bims-enlima Biomed News
on Engineered living materials
Issue of 2025–08–31
38 papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. PhoCoil: A photodegradable and injectable single-component recombinant protein hydrogel for minimally invasive delivery and degradation.
  2. Bioorthogonal Engineering of Cellular Microenvironments Using Isonitrile Ligations.
  3. Beaded metamaterials.
  4. Particle-based hydrogel inks and support matrices for biofabricating structural complexity, soluble gradients, and cell-lined channels in fully granular bioprinted systems.
  5. Site-selective protein editing by backbone extension acyl rearrangements.
  6. Conversion of natural cytokine receptors into orthogonal synthetic biosensors.
  7. Adaptive Mechanical Metamaterials with On-Demand Binary Local Modulus for Embodied Intelligence.
  8. Engineering kidney developmental trajectory using culture boundary conditions.
  9. Bicyclic-Guanidinium Benzenesulfonate: A Fingerprint Monomer for Self-Recognizably Recyclable Polyester with Antibacterial Performance.
  10. Strategies and applications of synthetic cell communication.
  11. Viscoelasticity of Fibrous Hydrogels Driven by Dynamic Intrafibrillar Imine Cross-Linking.
  12. Reversible biobased adhesives enable closed-loop engineered composites.
  13. Class I histone deacetylases catalyze lysine lactylation.
  14. Aqueous Synthesis of Poly(ethylene glycol)-amide-Norbornene-Carboxylate for Modular Hydrogel Crosslinking.
  15. Designing Protein-Based Nanoparticles for Therapeutic Applications.
  16. Development of a Hydrogel Platform with GBM and Microglia: A Potential Glioblastoma Tumor Model.
  17. Glycosyl Radicals Induced Ultrafast and Homogeneous Gelation for Mechanically Robust Hydrogels.
  18. RNA-Polymer Conjugates via Direct Incorporation of the Chain Transfer Agent and PET-RAFT Polymerization.
  19. Rational Design of Thermoresponsive Elastin-Like Protein Monolayers for Nonenzymatic Cell Harvesting.
  20. Introduction to "Biomolecular Technologies".
  21. Split-Small GTPase Reassembly as a Method to Control Cellular Signaling with User-Defined Inputs.
  22. Microscopic geared metamachines.
  23. Multistep catalytic abiotic CO2 conversion to sugars through C1 intermediates.
  24. Cyclic Stretch Bioreactor Enhances Tenogenic Differentiation of MSCs in Biomimicked PCL-tdECM Membranes through Dynamic Mechanical Loading.
  25. Improved provenance tracking by documenting plasmids within their own sequence.
  26. One-Step Coordinated Multi-Kinetic 4D Printing of Human Vascularized Cardiac Tissues with Selective Fast-Shrinking Capillaries.
  27. Challenges and Opportunities in Smart Biosensing for Biomanufacturing.
  28. Programmable epigenome editing by transient delivery of CRISPR epigenome editor ribonucleoproteins.
  29. Impact of 3D cell culture hydrogels derived from basement membrane extracts or nanofibrillar cellulose on CAR-T cell activation.
  30. Focusing plastic solutions up the waste hierarchy: Pathways for a more circular economy.
  31. Probiotic acoustic biosensors for noninvasive imaging of gut inflammation.
  32. BioFuse: A programmable timer switch of gene expression.
  33. Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
  34. Engineering Energy Dissipation Pathway via Topological Design: Toward Tunable Macroscopic Mechanical Performances of Dynamic Polymer Networks.
  35. Feeding bees with engineered yeast combats colony decline.
  36. Uncovering phenotypic inheritance from single cells with Microcolony-seq.
  37. Designing a DNA synchronizer for compact single-rail DNA logic circuits.
  38. A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
  1. Sci Adv. 2025 Aug 29. 11(35): eadx3472
    PhoCoil: A photodegradable and injectable single-component recombinant protein hydrogel for minimally invasive delivery and degradation.
    Nicole E Gregorio, Fan Zhang, Yusuke Suita, Lisa S Ang, Olivia Prado, Arafat Fasuyi, James M Olson, Kelly R Stevens, Cole A DeForest.
      Hydrogel biomaterials offer great promise for three-dimensional cell culture and therapeutic delivery. Despite many successes, challenges persist in that gels formed from natural proteins are only marginally tunable whereas those derived from synthetic polymers lack intrinsic bioinstructivity. Toward the creation of biomaterials with both excellent biocompatibility and customizability, recombinant protein-based hydrogels have emerged as molecularly defined and user-programmable platforms that mimic the proteinaceous nature of the extracellular matrix. Here, we introduce PhoCoil, a dynamically tunable recombinant hydrogel formed from a single protein component with unique multistimuli responsiveness. Physical cross-linking through coiled-coil interactions promotes rapid shear-thinning and self-healing behavior, rendering the gel injectable, whereas an included photodegradable motif affords on-demand network dissolution via visible light. PhoCoil gel photodegradation can be spatiotemporally and lithographically controlled in a dose-dependent manner, through complex tissue, and without harm to encapsulated cells. We anticipate that PhoCoil will further enable applications in tissue engineering and regenerative medicine.
    DOI:  https://doi.org/10.1126/sciadv.adx3472
  2. Adv Funct Mater. 2025 May 30. pii: 2422047. [Epub ahead of print]
    Bioorthogonal Engineering of Cellular Microenvironments Using Isonitrile Ligations.
    Ping Zhou, Lauren Brown, Christopher M Madl.
      Hydrogels are routinely used as scaffolds to mimic the extracellular matrix for tissue engineering. However, common strategies to covalently crosslink hydrogels employ reaction conditions with potential off-target biological reactivity. The limited number of suitable bioorthogonal chemistries for hydrogel crosslinking restricts how many material properties can be independently addressed to control cell fate. To expand the bioorthogonal toolkit available for hydrogel crosslinking, we identify isonitrile ligations as a promising class of reactions. Isonitriles are compact, stable, selective, and biocompatible moieties that react with chlorooxime (ChO), tetrazine (Tz), and azomethine imine (AMI) functional groups under physiological conditions. We demonstrate that all three ligation reactions can form hydrogels, with isonitrile-ChO ligation exhibiting optimal gelation properties. Synthetic poly(ethylene glycol) (PEG) hydrogels crosslinked by isonitrile-ChO ligation exhibit rapid gelation kinetics, elastic mechanical properties, stability under physiological conditions, and high biocompatibility. By combining ChO-functionalized multi-arm PEGs with isonitrile-functionalized engineered elastin-like proteins (ELPs), we demonstrate simultaneous control over network connectivity and adhesive ligand presentation, which in turn regulate cell spreading. These hydrogels enable the long-term culture of numerous human cell types relevant to regenerative medicine. Furthermore, we demonstrate that isonitrile-ChO ligation is orthogonal to common azide-alkyne cycloaddition, enabling independent, bioorthogonal functionalization of hydrogels containing live cells.
    Keywords:  bioorthogonal chemistry; engineered extracellular matrices; hydrogels; isonitrile ligation; recombinant protein materials
    DOI:  https://doi.org/10.1002/adfm.202422047
  3. Nat Commun. 2025 Aug 25. 16(1): 7899
    Beaded metamaterials.
    Lauren Dreier, Trevor J Jones, Abigail Plummer, Andrej Košmrlj, P-T Brun.
      Beading transforms flexible fiber networks into load-bearing structures by incorporating rigid, discrete elements in programmable weave patterns. Beaded assemblies function as mechanical metamaterials, where emergent mechanical behaviors arise from the interplay between geometry and material properties. Here, we investigate how this interplay governs the global mechanics of bead-thread networks. Using a combination of experiment and simple modeling, we identify conditions under which beaded structures undergo superjamming - a mechanically locked state that dramatically enhances load capacity. Our results show how potentially limiting factors such as gravity and friction can be leveraged to extend the domain of soft materials design into applications that demand rigidity.
    DOI:  https://doi.org/10.1038/s41467-025-61809-8
  4. Biofabrication. 2025 Aug 22.
    Particle-based hydrogel inks and support matrices for biofabricating structural complexity, soluble gradients, and cell-lined channels in fully granular bioprinted systems.
    Julia Tumbic, Emily Ferrarese, Remington Martinez, Thomas Ackleson, Daniel Delgado, Christopher Highley.
      Towards achieving biomimetic complexity in biofabricated systems, an all-granular bioprinting system might use particle-based hydrogel inks to establish structures within a particle-based support matrix. In such a system, the granular support matrix can be designed to persist in the final construct and include cells incorporated prior to printing. To biofabricate complexity, bioprinting can introduce high-resolution heterogeneous structures that guide cell behaviors. The designs of the granular ink and support hydrogels are crucial to achieving complexity. High resolution structures and channels depend on small particles that flow and can be stabilized, and that can be printed and then removed, respectively. Herein, an all-granular system is described that used a granular formulation of an established, tunable hyaluronic acid-based hydrogel as the basis for a support matrix and a small particle gelatin hydrogel as an ink. Towards facilitating stabilization of the printed structure and flow during printing, the support and ink materials included soluble, interstitial components, and all exhibited yield stress behaviors characteristic of granular hydrogel systems. The support matrix's viscoelastic properties were dependent on intraparticle hydrogel network design, and it could be stabilized against flow by photoinitiated crosslinking. The gelatin ink could form fine filaments, as small as 100 µm in testing here, and melted to leave channels within crosslinked support matrices. Channels could support flows introduced by hydrostatic pressure and could be used to rapidly transport soluble factors into the construct, which could be used to establish soluble gradients by diffusion and support cell viability. The all-granular system supported printing of complex, multimaterial structures, with feature resolution on the order of 100 µm and spatial positioning on the order of 10s µm. The process and materials exhibited biocompatibility with respect to cells included within the support matrix during printing or introduced into channels to begin establishing endothelialized bioprinted vessels.&#xD.
    Keywords:  bioprinting; gelatin; granular hydrogels; hyaluronic acid; matrix assisted bioprinting; particles; removable ink
    DOI:  https://doi.org/10.1088/1758-5090/adfe97
  5. Nat Chem Biol. 2025 Aug 21.
    Site-selective protein editing by backbone extension acyl rearrangements.
    Leah T Roe, Isabel M Piper, Carly K Schissel, Taylor L Dover, Bhavana Shah, Noah X Hamlish, Arjun M Garapaty, Shuai Zheng, Diondra A Dilworth, Nicole Wong, Zhongqi Zhang, Abhishek Chatterjee, Matthew B Francis, Scott J Miller, Alanna Schepartz.
      Protein and polypeptide heteropolymers containing non-α-backbone monomers are highly desirable as potential materials and therapeutics but many remain difficult or impossible to biosynthesize in cells using traditional genetic code expansion. Here we describe a next-generation approach to such materials that relies instead on proximity-guided intramolecular rearrangements that edit the protein backbone post-translationally. This approach relies on orthogonal aminoacyl-tRNA synthetase enzymes that accept α-hydroxy acid monomers whose side chains contain masked nucleophiles. Introduction of such an α-hydroxy acid into a protein translated in vivo, followed by nucleophile unmasking, sets up a thermodynamically favored intramolecular backbone extension acyl rearrangement (BEAR) reaction that edits the protein to install an extended-backbone monomer. In the examples described here, BEAR reactions are used to generate protein heteropolymers containing a β-backbone, γ-backbone or δ-backbone. This report represents a general strategy to install extended backbones into genetically encoded proteins and peptides expressed in cells.
    DOI:  https://doi.org/10.1038/s41589-025-01999-w
  6. Nat Chem Biol. 2025 Aug 22.
    Conversion of natural cytokine receptors into orthogonal synthetic biosensors.
    Hailey I Edelstein, Amparo Cosio, Max L Ezekiel, William K Corcoran, Aaron H Morris, Joshua N Leonard.
      Synthetic receptors enable bioengineers to build cell-based therapies that perform therapeutic functions in a targeted or conditional fashion to enhance specificity and efficacy. Although many synthetic receptors exist, it remains challenging to generate new receptors that sense soluble cues and relay that detection through orthogonal mechanisms independent of native pathways. Here we co-opt natural cytokine receptor ectodomains into modular extracellular sensor architecture (MESA) receptors to form natural ectodomain (NatE) MESA receptors. We generated multiple functional, orthogonal synthetic cytokine receptors, identified design principles and constraints and propose guidance for extending this approach to other natural receptors. We demonstrate the utility of NatE MESA by engineering T cells to sense an immunosuppressive cue and respond with customized transcriptional output to support chimeric antigen receptor T cell activity. Lastly, we multiplex NatE MESA to logically evaluate multiple cues associated with the tumor microenvironment. These technologies and learnings will enable engineering cellular functions for new applications.
    DOI:  https://doi.org/10.1038/s41589-025-01986-1
  7. Adv Sci (Weinh). 2025 Aug 26. e09675
    Adaptive Mechanical Metamaterials with On-Demand Binary Local Modulus for Embodied Intelligence.
    Richard J Nash, Yunzheng Yang, Yaning Li.
      Biological materials in nature are inherently adaptive, evolving through continuous interaction with their environment. Achieving such adaptability and self-optimization in artificial materials remains a major challenge. In this work, a simple yet robust mechanism is introduced that enables instantaneous changes in local stiffness components in response to strain. This is realized by designing binary meta-capsules with two discrete states 0 and 1, each corresponding to a different modulus in one direction. These strain-responsive capsules switch states based on applied deformation, serving as the building blocks for a new class of adaptive mechanical metamaterials (AMMs). Computational tools are developed to guide the design, and selected structures are fabricated via multi-material polymer jetting. Mechanical experiments, including compression and indentation tests, confirm the functionality of the AMMs. Because the stiffness change in each meta-capsule is reversible, the material can reconfigure itself after loading-unloading cycle. This enables AMMs to dynamically adjust their local properties based on external loads and/or constraints, effectively "reprogramming" or redesigning themselves post-fabrication, paving the way for transforming 3D/4D printing into adaptive, "infinity-D" printing.
    Keywords:  adaptive materials; additive manufacturing; embodied intelligence; mechanical metamaterials; on‐demand
    DOI:  https://doi.org/10.1002/advs.202509675
  8. Nat Commun. 2025 Aug 22. 16(1): 7829
    Engineering kidney developmental trajectory using culture boundary conditions.
    Aria Zheyuan Huang, Louis S Prahl, Karen Xu, Robert L Mauck, Jason A Burdick, Alex J Hughes.
      Kidney explants are traditionally cultured at air-liquid interfaces, which disrupts 3D tissue structure and limits interpretation of developmental data. Here we develop a 3D culture technique using hydrogel embedding to capture kidney morphogenesis in real time. 3D culture better approximates in vivo-like niche spacing and tubule dynamics, as well as branching defects under control conditions and GDNF-RET signaling perturbations. To isolate the effect of material properties on explant development, we apply acrylated hyaluronic acid hydrogels that allow independent tuning of stiffness and adhesion. We find that sufficient stiffness and adhesive ligands are both required to maintain kidney shape. More adhesive hydrogels increase nephrons per ureteric bud (UB) tip while matrix stiffness has a "Goldilocks effect" centered at ~2 kPa. Our technique captures large-scale, in vivo-like tissue morphogenesis in 3D, improving insight into congenital disease phenotypes. Moreover, understanding the impact of boundary condition mechanics on kidney development benefits fundamental research and renal engineering.
    DOI:  https://doi.org/10.1038/s41467-025-63197-5
  9. Small. 2025 Aug 25. e05240
    Bicyclic-Guanidinium Benzenesulfonate: A Fingerprint Monomer for Self-Recognizably Recyclable Polyester with Antibacterial Performance.
    Li-Xia Fan, Lin Chen, Bei-Bei Zhang, Fang Wang, Shimei Xu, Xiu-Li Wang, Yu-Zhong Wang.
      The increasing complexity of waste mixed polymer materials requires an innovative strategy for the precise recognition and recycling of each type materials. Inspired by biometric self-recognition technologies, the study proposes a "fingerprint monomer" concept to endow polymers with self-recognizable recyclability in mixed wastes. Targeting poly(ethylene terephthalate) (PET, the most produced polycondensation polymer), a bicyclic-guanidinium benzenesulfonate (GS) fingerprint monomer is customized and chemically integrated into PET chain to synthesize PET-GS polyester. This novel PET-GS polyester combines high-value antibacterial activity during service stage and self-recognizable recyclability in mixed polymers at end-of-life. It is found for the first time that the bicyclic-guanidinium cation of the GS fingerprint unit can bind to the anion on the bacterial surface, thereby effectively destroying the bacterial structure and achieving a >99.9% antibacterial rate for PET-GS polyester. More interestingly, the GS fingerprint unit triggers the precise self-recognizable recycling of PET-GS polyester in mixed plastics and even in the same type of PET fibers through hydrogen bonding with nucleophiles, while other polymer materials remain unchanged for easy separation. Therefore, this work pioneers sustainable polymer material with high-value functionality and built-in precise recyclability, striving toward a sustainable and zero-waste circular economy.
    Keywords:  anti‐bacteria; chemical recycling; plastic waste; polyester; self‐recognition
    DOI:  https://doi.org/10.1002/smll.202505240
  10. Nat Chem Biol. 2025 Sep;21(9): 1317-1329
    Strategies and applications of synthetic cell communication.
    Hossein Moghimianavval, Charlie Newell, Parsa Parvizian, Michael J Booth, Allen P Liu.
      Cell signaling and communication are fundamental to living cellular communities. Over the past two decades, there has been a continuous development of bottom-up engineered synthetic cells, which have become increasingly similar to their natural counterparts. However, we are only scratching the surface with the development of synthetic cellular communities and their integration into natural tissues. Here we review different intercellular communication mechanisms engineered for synthetic cells and classify them based on their resemblance to natural cell signaling mechanisms-autocrine, paracrine and juxtacrine. In particular, we highlight recent advances in molecular tools for intercellular communication strategies and discuss potential applications of engineering synthetic cellular communities and synthetic cell-natural cell communication. With further advances in this area, synthetic cellular communities will be powerful tools for understanding and manipulating cellular functions, thus unlocking potential applications in biosensing, cellular reprogramming and sustainability.
    DOI:  https://doi.org/10.1038/s41589-025-02002-2
  11. Biomacromolecules. 2025 Aug 20.
    Viscoelasticity of Fibrous Hydrogels Driven by Dynamic Intrafibrillar Imine Cross-Linking.
    Zheyuan Miao, Zhengkun Chen, Elizaveta Gusarova, Yingshan Ma, Eugenia Kumacheva.
      Viscoelasticity of biological fibrous networks impacts cell fates and may reflect pathological conditions in vivo. Imine-cross-linked fibrous hydrogels can serve as effective in vitro models for studying viscoelastic properties of biological tissues; however, the specific role of intrafibrillar dynamic covalent bonds in governing hydrogel elasticity and stress relaxation remains unexplored. Here, for fibrous hydrogels derived from cellulose nanocrystals and polyethylene glycol, we systematically varied the content of intrafibrillar imine cross-links to explore their impact on hydrogels' elastic response, stress relaxation, and fibrous structure. We showed that higher imine group contents resulted in greater elastic moduli and higher degrees of stress relaxation in fibrous hydrogels. The fibrous structure did not significantly change with varying imine group contents, which enabled the decoupling of changes in hydrogel morphology and viscoelastic properties. This work provides the capability of designing fibrous hydrogels with controlled viscoelasticity and exploring their roles in bioengineering.
    DOI:  https://doi.org/10.1021/acs.biomac.5c01337
  12. Nat Commun. 2025 Aug 23. 16(1): 7871
    Reversible biobased adhesives enable closed-loop engineered composites.
    Jin Lv, Daxin Zhang, Xinkai Li, Yinggang Miao, Yuyan Wang, Ying Wang, Xinxing Zhang.
      Ubiquitous synthetic resin adhesives based on petrochemical brings environmental burdens and health concerns. Many researchers have been focused on developing biomass-derived alternatives, and reported many strong-adhesion products with high cohesive density. However, the stabilized structure-dependent adhesion contributes to greater difficulty in recycling, especially hetero-layered composites. Here, a supramolecularly connected nanoconfined network strategy is proposed for ultra-strong yet switchable biobased adhesives, where cellulose nanoconfinement phases takes up 36.5-46.3 wt%. Dependent on thermally responsive disulfide bond, resulting adhesives achieve both excellent adhesion strength (6.02 MPa) that can support a 65 kg weight with 4 cm2, and instant thermo-responsive detachment with a high switching ratio over 600 (debonding adhesion ≈0 MPa, response time ≤ 10 s). Under the alternating temperature, adhesive-based composites can be disassembled into different categories and fully recycled through the destruction of dynamic crosslinked network. The full life cycle impact assessment shows this strategy is able to avoid the inherent environmental (about 7.52 * 102 PAF m3 d/kgemitted) and health (about 2.04 * 10-4 cases/kgemitted) burden. This work establishes a paradigm for closed-loop engineered composites by the substantive breakthrough of green intelligent adhesives, providing ways to alleviate environmental stress.
    DOI:  https://doi.org/10.1038/s41467-025-62917-1
  13. J Biol Chem. 2025 Aug 18. pii: S0021-9258(25)02453-6. [Epub ahead of print] 110602
    Class I histone deacetylases catalyze lysine lactylation.
    Michelangelo B Gonzatti, Jordi C J Hintzen, Isha Sharma, Mohd Altaf Najar, Takeshi Tsusaka, Mariola M Marcinkiewicz, Claudia Veronica Da Silva Crispim, Nathaniel W Snyder, George M Burslem, Emily L Goldberg.
      Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the ε-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, a reactive intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine β-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDACs are sufficient to catalyze Kla formation and that HDACs are a major driver of lysine lactylation. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.
    Keywords:  glycolysis; histone deacetylase (HDAC); lactate; lactic acid; lysine lactylation; macrophage; post-translational modification (PTM); protein acylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110602
  14. Adv Mater Interfaces. 2025 Jan 05.
    Aqueous Synthesis of Poly(ethylene glycol)-amide-Norbornene-Carboxylate for Modular Hydrogel Crosslinking.
    Nathan H Dimmitt, Chien-Chi Lin.
      Poly(ethylene glycol)-norbornene (e.g., PEGNB) is a versatile macromer amenable to step-growth thiol-norbornene photopolymerization and inverse electron demand Diels-Alder (iEDDA) click reaction. The translational potentials of PEGNB-based hydrogels have been realized in the areas of stem cell differentiation, in vitro disease modeling, implantable therapeutic devices, and controlled release of therapeutics. Even with these advances, prior methods for synthesizing PEGNB all required heavy use of organic solvents that pose significant environmental and personal health burdens. Here, we report an all-aqueous synthesis of PEG-amide-norbornene-carboxylate (PEGaNBCA) via reacting carbic anhydride (CA) with multi-arm amino-terminated PEG. Like previously reported ester-bearing counterparts (i.e., PEGNB and PEGeNBCA), PEGaNBCA was readily crosslinked into modular hydrogels by either thiol-norbornene photopolymerization or tetrazine-norbornene iEDDA click reaction. Unlike its ester-bearing counterparts, PEGaNBCA crosslinked thiol-norbornene hydrogels provided long-term hydrolytic stability. However, through blending PEGaNBCA with hydrolytically labile PEGeNBCA, hydrogels could be engineered to undergo tunable hydrolytic degradation. The versatility of PEGaNBCA was further demonstrated via high-fidelity digital light processing (DLP) printing and in situ encapsulation and maintenance of human induced pluripotent stem cells (hiPSCs).
    DOI:  https://doi.org/10.1002/admi.202400952
  15. ACS Appl Mater Interfaces. 2025 Aug 27.
    Designing Protein-Based Nanoparticles for Therapeutic Applications.
    Jian Cui, Keqing Wang, Zheyu Wu, Wei Sun, Tian Gao, Xiaochen Shen, Wei Wang, Yi Cao, Bin Xue.
      Protein-based nanoparticles (PNPs) represent a versatile and promising class of nanocarriers for biomedical applications, offering inherent biocompatibility, biodegradability, and functional adaptability. By leveraging the diverse structural and chemical characteristics of natural and engineered proteins, certain PNP systems have demonstrated the potential to achieve precise control over drug loading, release kinetics, and targeting under specific design strategies, making them attractive platforms for therapeutic and diagnostic delivery. In this review, we aim to provide a comprehensive understanding of the design of protein-based nanoparticles and their clinical translation by conducting an in-depth analysis of recent studies on protein nanoparticles, in conjunction with protein-related formulations approved by the FDA in the past five years. We outline the biological rationale for their use and examine key challenges─including stability, immunogenicity, and manufacturing scalability─that impact their clinical translation. Design strategies such as surface modification, ligand targeting, modularity, stimuli-responsive engineering, and computational approaches are highlighted for their role in overcoming these barriers and enhancing performance. We further explore applications across neurological disorders, cancer, infectious diseases, and diagnostics, illustrating the broad potential of these systems. Finally, we provide an in-depth analysis of the clinical landscape and manufacturing challenges of protein-based therapeutics, highlighting the potential of emerging in vivo gene and protein editing technologies to accelerate the development of innovative protein drugs with the aim of facilitating the clinical translation of PNPs. By synthesizing insights from materials science, biology, and medicine, this Perspective aims to guide the rational design of next-generation PNPs for effective and personalized healthcare solutions.
    Keywords:  clinical translation; design strategy; nanocarrier; protein-based nanoparticles; therapeutic delivery
    DOI:  https://doi.org/10.1021/acsami.5c10918
  16. ACS Appl Bio Mater. 2025 Aug 25.
    Development of a Hydrogel Platform with GBM and Microglia: A Potential Glioblastoma Tumor Model.
    Seyma Isik, Deniz Yucel, Vasif Hasirci.
      Glioblastoma (GBM) is an aggressive brain tumor with a complex microenvironment shaped by a dense extracellular matrix (ECM) and dynamic interactions with stromal cells, presenting major challenges for in vitro modeling. In this study, we developed a biomimetic hydrogel platform by integrating a brain-derived decellularized extracellular matrix (dECM) with hyaluronic acid methacrylate (HAMA), yielding a composite (1H3D) that closely reflects the ECM characteristics of GBM tissue. Mechanically, 1H3D hydrogels exhibited a compressive modulus of 9.44 ± 0.73 kPa and an elastic modulus of 458.30 ± 13.39 Pa, resembling native GBM tissue. By retaining biochemical components from the brain dECM, hydrogels support key cellular processes such as adhesion, matrix remodeling, and invasion. These functions are essential for mimicking the highly invasive, plastic, and adaptive behavior of glioblastoma, thereby enhancing the physiological relevance of the in vitro platform. Coculture with microglia promoted glioblastoma progression, as evidenced by a 43% increase in Ki-67 expression and a 41% increase in invasion distance, underscoring the protumoral role of microglia-glioblastoma interactions within the engineered microenvironment. Altogether, integration of a GBM relevant hydrogel matrix with microglia coculture provides a biologically and mechanically representative in vitro platform that reproduces key features of tumor-stroma interactions, offering a useful tool for studying glioblastoma progression and enhancing the translational potential of preclinical models.
    Keywords:  Glioblastoma; brain decellularized ECM; hyaluronic acid methacrylate; in vitro model; tissue engineering
    DOI:  https://doi.org/10.1021/acsabm.5c00735
  17. ACS Appl Mater Interfaces. 2025 Aug 27.
    Glycosyl Radicals Induced Ultrafast and Homogeneous Gelation for Mechanically Robust Hydrogels.
    Rong Shi, Shengming Yang, Shiyang Xu, Dawen Niu, Yi Wang, Jinrong Wu.
      Rapid gelation remains essential in maintaining uniform network structures and mechanical properties under mild conditions. Here, we report a strategy based on a glycosyl radical to achieve rapid gelation within tens of seconds. Mechanistically, glycosyl sulfinates serve as efficient precursors to glycosyl radicals upon treatment with potassium persulfate (KPS) through a single-electron transfer process. The following polymerization process exhibits a gentle increase in exotherms and viscosity, which promotes the homogeneity of the polymer network. Glycosyl units are partially incorporated into polymer chains as hydroxyl-rich termini with the remainder freely dispersed throughout the hydrogel matrix, both forming extensive dynamic hydrogen bonds with polymer backbones. Consequently, the hydrogels exhibit exceptional mechanical performance, including high strength, toughness, elasticity, and fatigue resistance. This robust method is compatible with various vinyl monomers, glycosyl sulfinate derivatives, and even harsh environmental conditions. As a proof-of-concept application, the precursor solution can rapidly form uniform gel films via controlled spraying, highlighting potential applications in flexible electronics, wearable sensors, and biomedical dressings.
    Keywords:  dynamic hydrogen bonding; glycosyl radicals; homogeneous network; redox reaction; sprayable hydrogel; ultrafast gelation hydrogel
    DOI:  https://doi.org/10.1021/acsami.5c13110
  18. Biomacromolecules. 2025 Aug 25.
    RNA-Polymer Conjugates via Direct Incorporation of the Chain Transfer Agent and PET-RAFT Polymerization.
    Xiaolei Hu, Jaepil Jeong, Hironobu Murata, Rongguan Yin, Subha R Das, Krzysztof Matyjaszewski.
      Covalent conjugation of RNA with synthetic polymers has emerged as a powerful approach for creating bioconjugates with synergistically enhanced properties. However, conventional methods require solid-phase synthesis to preinstall functional groups in RNA, significantly limiting practical applications. Here, we present a novel approach for synthesizing RNA-polymer conjugates via direct incorporation of chain transfer agent (CTA) into RNA through acylation chemistry and reversible addition-fragmentation chain transfer (RAFT) polymerization. A CTA-functionalized acyl imidazole reagent was synthesized to facilitate direct and covalent modification of various RNAs by reacting with their 2'-hydroxyl groups. Subsequent RAFT polymerization using RNA-CTA as a macro-CTA enabled direct grafting-from RNA, yielding RNA conjugates with controlled molecular weight and low dispersity. Notably, this postsynthetic modification strategy was successfully extended to modify biomass RNA, yielding thermoresponsive conjugates and biodegradable hydrogels. Overall, this advance allowed for the direct modification of synthetic and biomass RNAs, significantly enhancing the accessibility of functional RNA-polymer materials.
    DOI:  https://doi.org/10.1021/acs.biomac.5c00838
  19. Biomacromolecules. 2025 Aug 21.
    Rational Design of Thermoresponsive Elastin-Like Protein Monolayers for Nonenzymatic Cell Harvesting.
    Adam Quintana, Linying Li, Ashutosh Chilkoti, Gabriel P López, Nick J Carroll.
      A combined theoretical and experimental investigation presents a consistent parabolic potential model for the prediction and optimization of mammalian cell adhesion and detachment from genetically engineered thermoresponsive elastin-like protein (ELP) modified surfaces. Linear ELP chains concatenated with both thiol-gold surface-binding and RGD cell-binding domains serve as thermally responsive cell harvesting surfaces. This architecture of a 1:1 ratio of cell binding domain to linear polymer chain provides precise control of the chemical representation of the cell binding and thermoresponsive properties. The parabolic potential model of surface-grafted phase-separating polymers describing the ELP brush films, combined with surface-bound cell culture measurements, is used to analyze the effects of protein chain length N and surface area per chain σ. The cell binding fractions allow the calculation of system free energies, which are consistent with the parabolic potential model through identification of the underlying polymer lengths. This offers the ability for the model to identify optimal conditions that promote cell attachment and detachment. This model represents a quantitative framework for optimizing surface grafted protein layer thickness and cell displacement energy, which is a crucial technical step forward for programming of thermoresponsive biopolymer substrates for nonenzymatic cell harvesting.
    DOI:  https://doi.org/10.1021/acs.biomac.5c00861
  20. RSC Chem Biol. 2025 Aug 27. 6(9): 1364-1365
    Introduction to "Biomolecular Technologies".
    Sheel C Dodani, Ariel Furst.
      As both chemical and biological engineering approaches continue to expand, the landscape of biomolecular technologies is rapidly evolving, affording new opportunities from basic science to real-world applications. This themed collection brings together engineered biomolecule-based technologies spanning small molecules, nucleic acids, and proteins, with applications in biocatalysis, biosensing, and synthetic biology. Each study showcases the modular and tunable nature of biomolecular design to tailor properties for function in both aqueous solutions and biological environments, as summarized below.
    DOI:  https://doi.org/10.1039/d5cb90031j
  21. ACS Chem Biol. 2025 Aug 26.
    Split-Small GTPase Reassembly as a Method to Control Cellular Signaling with User-Defined Inputs.
    Yuchen He, Benjamin M Faulkner, Rachel S Weatherford, Emily Hyun, Cliff I Stains.
      Small GTPases are critical signaling enzymes that control diverse cellular functions, such as cell migration and proliferation. However, dissecting the roles of these enzymes in cellular signaling is hindered by the lack of a plug-and-play methodology for the direct, temporal control of small GTPase activity by using user-defined inputs. Herein, we present a method that pairs split-small GTPases with user-defined chemical inducer of dimerization (CID) systems in a plug-and-play manner to directly control small GTPase signaling in living cells. The modularity of split-small GTPase systems allows for the selection of CIDs with minimal off-target effects on the pathway being studied. Our results highlight the ability to obtain consistent pathway activation with varying CID systems for direct control of MAPK signaling, filopodia formation, and cell retraction. Thus, split-small GTPase systems provide a customizable platform for the development of temporally gated systems for directly controlling cellular signaling with user-defined inputs.
    DOI:  https://doi.org/10.1021/acschembio.5c00083
  22. Nat Commun. 2025 Aug 20. 16(1): 7767
    Microscopic geared metamachines.
    Gan Wang, Marcel Rey, Antonio Ciarlo, Mahdi Shanei, Kunli Xiong, Giuseppe Pesce, Mikael Käll, Giovanni Volpe.
      The miniaturization of mechanical machines is critical for advancing nanotechnology and reducing device footprints. Traditional efforts to downsize gears and micromotors have faced limitations at around 0.1 mm for over thirty years due to the complexities of constructing drives and coupling systems at such scales. Here, we present an alternative approach utilizing optical metasurfaces to locally drive microscopic machines, which can then be fabricated using standard lithography techniques and seamlessly integrated on the chip, achieving sizes down to tens of micrometers with movements precise to the sub-micrometer scale. As a proof of principle, we demonstrate the construction of microscopic gear trains powered by a single driving gear with a metasurface activated by a plane light wave. Additionally, we develop a versatile pinion and rack micromachine capable of transducing rotational motion, performing periodic motion, and controlling microscopic mirrors for light deflection. Our on-chip fabrication process allows for straightforward parallelization and integration. Using light as a widely available and easily controllable energy source, these miniaturized metamachines offer precise control and movement, unlocking new possibilities for micro- and nanoscale systems.
    DOI:  https://doi.org/10.1038/s41467-025-62869-6
  23. Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2514826122
    Multistep catalytic abiotic CO2 conversion to sugars through C1 intermediates.
    Nathan Soland, Jie Luo, Arifin Luthfi Maulana, Julian Feijoo, Hye-Jin Jo, Alexander M Oddo, Yu Shan, Tianle Wang, Geonhui Lee, Jihoon Choi, Wei-Shan Huynh, Maria Fonseca Guzman, Lihini Jayasinghe, Cheng Zhu, Yao Yang, Peidong Yang.
      Carbon dioxide (CO2) to multicarbon (Cn) upgrading for commodity chemicals, fuel production, or artificial food synthesis using renewable energy input is a golden target for researchers in sustainable carbon emission reduction. Here, we explore and analyze a flexible modular roadmap for the task, utilizing sequential electro-, photo-, and organocatalysis to develop a strategy for CO2 conversion using the key and elusive formaldehyde precursor of interest for sugar generation. We study the electrochemical carbon dioxide reduction reaction to methanol in a flow cell and its discontinuous photooxidation to formaldehyde (PMOR) with excellent selectivity. Utilizing a highly active N-heterocyclic carbene catalyst enables tunable generation of C4-C6 aldoses without undesirable byproducts, with carbon conversion yield reaching 60 to 80% for desired pentose, tetrose, and triose product mixtures and over 20% for hexose. This approach presents a roadmap for CO2 valorization, aiming to bridge carbon waste streams with sustainable sugar synthesis and opening broad avenues for green chemical production.
    Keywords:  CO2 conversion; electrocatalysis; photocatalysis; sugar synthesis
    DOI:  https://doi.org/10.1073/pnas.2514826122
  24. ACS Biomater Sci Eng. 2025 Aug 23.
    Cyclic Stretch Bioreactor Enhances Tenogenic Differentiation of MSCs in Biomimicked PCL-tdECM Membranes through Dynamic Mechanical Loading.
    Amrutha Datla, Akshay Bhatt, Aakanksha Ruhela, Chandra Shekhar Sharma, Subha Narayan Rath.
      Tendon injuries are widespread, often leading to tendinopathy due to a lack of early recognition, resulting in discomfort and reduced mobility. Despite their mechanically active nature, tendons possess limited self-healing capacity, and current clinical interventions fall short in fully regenerating the tendon structure. To address this challenge, we propose an in vitro model to study disease progression and develop an effective tissue regeneration strategy. Here, we show that an electrospun bioactive polymeric membrane comprising poly(ε-caprolactone) (PCL) and goat tendon decellularized extracellular matrix (tdECM) is an ideal polymer-tdECM complex to increase strength and provide native tendon tissue biomolecules crucial for its development. Culturing these membranes with umbilical cord mesenchymal stem cells (uMSCs) under mechanical stimulation in a bioreactor mimics native tissue conditions, which are essential for effective tendon regeneration. The study demonstrates a tissue engineering approach combining dynamic mechanical cues from a bioreactor and biochemical cues from tdECM to induce tenogenesis in uMSCs. Biological results indicate that membranes are biocompatible, and optimal membrane strength and stiffness are retained after 14 days of culture. Furthermore, qPCR and immunofluorescence studies have shown an increase in the number of tenogenic markers in response to biomechanical cues. The synergy between PCL and tdECM presents promising prospects for advancing tendon tissue engineering.
    Keywords:  bioreactor; electrospinning; mechanotransduction; tendon decellularized extracellular matrix; tendon tissue engineering; tenogenesis
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c02145
  25. Trends Biotechnol. 2025 Aug 19. pii: S0167-7799(25)00319-1. [Epub ahead of print]
    Improved provenance tracking by documenting plasmids within their own sequence.
    Chris J Myers.
      In a recent article, Hernandez et al. introduced a framework for plasmid self-documentation. It uses the data storage capabilities of the DNA of a plasmid to capture either direct documentation or a reference to full documentation. The approach is robust and experimentally verified to both write information to, and read information from, the plasmid of interest.
    DOI:  https://doi.org/10.1016/j.tibtech.2025.08.001
  26. Adv Mater. 2025 Aug 21. e12879
    One-Step Coordinated Multi-Kinetic 4D Printing of Human Vascularized Cardiac Tissues with Selective Fast-Shrinking Capillaries.
    Ester Sapir Baruch, Roni Cohen, Eric Silberman, Michael Namestnikov, Itai Cabilly, Assaf Shapira, Tal Dvir.
      The field of 3D bioprinting has made substantial progress in recent years, enabling the fabrication of vascular networks within engineered tissues to support the efficient transfer of oxygen and nutrients. However, a critical limitation remains: the restricted resolution of cell-laden bioink hydrogels, which impedes the precise formation of microscale structures such as capillaries. In this study, a novel, sequential, one-step bioprinting approach is introduced that enables the deposition of multiple cell-laden bioinks, facilitating the fabrication of functional, complex cardiac tissues with hierarchical microvasculature. Remarkably, this strategy enables pre-designed blood vessels to undergo selective shrinkage to capillary-scale dimensions within the parenchymal tissue under physiological conditions. Engineered cardiac tissues with perfusable, endothelialized vascular networks exhibit robust contractile function, and in vivo implantation demonstrate successful anastomosis of the vasculature with the host. This bioprinting strategy represents a significant advancement in the engineering of physiologically relevant tissue architectures, paving the way for the development of functional organotypic constructs for regenerative medicine and transplantation.
    Keywords:  4D printing; biomaterials; engineered cardiac tissue; stem cells; vascularization
    DOI:  https://doi.org/10.1002/adma.202512879
  27. ACS Synth Biol. 2025 Aug 22.
    Challenges and Opportunities in Smart Biosensing for Biomanufacturing.
    Mara Pisani, Pablo Carbonell.
      Traditional metabolic engineering has largely focused on the direct construction of synthetic metabolic pathways, often overlooking the critical role of regulation. In contrast, natural metabolic pathways are inherently tightly regulated, enabling robust performance in dynamic environments. Dynamic regulation of synthetic metabolic pathways enhances the reliability of cell factories by improving their performance and ensuring greater robustness, scalability, and stability. Therefore, modern approaches to metabolic engineering should embrace genetic circuits that incorporate dynamic regulatory mechanisms. Biosensors, as key components of these circuits, not only enable precise genetic regulation but also provide real-time monitoring and external interfacing capabilities with diverse signal modalities, including electrical and optical systems. By the incorporation of dynamic control mechanisms, synthetic pathways can be rendered more robust to environmental fluctuations during scale-up and more precisely regulated in therapeutic contexts, such as responsive drug delivery. These capabilities are critical to advancing the reliability and applicability of engineered metabolic systems. Furthermore, the potential for the external control of synthetic metabolic processes, guided by advanced algorithms, underscores the growing importance of machine learning and data-driven approaches. This perspective highlights the necessity of integrating regulation into synthetic pathways and leveraging biosensors to drive the next generation of scalable and adaptive metabolic engineering solutions.
    Keywords:  biosensor; computer-in-the-loop; dynamic regulation; high-throughput screening
    DOI:  https://doi.org/10.1021/acssynbio.5c00203
  28. Nat Commun. 2025 Aug 26. 16(1): 7948
    Programmable epigenome editing by transient delivery of CRISPR epigenome editor ribonucleoproteins.
    Da Xu, Swen Besselink, Gokul N Ramadoss, Philip H Dierks, Justin P Lubin, Rithu K Pattali, Jinna I Brim, Anna E Christenson, Peter J Colias, Izaiah J Ornelas, Carolyn D Nguyen, Sarah E Chasins, Bruce R Conklin, James K Nuñez.
      Programmable epigenome editors modify gene expression in mammalian cells by altering the local chromatin environment at target loci without inducing DNA breaks. However, the large size of CRISPR-based epigenome editors poses a challenge to their broad use in biomedical research and as future therapies. Here, we present Robust ENveloped Delivery of Epigenome-editor Ribonucleoproteins (RENDER) for transiently delivering programmable epigenetic repressors (CRISPRi, DNMT3A-3L-dCas9, CRISPRoff) and activator (TET1-dCas9) as ribonucleoprotein complexes into human cells to modulate gene expression. After rational engineering, we show that RENDER induces durable epigenetic silencing of endogenous genes across various human cell types, including primary T cells. Additionally, we apply RENDER to epigenetically repress endogenous genes in human stem cell-derived neurons, including the reduction of the neurodegenerative disease associated V337M-mutated Tau protein. Together, our RENDER platform advances the delivery of CRISPR-based epigenome editors into human cells, broadening the use of epigenome editing in fundamental research and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-025-63167-x
  29. iScience. 2025 Sep 19. 28(9): 113234
    Impact of 3D cell culture hydrogels derived from basement membrane extracts or nanofibrillar cellulose on CAR-T cell activation.
    Sonia Aristin Revilla, Alessandro Cutilli, Eugenia Cambiaso, Dedeke Rockx-Brouwer, Cynthia Lisanne Frederiks, Marc Falandt, Riccardo Levato, Onno Kranenburg, Caroline A Lindemans, Paul James Coffer, Victor Peperzak, Enric Mocholi, Marta Cuenca.
      Hydrogel-based 3D culture systems are increasingly used for preclinical evaluation of cell-based immunotherapies, including chimeric antigen receptor T (CAR-T) cells. However, hydrogel properties can influence T cell behavior, potentially affecting interpretation of immunotherapy studies. We assessed CD4+ T and CAR-T cell responses in two chemically undefined matrices-Matrigel and basement membrane extract (BME)- and in a synthetic nanofibrillar cellulose (NFC) hydrogel. Although NFC was mechanically stiffer, T cell activation and proliferation were higher in NFC than in Matrigel or BME. Murine CD4+ T cells acquired a regulatory phenotype in Matrigel and BME but not in NFC. Similarly, CAR-T cell function was reduced in Matrigel and BME but maintained in NFC. These findings underscore how matrix composition can shape T cell responses in 3D culture. NFC provides a chemically defined alternative that preserves T cell activity, supporting its use in more accurate preclinical testing of immunotherapies.
    Keywords:  Biological sciences; Biomaterials; Cell biology; Immune response; Materials science
    DOI:  https://doi.org/10.1016/j.isci.2025.113234
  30. iScience. 2025 Sep 19. 28(9): 113217
    Focusing plastic solutions up the waste hierarchy: Pathways for a more circular economy.
    Kathryn A Willis, Murray Richards, Britta Denise Hardesty.
      Plastic pollution requires urgent global action, including continued Global Plastics Treaty negotiations. A systems change approach is essential, with growing momentum for a plastics circular economy that emphasizes recycling and bio-based plastics derived from vegetable and algae oils. Focusing on downstream solutions and alternative materials presents three challenges: (1) New materials introduce complexity that complicate waste sorting and management; (2) the potential implications of bio-based plastics not reducing overall demand on single-use packaging consumption; and (3) the lost art of repairing plastic and non-plastic products such as clothing, or electronic devices, which exacerbates waste generation. These challenges can be addressed by reducing plastic consumption; improving product design for better recyclability; incorporating reuse, refill, and redesign systems in current practices; and emphasizing regulatory changes that support a repair culture. Ultimately, we argue that a comprehensive approach is essential to mitigate plastic pollution effectively, requiring collaboration across sectors to drive systemic change.
    Keywords:  Engineering; Environmental policy; Environmental science
    DOI:  https://doi.org/10.1016/j.isci.2025.113217
  31. Nat Commun. 2025 Aug 25. 16(1): 7931
    Probiotic acoustic biosensors for noninvasive imaging of gut inflammation.
    Marjorie T Buss, Lian Zhu, Jamie H Kwon, Jeffrey J Tabor, Mikhail G Shapiro.
      Inflammatory bowel diseases (IBD) affect millions of people globally, result in severe symptoms, and are difficult to diagnose and monitor - often necessitating the use of invasive and costly methods such as colonoscopies or endoscopies. Engineered gut bacteria offer a promising alternative due to their ability to persist in the gastrointestinal (GI) tract and sense and respond to specific environmental signals. However, probiotics that have previously been engineered to report on inflammatory and other disease biomarkers in the Gl tract rely on fluorescent or bioluminescent reporters, whose signals cannot be resolved in situ due to the poor penetration of light in tissue, or on colorimetric reporters which rely on plating feces. To overcome this limitation, we introduce probiotic biosensors that can be imaged in situ using ultrasound - a widely available, inexpensive imaging modality providing sub-mm spatial resolution deep inside the body. These biosensors are based on the clinically approved probiotic bacterium E. coli Nissle, which we engineered to transiently colonize the GI tract, sense inflammatory biomarkers, and respond by expressing air-filled sound-scattering protein nanostructures called gas vesicles. After optimizing biomolecular signaling circuits to respond sensitively to the biomarkers thiosulfate and tetrathionate and produce strong and stable ultrasound contrast, we validated our living biosensors in vivo by noninvasively imaging antibiotic-induced inflammation in mice. By connecting cell-based diagnostic agents to ultrasound, these probiotic biosensors will potentially make it easier and cheaper to diagnose and monitor IBD or other GI conditions.
    DOI:  https://doi.org/10.1038/s41467-025-62569-1
  32. Sci Adv. 2025 Aug 29. 11(35): eadv7892
    BioFuse: A programmable timer switch of gene expression.
    Cheng Huang, Jie Zhao, Zichun Tan, Shang Dai, Binqiang Wang, Zhenming Xie, Furong Zhang, Yulong Zhou, Ning Yu, Chunhui Cai, Yonghua Yao, Baojun Wang, Bing Tian.
      Current gene circuits designed to time gene expression depend on the intricate interactions among various regulators and their targets, which confines them to a limited range of temporal tunability. Here, we report a programmable timer switch of gene expression termed BioFuse, which allows the reaction time ranging from hours to days. BioFuse comprises a series of fuse-like tandem DNA cassettes that can be sequentially edited by the adenine base editors (ABEs), resulting in either the activation or deactivation of a downstream gene once the editing is complete. Adjusting the number of DNA cassettes incorporated allows precise programming of BioFuse's reaction time. Applying BioFuse to control carotenoid biosynthesis genes decouples lycopene production from growth in E. coli and increases lycopene yield without external inducers. Using BioFuse in a bacterial autolysis system enables timely and efficient protein release. BioFuse offers a versatile tool for precise, wide-range timing of gene expression and metabolic activities in bacteria, with potential applications in industry and biomedicine.
    DOI:  https://doi.org/10.1126/sciadv.adv7892
  33. Science. 2025 Aug 21. eadr8785
    Mapping early human blood cell differentiation using single-cell proteomics and transcriptomics.
    Benjamin Furtwängler, Nil Üresin, Sabrina Richter, Mikkel Bruhn Schuster, Despoina Barmpouri, Henrietta Holze, Anne Wenzel, Kirsten Grønbæk, Kim Theilgaard-Mönch, Fabian J Theis, Erwin M Schoof, Bo T Porse.
      Single-cell transcriptomics (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of mRNA measurements comes at the risk of missing important biological information. Here we leveraged recent technological advances in single-cell proteomics by Mass Spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing over 2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins that are important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multi-omics studies across biological systems.
    DOI:  https://doi.org/10.1126/science.adr8785
  34. Angew Chem Int Ed Engl. 2025 Aug 25. e202513613
    Engineering Energy Dissipation Pathway via Topological Design: Toward Tunable Macroscopic Mechanical Performances of Dynamic Polymer Networks.
    Shaolei Qu, Guoquan Liu, Yuhang Liu, Mengling Yang, Li Yang, Jingxi Deng, Ruixue Bai, Chunyu Wang, Yuanhao Wang, Yi Ding, Wei You, Wei Yu, Xuzhou Yan, Zhaoming Zhang.
      The incorporation of multiple supramolecular interactions as sacrificial bonds for energy dissipation has emerged as a powerful strategy to enhance the mechanical properties of elastomeric materials. However, precise control over energy dissipation pathways remains challenging, primarily due to the difficulty in selectively activating specific interactions on demand. Herein, we present an orthogonal self-assembly strategy that integrates host-guest recognition and metal-coordination to tailor energy dissipation mechanisms. We demonstrate that subtle modifications at the axial terminals of host-guest motifs dictate the formation of supramolecular polymer networks (SPNs) or mechanically interlocked networks (MINs), respectively. Upon external force, SPNs dissipate energy primarily through host‒guest dissociation, while coordination bonds remain intact. In contrast, in MINs, force transmission from the host to the axial stoppers following host‒guest dissociation leads to the rupture of metal-coordination bonds, enabling additional dissipate energy. This fundamental divergence in energy dissipation pathways results in superior mechanical performance in MIN-2, with higher strength (19.1 versus 14.5 MPa), toughness (57.7 versus 45.9 MJ m-3), and puncture resistance compared to SPN-2. These findings highlight the potential of topological structure design in precisely tuning energy dissipation pathways, offering a robust and versatile strategy for developing high-performance supramolecular elastomers.
    Keywords:  Dynamic supramolecular materials; Energy dissipation pathway; Mechanically interlocked networks; Orthogonal self‐assembly; Topological design
    DOI:  https://doi.org/10.1002/anie.202513613
  35. Nature. 2025 Aug 20.
    Feeding bees with engineered yeast combats colony decline.
      
    Keywords:  Agriculture; Biotechnology; Zoology
    DOI:  https://doi.org/10.1038/d41586-025-02600-z
  36. Cell. 2025 Aug 19. pii: S0092-8674(25)00915-8. [Epub ahead of print]
    Uncovering phenotypic inheritance from single cells with Microcolony-seq.
    Raya Faigenbaum-Romm, Noam Yedidi, Orit Gefen, Naama Katsowich-Nagar, Lior Aroeti, Irine Ronin, Maskit Bar-Meir, Ilan Rosenshine, Nathalie Q Balaban.
      Uncovering phenotypic heterogeneity is fundamental to understanding processes such as development and stress responses. Due to the low mRNA abundance in single bacteria, determining biologically relevant heterogeneity remains a challenge. Using Microcolony-seq, a methodology that captures inherited heterogeneity by analyzing microcolonies originating from single bacterial cells, we uncover the ubiquitous ability of bacteria to maintain long-term inheritance of the host environment. Notably, we observe that growth to stationary phase erases the epigenetic inheritance. By leveraging this memory within each microcolony, Microcolony-seq combines bulk RNA sequencing (RNA-seq) with whole-genome sequencing and phenotypic assays to detect the distinct subpopulations and their fitness advantages. Applying this directly to infected human samples enables us to uncover a wealth of diverse inherited phenotypes. Our observations suggest that bacterial memory may be a widespread phenomenon in both Gram-negative and Gram-positive bacteria. Microcolony-seq provides potential targets for the rational design of therapies with the power to simultaneously target the coexisting subpopulations.
    Keywords:  EPEC; S. aureus; UPEC; UTI; adhesion factor; bacterial differentiation; bet-hedging; bloodstream infection; division of labor; epigenetic inheritance; pathogens; single-cell; single-cell heterogeneity; virulence factors
    DOI:  https://doi.org/10.1016/j.cell.2025.08.001
  37. Sci Adv. 2025 Aug 22. 11(34): eady8165
    Designing a DNA synchronizer for compact single-rail DNA logic circuits.
    Chenyun Sun, Zhikun Zhao, Jinyan Zhang, Hui Lv, Haozhi Wang, Haitao Song, Jiabin Wang, Kai Xia, Xiurong Yang, Chunhai Fan, Fei Wang.
      DNA has emerged as a robust platform for engineering molecular circuits with arbitrary logic operations. Nevertheless, implementing DNA circuits for such functions generally relies on the use of dual-rail expression that doubles the number of required gates, constraining the achievable complexity in a single solution. A fundamental limitation is that conventional single-rail circuits cannot support nonfirst-layer NOT operations. Here, we introduce the design of a DNA synchronizer (DSN), a temporal regulation module that enables time-dependent NOT function, to circumvent the fundamental limitation of conventional single-rail designs. Tuning the binding affinity between the DSN strand and an inverter strand allows for regulating the execution time of NOT gates at varying cascade depths. Single-rail NAND and NOR gates are implemented using DSNs, which are Boolean complete. We further demonstrate a 4-bit square root circuit using a minimal set of only five gates. This single-rail architecture holds promise for developing compact yet scalable DNA computing circuits while advancing applications in diagnostics and therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.ady8165
  38. Nat Commun. 2025 Aug 23. 16(1): 7863
    A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
    Abner Gonzalez, Alex Pon, Kelly Servage, Krzysztof Pawłowski, Yan Han, Anju Sreelatha.
      Protein AMPylation, the covalent addition of adenosine monophosphate (AMP) to protein substrates, has been known as a post translational modification for over 50 years. Research in this field is largely underdeveloped due to the lack of tools that enable the systematic identification of AMPylated substrates. Here, we address this gap by developing an enrichment technique to isolate and study AMPylated proteins using a nucleotide-binding protein, hinT. Cryo-EM reconstruction of an AMPylated protein bound to hinT provides a structural basis for AMP selectivity. Using structure guided mutagenesis, we optimize enrichment to identify novel substrates of the evolutionarily conserved AMPylase, Selenoprotein O. We show that mammalian Selenoprotein O regulates metabolic flux through AMPylation of key mitochondrial proteins including glutamate dehydrogenase and pyruvate dehydrogenase. Our findings highlight the broader significance of AMPylation, an emerging post translational modification with critical roles in signal transduction and disease pathology. Furthermore, we establish a powerful enrichment platform for the discovery of novel AMPylated proteins to study the mechanisms and significance of protein AMPylation in cellular function.
    DOI:  https://doi.org/10.1038/s41467-025-63014-z
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