{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:10:52Z","timestamp":1787836252224,"version":"build-2784847793"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pore-forming peptides (PFPs) hold strong anti-tumor potential but require delivery systems to ensure stability and prevent off-target effects. In this study, we develop a strategy to transport a PFP in a biologically latent, precursor-like state. Specifically, based on the therapeutic antibody atezolizumab, which targets the tumor-associated programmed death-ligand 1, we engineered a single-chain IgG (scIgG) construct with flexible linkers embedding the melittin sequence. To further enable tumor-specific activation, melittin was flanked by regions cleavable by matriptase\/ST14 (MT), a protease overexpressed in carcinomas. Initial constructs failed due to cytotoxicity during expression, prompting the redesign of melittin into a variant named Pmod2-2. This peptide retained potent pore-forming ability and was compatible with IgG fusion. The resulting scIgG-Pmod2-2 hybrid preserved Fab and Fc functionalities of the atezolizumab IgG, displayed favorable pharmacokinetics and released the active peptide in response to MT. These results highlight the potential of integrating cytolytic PFPs into antibody-based therapeutics.<\/jats:p>","DOI":"10.1038\/s42003-025-09066-9","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T13:44:20Z","timestamp":1764078260000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Engineering a single-chain immunoglobulin scaffold loaded with a latent-releasable cytotoxic pore-forming peptide"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-5076","authenticated-orcid":false,"given":"Izaskun","family":"Morillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5106-0615","authenticated-orcid":false,"given":"Joao","family":"Zulaica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8796-7509","authenticated-orcid":false,"given":"Asier","family":"R. Caballero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7846-4014","authenticated-orcid":false,"given":"Jaione","family":"Auzmendi-Iriarte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4400-3521","authenticated-orcid":false,"given":"Eneko","family":"Largo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1573-5440","authenticated-orcid":false,"given":"Beatriz","family":"Apellaniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5957-1260","authenticated-orcid":false,"given":"Arkaitz","family":"Carracedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-6065","authenticated-orcid":false,"given":"Marco","family":"Piva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6446-5649","authenticated-orcid":false,"given":"Jos\u00e9 L.","family":"Nieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4465-5071","authenticated-orcid":false,"given":"Edurne","family":"Rujas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"9066_CR1","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/0968-0004(91)90090-I","volume":"16","author":"DM Ojcius","year":"1991","unstructured":"Ojcius, D. M. & Young, J. D. Cytolytic pore-forming proteins and peptides: is there a common structural motif?. Trends Biochem. Sci. 16, 225\u2013229 (1991).","journal-title":"Trends Biochem. Sci."},{"key":"9066_CR2","doi-asserted-by":"publisher","first-page":"715","DOI":"10.2174\/1381612023395367","volume":"8","author":"Y Shai","year":"2002","unstructured":"Shai, Y. From innate immunity to de-novo designed antimicrobial peptides. Curr. Pharm. Des. 8, 715\u2013725 (2002).","journal-title":"Curr. Pharm. Des."},{"key":"9066_CR3","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.bbamem.2007.11.008","volume":"1778","author":"DW Hoskin","year":"2008","unstructured":"Hoskin, D. W. & Ramamoorthy, A. Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta 1778, 357\u2013375 (2008).","journal-title":"Biochim. Biophys. Acta"},{"key":"9066_CR4","doi-asserted-by":"publisher","first-page":"6040","DOI":"10.1021\/acs.chemrev.8b00520","volume":"119","author":"S Guha","year":"2019","unstructured":"Guha, S., Ghimire, J., Wu, E. & Wimley, W. C. Mechanistic landscape of membrane-permeabilizing peptides. Chem. Rev. 119, 6040\u20136085 (2019).","journal-title":"Chem. Rev."},{"key":"9066_CR5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S0005-2736(99)00200-X","volume":"1462","author":"Y Shai","year":"1999","unstructured":"Shai, Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by \u03b1-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim. Biophys. Acta 1462, 55\u201370 (1999).","journal-title":"Biochim. Biophys. Acta"},{"key":"9066_CR6","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1007\/s00018-005-4560-2","volume":"62","author":"N Papo","year":"2005","unstructured":"Papo, N. & Shai, Y. Host defense peptides as new weapons in cancer treatment. Cell Mol. Life Sci. 62, 784\u2013790 (2005).","journal-title":"Cell Mol. Life Sci."},{"key":"9066_CR7","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.ejpb.2021.07.010","volume":"167","author":"AB Ilangala","year":"2021","unstructured":"Ilangala, A. B., Lechanteur, A., Fillet, M. & Piel, G. Therapeutic peptides for chemotherapy: Trends and challenges for advanced delivery systems. Eur. J. Pharm. Biopharm. 167, 140\u2013158 (2021).","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"9066_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2021.114769","volume":"193","author":"S Guha","year":"2021","unstructured":"Guha, S. et al. Applications and evolution of melittin, the quintessential membrane active peptide. Biochem. Pharm. 193, 114769 (2021).","journal-title":"Biochem. Pharm."},{"key":"9066_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cocis.2018.06.009","volume":"38","author":"L Nystr\u00f6m","year":"2018","unstructured":"Nystr\u00f6m, L. & Malmsten, M. Membrane interactions and cell selectivity of amphiphilic anticancer peptides. Curr. Opin. Colloid Interface Sci. 38, 1\u201317 (2018).","journal-title":"Curr. Opin. Colloid Interface Sci."},{"key":"9066_CR10","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/0304-4157(90)90006-X","volume":"1031","author":"CE Dempsey","year":"1990","unstructured":"Dempsey, C. E. The actions of melittin on membranes. Biochim. Biophys. Acta 1031, 143\u2013161 (1990).","journal-title":"Biochim. Biophys. Acta"},{"key":"9066_CR11","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.canlet.2017.05.010","volume":"402","author":"I Rady","year":"2017","unstructured":"Rady, I., Siddiqui, I. A., Rady, M. & Mukhtar, H. Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy. Cancer Lett. 402, 16\u201331 (2017).","journal-title":"Cancer Lett."},{"key":"9066_CR12","doi-asserted-by":"publisher","first-page":"17158","DOI":"10.1021\/acsami.1c03640","volume":"13","author":"J Zhou","year":"2021","unstructured":"Zhou, J. et al. Delivery strategies for melittin-based cancer therapy. ACS Appl. Mater. Interfaces 13, 17158\u201317173 (2021).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"9066_CR13","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1002\/jmr.1032","volume":"24","author":"K Hall","year":"2011","unstructured":"Hall, K., Lee, T. H. & Aguilar, M. I. The role of electrostatic interactions in the membrane binding of melittin. J. Mol. Recognit. 24, 108\u2013118 (2011).","journal-title":"J. Mol. Recognit."},{"key":"9066_CR14","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.bbamem.2004.08.012","volume":"1667","author":"I Constantinescu","year":"2004","unstructured":"Constantinescu, I. & Lafleur, M. Influence of the lipid composition on the kinetics of concerted insertion and folding of melittin in bilayers. Biochim. Biophys. Acta 1667, 26\u201337 (2004).","journal-title":"Biochim. Biophys. Acta"},{"key":"9066_CR15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/S0005-2736(03)00107-X","volume":"1612","author":"MJ G\u00f3mara","year":"2003","unstructured":"G\u00f3mara, M. J., Nir, S. & Nieva, J. L. Effects of sphingomyelin on melittin pore formation. Biochim. Biophys. Acta 1612, 83\u201389 (2003).","journal-title":"Biochim. Biophys. Acta"},{"key":"9066_CR16","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.canlet.2009.09.010","volume":"290","author":"E Barraj\u00f3n-Catal\u00e1n","year":"2010","unstructured":"Barraj\u00f3n-Catal\u00e1n, E. et al. Selective death of human breast cancer cells by lytic immunoliposomes: Correlation with their HER2 expression level. Cancer Lett. 290, 192\u2013203 (2010).","journal-title":"Cancer Lett."},{"key":"9066_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-023-02026-7","volume":"21","author":"Y Dai","year":"2023","unstructured":"Dai, Y. et al. Effective treatment of metastatic sentinel lymph nodes by dual-targeting melittin nanoparticles. J. Nanobiotechnol. 21, 245 (2023).","journal-title":"J. Nanobiotechnol."},{"key":"9066_CR18","doi-asserted-by":"publisher","first-page":"55902","DOI":"10.1021\/acsami.1c17618","volume":"13","author":"R Ye","year":"2021","unstructured":"Ye, R. et al. Stable loading and delivery of melittin with lipid-coated polymeric nanoparticles for effective tumor therapy with negligible systemic toxicity. ACS Appl Mater. Interfaces 13, 55902\u201355912 (2021).","journal-title":"ACS Appl Mater. Interfaces"},{"key":"9066_CR19","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1021\/nl073290r","volume":"8","author":"NR Soman","year":"2008","unstructured":"Soman, N. R., Lanza, G. M., Heuser, J. M., Schlesinger, P. H. & Wickline, S. A. Synthesis and characterization of stable fluorocarbon nanostructures as drug delivery vehicles for cytolytic peptides. Nano Lett. 8, 1131\u20131136 (2008).","journal-title":"Nano Lett."},{"key":"9066_CR20","doi-asserted-by":"publisher","first-page":"5791","DOI":"10.1021\/nn400683s","volume":"7","author":"C Huang","year":"2013","unstructured":"Huang, C. et al. Hybrid melittin cytolytic Peptide-driven ultrasmall lipid nanoparticles block melanoma growth in vivo. ACS Nano 7, 5791\u20135800 (2013).","journal-title":"ACS Nano"},{"key":"9066_CR21","doi-asserted-by":"publisher","first-page":"13069","DOI":"10.1039\/C9NR01820D","volume":"11","author":"H Wang","year":"2019","unstructured":"Wang, H. et al. Co-delivery of paclitaxel and melittin by glycopeptide-modified lipodisks for synergistic anti-glioma therapy. Nanoscale 11, 13069\u201313077 (2019).","journal-title":"Nanoscale"},{"key":"9066_CR22","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.jconrel.2011.08.029","volume":"156","author":"MM Zetterberg","year":"2011","unstructured":"Zetterberg, M. M. et al. PEG-stabilized lipid disks as carriers for amphiphilic antimicrobial peptides. J. Cont. Release 156, 323\u2013328 (2011).","journal-title":"J. Cont. Release"},{"key":"9066_CR23","doi-asserted-by":"publisher","first-page":"7209","DOI":"10.1039\/C5NR05577F","volume":"8","author":"J Gao","year":"2016","unstructured":"Gao, J. et al. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery. Nanoscale 8, 7209\u20137216 (2016).","journal-title":"Nanoscale"},{"key":"9066_CR24","doi-asserted-by":"publisher","first-page":"2325","DOI":"10.1016\/j.nano.2017.06.020","volume":"13","author":"S Ahlgren","year":"2017","unstructured":"Ahlgren, S., Reijmar, K. & Edwards, K. Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells. Nanomed.Nanotechnol. Biol. Med. 13, 2325\u20132328 (2017).","journal-title":"Nanomed.Nanotechnol. Biol. Med."},{"key":"9066_CR25","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0161-5890(98)00109-6","volume":"36","author":"HS Lee","year":"1999","unstructured":"Lee, H. S. et al. Generation and characterization of a novel single-gene-encoded single-chain immunoglobulin molecule with antigen binding activity and effector functions. Mol. Immunol. 36, 61\u201371 (1999).","journal-title":"Mol. Immunol."},{"key":"9066_CR26","doi-asserted-by":"publisher","first-page":"73","DOI":"10.4161\/mabs.2.1.10784","volume":"2","author":"T Schirrmann","year":"2010","unstructured":"Schirrmann, T. et al. Oligomeric forms of single chain immunoglobulin (scIgG). mAbs 2, 73\u201376 (2010).","journal-title":"mAbs"},{"key":"9066_CR27","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1111\/j.1742-4658.2009.06950.x","volume":"276","author":"F B\u00e9liveau","year":"2009","unstructured":"B\u00e9liveau, F., D\u00e9silets, A. & Leduc, R. Probing the substrate specificities of matriptase, matriptase-2, hepsin and DESC1 with internally quenched fluorescent peptides. FEBS J. 276, 2213\u20132226 (2009).","journal-title":"FEBS J."},{"key":"9066_CR28","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114002","volume":"43","author":"F Ye","year":"2024","unstructured":"Ye, F. et al. Endocytic activation and exosomal secretion of matriptase stimulate the second wave of EGF signaling to promote skin and breast cancer invasion. Cell Rep. 43, 114002 (2024).","journal-title":"Cell Rep."},{"key":"9066_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7776","volume":"6","author":"GL Zoratti","year":"2015","unstructured":"Zoratti, G. L. et al. Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling. Nat. Commun. 6, 6776 (2015).","journal-title":"Nat. Commun."},{"key":"9066_CR30","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1111\/febs.13971","volume":"284","author":"LM Tanabe","year":"2017","unstructured":"Tanabe, L. M. & List, K. The role of type II transmembrane serine protease-mediated signaling in cancer. FEBS J. 284, 1421\u20131436 (2017).","journal-title":"FEBS J."},{"key":"9066_CR31","doi-asserted-by":"publisher","first-page":"12185","DOI":"10.1039\/D1NR03084A","volume":"13","author":"L Sun","year":"2021","unstructured":"Sun, L., Hristova, K. & Wimley, W. C. Membrane-selective nanoscale pores in liposomes by a synthetically evolved peptide: implications for triggered release. Nanoscale 13, 12185\u201312197 (2021).","journal-title":"Nanoscale"},{"key":"9066_CR32","doi-asserted-by":"publisher","first-page":"3581","DOI":"10.3892\/mmr.2017.6970","volume":"16","author":"SF Zhang","year":"2017","unstructured":"Zhang, S. F. & Chen, Z. Melittin exerts an antitumor effect on non\u2011small cell lung cancer cells. Mol. Med. Rep. 16, 3581\u20133586 (2017).","journal-title":"Mol. Med. Rep."},{"key":"9066_CR33","doi-asserted-by":"publisher","first-page":"e0224028","DOI":"10.1371\/journal.pone.0224028","volume":"14","author":"C Soliman","year":"2019","unstructured":"Soliman, C., Eastwood, S., Truong, V. K., Ramsland, P. A. & Elbourne, A. The membrane effects of melittin on gastric and colorectal cancer. PLoS ONE 14, e0224028 (2019).","journal-title":"PLoS ONE"},{"key":"9066_CR34","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.fct.2014.03.022","volume":"68","author":"YJ Jeong","year":"2014","unstructured":"Jeong, Y. J. et al. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K\/Akt\/mTOR signaling pathway in breast cancer cells. Food Chem. Toxicol. 68, 218\u2013225 (2014).","journal-title":"Food Chem. Toxicol."},{"key":"9066_CR35","doi-asserted-by":"publisher","first-page":"14040","DOI":"10.1021\/acs.jmedchem.4c00912","volume":"67","author":"R Deb","year":"2024","unstructured":"Deb, R. et al. Computational design of pore-forming peptides with potent antimicrobial and anticancer activities. J. Med. Chem. 67, 14040\u201314061 (2024).","journal-title":"J. Med. Chem."},{"key":"9066_CR36","doi-asserted-by":"publisher","first-page":"2101","DOI":"10.1093\/bioinformatics\/btn392","volume":"24","author":"R Gautier","year":"2008","unstructured":"Gautier, R., Douguet, D., Antonny, B. & Drin, G. HELIQUEST: a web server to screen sequences with specific alpha-helical properties. Bioinformatics 24, 2101\u20132102 (2008).","journal-title":"Bioinformatics"},{"key":"9066_CR37","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1529\/biophysj.104.043596","volume":"87","author":"H Raghuraman","year":"2004","unstructured":"Raghuraman, H. & Chattopadhyay, A. Interaction of melittin with membrane cholesterol: a fluorescence approach. Biophys. J. 87, 2419\u20132432 (2004).","journal-title":"Biophys. J."},{"key":"9066_CR38","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/S0005-2736(01)00382-0","volume":"1514","author":"AS Ladokhin","year":"2001","unstructured":"Ladokhin, A. S. & White, S. H. Detergent-like\u2019 permeabilization of anionic lipid vesicles by melittin. Biochim. Biophys. Acta 1514, 253\u2013260 (2001).","journal-title":"Biochim. Biophys. Acta"},{"key":"9066_CR39","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1529\/biophysj.107.106005","volume":"93","author":"G van den Bogaart","year":"2007","unstructured":"van den Bogaart, G., Mika, J. T., Krasnikov, V. & Poolman, B. The lipid dependence of melittin action investigated by dual-color fluorescence burst analysis. Biophys. J. 93, 154\u2013163 (2007).","journal-title":"Biophys. J."},{"key":"9066_CR40","doi-asserted-by":"publisher","first-page":"4724","DOI":"10.1021\/ja500462s","volume":"136","author":"G Wiedman","year":"2014","unstructured":"Wiedman, G. et al. Highly efficient macromolecule-sized poration of lipid bilayers by a synthetically evolved peptide. J. Am. Chem. Soc. 136, 4724\u20134731 (2014).","journal-title":"J. Am. Chem. Soc."},{"key":"9066_CR41","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1016\/S0006-3495(97)78822-2","volume":"72","author":"AS Ladokhin","year":"1997","unstructured":"Ladokhin, A. S., Selsted, M. E. & White, S. H. Sizing membrane pores in lipid vesicles by leakage of co-encapsulated markers: pore formation by melittin. Biophys. J. 72, 1762\u20131766 (1997).","journal-title":"Biophys. J."},{"key":"9066_CR42","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1021\/acs.biochem.2c00358","volume":"61","author":"MC Yoon","year":"2022","unstructured":"Yoon, M. C., Hook, V. & O\u2019Donoghue, A. J. Cathepsin B dipeptidyl carboxypeptidase and endopeptidase activities demonstrated across a broad pH range. Biochemistry 61, 1904\u20131914 (2022).","journal-title":"Biochemistry"},{"key":"9066_CR43","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1007\/s40262-013-0079-0","volume":"52","author":"L Diao","year":"2013","unstructured":"Diao, L. & Meibohm, B. Pharmacokinetics and pharmacokinetic\u2013pharmacodynamic correlations of therapeutic peptides. Clin. Pharmacokinet. 52, 855\u2013868 (2013).","journal-title":"Clin. Pharmacokinet."},{"key":"9066_CR44","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1208\/s12248-014-9687-3","volume":"17","author":"L Di","year":"2015","unstructured":"Di, L. Strategic approaches to optimizing peptide ADME properties. AAPS J. 17, 134\u2013143 (2015).","journal-title":"AAPS J."},{"key":"9066_CR45","doi-asserted-by":"publisher","first-page":"59934","DOI":"10.1021\/acsami.4c13353","volume":"16","author":"S Insausti","year":"2024","unstructured":"Insausti, S. et al. Generation of a nonbilayer lipid nanoenvironment after epitope binding potentiates neutralizing HIV-1 MPER antibody. ACS Appl. Mater. Interfaces 16, 59934\u201359948 (2024).","journal-title":"ACS Appl. Mater. Interfaces"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-09066-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-09066-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-09066-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:06:04Z","timestamp":1764083164000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-025-09066-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["9066"],"URL":"https:\/\/doi.org\/10.1038\/s42003-025-09066-9","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]},"assertion":[{"value":"16 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1665"}}