelastic mechanics

DOI:  https://doi.org/10.1016/j.plrev.2025.07.021
Nat Commun. 2025 Jul 29. 16(1): 6948

Cas13d-mediated isoform-specific RNA knockdown with a unified computational and experimental toolbox.

Megan D Schertzer, Andrew Stirn, Keren Isaev, Laura Pereira, Stella H Park, Anjali Das, Aline Réal, Erin D Jeffery, Claire Harbison, Hans-Hermann Wessels, Gloria M Sheynkman, Neville E Sanjana, David A Knowles.

Pre- and post-transcriptional mechanisms, including alternative promoters, termination signals, and splicing, play essential roles in diversifying protein output by generating distinct RNA and protein isoforms. Two major challenges in characterizing the cellular function of alternative isoforms are the lack of experimental methods to specifically and efficiently modulate isoform expression and computational tools for complex experimental design and analysis. To address these gaps, we develop and methodically test an isoform-specific knockdown strategy which pairs the RNA-targeting CRISPR/Cas13d system with guide RNAs that span exon-exon junctions. In parallel, we provide computational tools for experimental design and analysis. In this study, we demonstrate that junction-targeting achieves robust and isoform-specific RNA knockdown across diverse alternative isoform events, genes, and cell types.

DOI: https://doi.org/10.1038/s41467-025-62066-5