bims-ecemfi 2026-10-25 papers

Nat Commun. 2026 09 21. pii: 11006. [Epub ahead of print]17(1):

Generating protein hydrogels with customizable stress relaxation behavior via deep learning-driven entanglement design.

Puqing Deng, Yutong Wu, Hong Kiu Francis Fok, Linyan Li, Wen-Bin Zhang, Fei Sun, Hanyu Gao.

Protein hydrogels are promising artificial extracellular matrices (ECMs) for 3D stem cell and organoid culture due to their favorable stress relaxation behavior (a decrease in stress in response to strain). Inter-chain entangled motifs, in which different protein chains are interlaced, represent a powerful strategy to synthesize such hydrogels. However, designing these motifs with tailored properties such as binding energy remains a major challenge due to the difficulty of simultaneously controlling these properties while ensuring entanglement. Here, we introduce TangleDiff, a deep learning framework for the de novo design of homodimeric entangled proteins with programmable features. TangleDiff generates diverse foldable entangled sequences with an in-silico success rate exceeding 70%, markedly outperforming current models (~1%). By conditioning TangleDiff on inter-chain binding energy, we generate novel protein dimers whose binding energies closely match the specified ranges, with approximately 70% of successful designs conforming to expected values. We experimentally validate TangleDiff by designing nine homodimers targeting various binding energies; seven successfully form hydrogels, with stress relaxation dynamics correlated with specified binding energies. This work establishes a general strategy for entangled protein design, opening avenues for entanglement-based biomaterial innovation.

DOI: https://doi.org/10.1038/s41467-026-77607-9

Nat Commun. 2026 Sep 23. pii: 11062. [Epub ahead of print]17(1):

A principal-stress rule for cell division in epithelia.

Lucas Anger, Tianxiang Ma, Fanny Wodrascka, Andreas Schoenit, Kristian Thijssen, Satish Kailasam Mani, Marc-Antoine Fardin, Carine Rossé, René-Marc Mège, Amin Doostmohammadi, Benoit Ladoux.

Dense active materials must continuously relieve internal mechanical stress to remain structurally stable as they are driven far from equilibrium. In epithelial tissues, this relief occurs through cell division, where, according to Hertwig's century-old rule, cells divide along their long axis. We show that as epithelia densify, this geometric rule is superseded by a mechanical one: cells divide along the principal axis of anisotropic stress, independently of the isotropic stress state. Using direct force measurements and stress inference, we demonstrate that stress orientation governs division across mechanically distinct systems, from fluid-like to jammed monolayers and structurally heterogeneous organoids, remaining predictive where cell shape fails. This stress-oriented remodeling is reciprocally coupled to the material's mechanical state: anisotropic stress accelerates cell-cycle progression, while division locally dissipates it, closing a negative feedback loop. This "principal-stress rule" provides a general mechanical framework linking internal stress, structural remodeling and homeostasis in living materials.

DOI: https://doi.org/10.1038/s41467-026-77813-5

Matrix Biol. 2026 Oct 22. pii: S0945-053X(26)00109-5. [Epub ahead of print] 102067

Breast cancer cells with decreased fibronectin-integrin adhesion strength attenuate the malignancy of its microenvironment.

Natalia Burday, Gemma Guerrero-Barberà, Asier Jayo, Manuel M Sánchez Del Pino, Elena Ortiz-Zapater, Mercedes Costell.

Fibronectin (FN), a key component of many solid tumors microenvironment, increases their mechanical stiffening and promotes cancer progression and metastasis. We studied Fn1syn/syn;PyMT mice carrying the breast cancer-inducing PyMT oncogene and a Fn1 gene with a nonfunctional synergy site (FNsyn), which impairs the reinforcement of the α5β1 integrin adhesion to the FN-RGD motif. Here, we show that Fn1syn/syn;PyMT mice exhibit delayed tumor onset in the mammary glands and reduced lung metastasis associated with decreased tumor vascularization, reduced cancer cell proliferation and lower abundance of ECM fibrillar proteins within the tumor stroma. Isolated cancer-associated fibroblasts with high αSMA expression levels (H-αSMA CAFs) and tumor cells reveal that FNsyn reduces their response when the substrate stiffness rises. Consequently, Fn1syn/syn CAFs express low αSMA and reduced Lysyl-2 and -3 oxidases leading to the assembly of loose fibrotic ECMs. Moreover, luminal breast cancer cells grown as organoids showed reduced incidence of invasive traits on stiff FNsyn substrates. Importantly, these key alterations were strongly correlated with the phenotypic changes observed in the stroma of Fn1syn/syn;PyMT tumors, contributing to the establishment of a microenvironment characterized by a reduced abundance of immunosuppressive cytokines and an increased infiltration of immune cells. Therapeutic targeting the FN synergy site is sufficient to reprogram the tumor microenvironment toward a less fibrotic and immunoactive state.

Keywords: a5b1 integrins; cancer microenvironment; fibronectin; fibrotic extracellular matrix; mechanosignaling

DOI: https://doi.org/10.1016/j.matbio.2026.102067

Nat Biomed Eng. 2026 Oct 23.

Hydrogel for sustained and localized delivery of a regulatory T cell-inducing agent promotes bone regeneration.

Gabriele Nasello, Nuria Lafuente-Gómez, Leila Krajnovic, David T Wu, Mason T Dacus, Einat B Vitner, Shawn Kang, Emily Roloson, Giovanni Bovone, Liesbet Geris, David J Mooney.

Local activation of regulatory T (Treg) cells represents a promising strategy for wound repair and tissue regeneration. However, current Treg-based therapies rely on adoptive cell transfer, which requires ex vivo expansion and reinfusion, posing challenges to donor variability and tissue specificity. Here we engineer a hydrogel-based system for in situ Treg activation at injury sites through the controlled release of AS2863619 (AS), a cyclin-dependent kinase inhibitor. AS is incorporated into collagen hydrogels at concentrations exceeding its solubility limit, reducing burst release and extending the release half-life. This continuous exposure to Treg-inducing agents stabilizes Foxp3 expression in CD4+ T cells, thereby enabling Treg induction and stabilization. The incorporation of laponite nanoparticles further slows AS release and prolongs drug retention. In a calvarial bone-defect model, AS-loaded hydrogels induce dose-dependent Treg cell activation, reduce pro-inflammatory macrophage responses and enhance bone regeneration. Notably, AS-laponite hydrogels achieve complete defect bridging in some cases. By providing spatiotemporal control over Treg populations without the need for cell isolation and expansion, this approach offers a scalable alternative for immunomodulation and tissue repair.

DOI: https://doi.org/10.1038/s41551-026-01817-1