{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T07:58:03Z","timestamp":1776326283077,"version":"3.50.1"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:00:00Z","timestamp":1731110400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T00:00:00Z","timestamp":1731110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203885"],"award-info":[{"award-number":["82203885"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-024-79069-9","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T12:54:25Z","timestamp":1731156865000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ultrasound-triggered nano delivery of lenvatinib for selective immunotherapy treatment against hepatocellular carcinoma"],"prefix":"10.1038","volume":"14","author":[{"given":"Lu","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guofeng","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,9]]},"reference":[{"key":"79069_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J. Clin. 71, 209\u2013249. https:\/\/doi.org\/10.3322\/caac.21660 (2021).","journal-title":"Ca-a Cancer J. Clin."},{"key":"79069_CR2","doi-asserted-by":"publisher","unstructured":"Rossetto, A. et al. Carcinogenesis and metastasis in liver: cell physiological basis. Cancers (Basel)  11 https:\/\/doi.org\/10.3390\/cancers11111731 (2019).","DOI":"10.3390\/cancers11111731"},{"key":"79069_CR3","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1002\/kjm2.12401","volume":"37","author":"TC Wu","year":"2021","unstructured":"Wu, T. C., Shen, Y. C. & Cheng, A. L. Evolution of systemic treatment for advanced hepatocellular carcinoma. Kaohsiung J. Med. Sci. 37, 643\u2013653. https:\/\/doi.org\/10.1002\/kjm2.12401 (2021).","journal-title":"Kaohsiung J. Med. Sci."},{"key":"79069_CR4","doi-asserted-by":"publisher","first-page":"16018","DOI":"10.1038\/nrdp.2016.18","volume":"2","author":"JM Llovet","year":"2016","unstructured":"Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 2, 16018. https:\/\/doi.org\/10.1038\/nrdp.2016.18 (2016).","journal-title":"Nat. Reviews Disease Primers"},{"key":"79069_CR5","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41572-020-00240-3","volume":"7","author":"JM Llovet","year":"2021","unstructured":"Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 7, 6. https:\/\/doi.org\/10.1038\/s41572-020-00240-3 (2021).","journal-title":"Nat. Rev. Dis. Primers"},{"key":"79069_CR6","doi-asserted-by":"publisher","first-page":"85","DOI":"10.5582\/bst.2015.01128","volume":"10","author":"Z Sun","year":"2016","unstructured":"Sun, Z. et al. Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials. Biosci. Trends 10, 85\u201391. https:\/\/doi.org\/10.5582\/bst.2015.01128 (2016).","journal-title":"Biosci. Trends"},{"key":"79069_CR7","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s40291-018-0361-9","volume":"22","author":"N Pandey","year":"2018","unstructured":"Pandey, N., Chauhan, A. & Jain, N. TLR4 polymorphisms and expression in solid cancers. Mol. Diagn. Ther. 22, 683\u2013702. https:\/\/doi.org\/10.1007\/s40291-018-0361-9 (2018).","journal-title":"Mol. Diagn. Ther."},{"key":"79069_CR8","doi-asserted-by":"publisher","first-page":"e1074376","DOI":"10.1080\/2162402X.2015.1074376","volume":"5","author":"A Lin","year":"2016","unstructured":"Lin, A. et al. TLR4 signaling promotes a COX-2\/PGE2\/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells. Oncoimmunology 5, e1074376. https:\/\/doi.org\/10.1080\/2162402X.2015.1074376 (2016).","journal-title":"Oncoimmunology"},{"key":"79069_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/annonc\/mdp281","volume":"20","author":"C Verslype","year":"2009","unstructured":"Verslype, C. et al. The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008. Ann. Oncol. 20, 1\u20136. https:\/\/doi.org\/10.1093\/annonc\/mdp281 (2009).","journal-title":"Ann. Oncol."},{"key":"79069_CR10","doi-asserted-by":"crossref","unstructured":"Liu, L. et al. Sorafenib blocks the RAF\/MEK\/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma Model PLC\/PRF\/5. Cancer Res. 66, 11851\u201311858, (2006).","DOI":"10.1158\/0008-5472.CAN-06-1377"},{"key":"79069_CR11","doi-asserted-by":"crossref","unstructured":"Pang, R. W. C. & Poon, R. T. P. From molecular biology to targeted therapies for hepatocellular carcinoma: The future is now. Oncology 72 30\u201344, (2007).","DOI":"10.1159\/000111705"},{"key":"79069_CR12","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1056\/NEJMoa0708857","volume":"359","author":"JM Llovet","year":"2008","unstructured":"Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378\u2013390. https:\/\/doi.org\/10.1056\/NEJMoa0708857 (2008).","journal-title":"N. Engl. J. Med."},{"key":"79069_CR13","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/s1470-2045(08)70285-7","volume":"10","author":"AL Cheng","year":"2009","unstructured":"Cheng, A. L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25\u201334. https:\/\/doi.org\/10.1016\/s1470-2045(08)70285-7 (2009).","journal-title":"Lancet Oncol."},{"key":"79069_CR14","doi-asserted-by":"publisher","unstructured":"Tang, W. et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal. Transduct. Target. Ther. 5 https:\/\/doi.org\/10.1038\/s41392-020-0187-x (2020).","DOI":"10.1038\/s41392-020-0187-x"},{"key":"79069_CR15","doi-asserted-by":"publisher","unstructured":"Tohyama, O. et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J. Thyroid Res. 2014 (638747\u2013638747). https:\/\/doi.org\/10.1155\/2014\/638747 (2014).","DOI":"10.1155\/2014\/638747"},{"key":"79069_CR16","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1007\/s00535-016-1263-4","volume":"52","author":"K Ikeda","year":"2016","unstructured":"Ikeda, K. et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J. Gastroenterol. 52, 512\u2013519. https:\/\/doi.org\/10.1007\/s00535-016-1263-4 (2016).","journal-title":"J. Gastroenterol."},{"key":"79069_CR17","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.1111\/cas.13806","volume":"109","author":"T Kimura","year":"2018","unstructured":"Kimura, T. et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 109, 3993\u20134002. https:\/\/doi.org\/10.1111\/cas.13806 (2018).","journal-title":"Cancer Sci."},{"key":"79069_CR18","doi-asserted-by":"publisher","unstructured":"Han, J. W. & Yoon, S. K. Immune responses following locoregional treatment for hepatocellular carcinoma: possible roles of adjuvant immunotherapy. Pharmaceutics 13 https:\/\/doi.org\/10.3390\/pharmaceutics13091387 (2021).","DOI":"10.3390\/pharmaceutics13091387"},{"key":"79069_CR19","doi-asserted-by":"publisher","first-page":"36","DOI":"10.4161\/viru.25436","volume":"5","author":"WJ Wiersinga","year":"2014","unstructured":"Wiersinga, W. J., Leopold, S. J., Cranendonk, D. R. & van der Poll, T. Host innate immune responses to sepsis. Virulence 5, 36\u201344. https:\/\/doi.org\/10.4161\/viru.25436 (2014).","journal-title":"Virulence"},{"key":"79069_CR20","doi-asserted-by":"publisher","unstructured":"Patel, K., Lamm, R., Altshuler, P., Dang, H. & Shah, A. P. Hepatocellular carcinoma-the influence of immunoanatomy and the role of immunotherapy. Int. J. Mol. Sci. 21 https:\/\/doi.org\/10.3390\/ijms21186757 (2020).","DOI":"10.3390\/ijms21186757"},{"key":"79069_CR21","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1007\/s11912-020-00943-6","volume":"22","author":"P Zeng","year":"2020","unstructured":"Zeng, P., Shen, D., Zeng, C. H., Chang, X. F. & Teng, G. J. Emerging opportunities for combining locoregional therapy with immune checkpoint inhibitors in hepatocellular carcinoma. Curr. Oncol. Rep. 22, 76. https:\/\/doi.org\/10.1007\/s11912-020-00943-6 (2020).","journal-title":"Curr. Oncol. Rep."},{"key":"79069_CR22","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/s43856-023-00390-x","volume":"3","author":"M Yamauchi","year":"2023","unstructured":"Yamauchi, M. et al. Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma. Commun. Med. 3, 152. https:\/\/doi.org\/10.1038\/s43856-023-00390-x (2023).","journal-title":"Commun. Med."},{"key":"79069_CR23","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/s43018-021-00234-4","volume":"2","author":"WJ Ho","year":"2021","unstructured":"Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity. Nat. Cancer  2, 891\u2013. https:\/\/doi.org\/10.1038\/s43018-021-00234-4 (2021).","journal-title":"Nat. Cancer"},{"key":"79069_CR24","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1016\/s0140-6736(18)30207-1","volume":"391","author":"M Kudo","year":"2018","unstructured":"Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163\u20131173. https:\/\/doi.org\/10.1016\/s0140-6736(18)30207-1 (2018).","journal-title":"Lancet"},{"key":"79069_CR25","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1007\/s00535-016-1263-4","volume":"52","author":"K Ikeda","year":"2017","unstructured":"Ikeda, K. et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J. Gastroenterol. 52, 512\u2013519. https:\/\/doi.org\/10.1007\/s00535-016-1263-4 (2017).","journal-title":"J. Gastroenterol."},{"key":"79069_CR26","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1186\/s13046-019-1396-4","volume":"38","author":"Y Fu","year":"2019","unstructured":"Fu, Y., Liu, S., Zeng, S. & Shen, H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J. Exp. Clin. Cancer Res. 38, 396. https:\/\/doi.org\/10.1186\/s13046-019-1396-4 (2019).","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"79069_CR27","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1039\/c9bm01575b","volume":"8","author":"T Li","year":"2020","unstructured":"Li, T. et al. PD-L1-targeted microbubbles loaded with docetaxel produce a synergistic effect for the treatment of lung cancer under ultrasound irradiation. Biomater. Sci. 8, 1418\u20131430. https:\/\/doi.org\/10.1039\/c9bm01575b (2020).","journal-title":"Biomaterials Sci."},{"key":"79069_CR28","doi-asserted-by":"publisher","unstructured":"Balali, Z., Safaei-Ghomi, J. & Mashhadi, E. Synthesis of 3,4-dihydropyrimidines and octahydroquinazolinones by SBA-15 supported schiff-base iron (III) complex as durable and reusable catalyst under ultrasound irradiation. Sci. Rep. 14 https:\/\/doi.org\/10.1038\/s41598-024-65519-x (2024).","DOI":"10.1038\/s41598-024-65519-x"},{"key":"79069_CR29","doi-asserted-by":"publisher","first-page":"3507","DOI":"10.1039\/d3mh00042g","volume":"10","author":"S Wu","year":"2023","unstructured":"Wu, S. et al. Ultrasound-triggered in situ gelation with ROS-controlled drug release for cartilage repair. Mater. Horiz. 10, 3507\u20133522. https:\/\/doi.org\/10.1039\/d3mh00042g (2023).","journal-title":"Mater. Horiz."},{"key":"79069_CR30","doi-asserted-by":"publisher","unstructured":"Park, J. H. et al. Drug delivery by sonosensitive liposome and microbubble with acoustic-lens attached ultrasound: an in vivo feasibility study in a murine melanoma model. Sci. Rep. 13 https:\/\/doi.org\/10.1038\/s41598-023-42786-8 (2023).","DOI":"10.1038\/s41598-023-42786-8"},{"key":"79069_CR31","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.canlet.2019.11.034","volume":"470","author":"LQ Zhou","year":"2020","unstructured":"Zhou, L. Q., Li, P., Cui, X. W. & Dietrich, C. F. Ultrasound nanotheranostics in fighting cancer: advances and prospects. Cancer Lett. 470, 204\u2013219. https:\/\/doi.org\/10.1016\/j.canlet.2019.11.034 (2020).","journal-title":"Cancer Lett."},{"key":"79069_CR32","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.jconrel.2020.04.023","volume":"323","author":"YJ Ho","year":"2020","unstructured":"Ho, Y. J., Li, J. P., Fan, C. H., Liu, H. L. & Yeh, C. K. Ultrasound in tumor immunotherapy: current status and future developments. J. Control Release  323, 12\u201323. https:\/\/doi.org\/10.1016\/j.jconrel.2020.04.023 (2020).","journal-title":"J. Control Release"},{"key":"79069_CR33","doi-asserted-by":"publisher","first-page":"e2205924","DOI":"10.1002\/adma.202205924","volume":"34","author":"D Wang","year":"2022","unstructured":"Wang, D. et al. Etching bulk covalent organic frameworks into nanoparticles of Uniform and controllable size by the molecular exchange etching method for sonodynamic and immune combination antitumor therapy. Adv. Mater. 34, e2205924. https:\/\/doi.org\/10.1002\/adma.202205924 (2022).","journal-title":"Adv. Mater."},{"key":"79069_CR34","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jconrel.2017.08.017","volume":"264","author":"Z Wang","year":"2017","unstructured":"Wang, Z., He, Q., Zhao, W., Luo, J. & Gao, W. Tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates overcome doxorubicin resistance in cancer therapy. J. Control Release  264, 66\u201375. https:\/\/doi.org\/10.1016\/j.jconrel.2017.08.017 (2017).","journal-title":"J. Control Release"},{"key":"79069_CR35","doi-asserted-by":"publisher","first-page":"e1902530","DOI":"10.1002\/adma.201902530","volume":"31","author":"X Pang","year":"2019","unstructured":"Pang, X. et al. Sono-immunotherapeutic nanocapturer to combat multidrug-resistant bacterial infections. Adv. Mater. 31, e1902530. https:\/\/doi.org\/10.1002\/adma.201902530 (2019).","journal-title":"Adv. Mater."},{"key":"79069_CR36","doi-asserted-by":"publisher","first-page":"4032","DOI":"10.1038\/s41467-022-31551-6","volume":"13","author":"J Li","year":"2022","unstructured":"Li, J. et al. Precision cancer sono-immunotherapy using deep-tissue activatable semiconducting polymer immunomodulatory nanoparticles. Nat. Commun. 13, 4032. https:\/\/doi.org\/10.1038\/s41467-022-31551-6 (2022).","journal-title":"Nat. Commun."},{"key":"79069_CR37","doi-asserted-by":"publisher","first-page":"2002927","DOI":"10.1002\/advs.202002927","volume":"8","author":"S Wang","year":"2021","unstructured":"Wang, S. et al. Photodynamic-chemodynamic cascade reactions for efficient drug delivery and enhanced combination therapy. Adv. Sci. (Weinh)  8, 2002927. https:\/\/doi.org\/10.1002\/advs.202002927 (2021).","journal-title":"Adv. Sci. (Weinh)"},{"key":"79069_CR38","doi-asserted-by":"publisher","unstructured":"Wu, W., Pu, Y. & Shi, J. Dual size\/charge-switchable nanocatalytic medicine for deep tumor therapy. Adv. Sci. 8 https:\/\/doi.org\/10.1002\/advs.202002816 (2021).","DOI":"10.1002\/advs.202002816"},{"key":"79069_CR39","doi-asserted-by":"publisher","unstructured":"Zhao, C. X. et al. Multiscale construction of bifunctional electrocatalysts for long-lifespan rechargeable zinc-air batteries. Adv. Funct. Mater. 30 https:\/\/doi.org\/10.1002\/adfm.202003619 (2020).","DOI":"10.1002\/adfm.202003619"},{"key":"79069_CR40","doi-asserted-by":"publisher","first-page":"22268","DOI":"10.1039\/d0nr04520a","volume":"12","author":"H Shan","year":"2020","unstructured":"Shan, H., Dou, W., Zhang, Y. & Qi, M. Targeted ferritin nanoparticle encapsulating CpG oligodeoxynucleotides induces tumor-associated macrophage M2 phenotype polarization into M1 phenotype and inhibits tumor growth. Nanoscale   12, 22268\u201322280. https:\/\/doi.org\/10.1039\/d0nr04520a (2020).","journal-title":"Nanoscale"},{"key":"79069_CR41","doi-asserted-by":"publisher","first-page":"e2004559","DOI":"10.1002\/adma.202004559","volume":"33","author":"G Ji","year":"2021","unstructured":"Ji, G. et al. Biopolymer immune implants\u2019 sequential activation of innate and adaptive immunity for colorectal cancer postoperative immunotherapy. Adv. Mater. 33, e2004559. https:\/\/doi.org\/10.1002\/adma.202004559 (2021).","journal-title":"Adv. Mater."},{"key":"79069_CR42","doi-asserted-by":"publisher","first-page":"14343","DOI":"10.1038\/s41598-024-65435-0","volume":"14","author":"J Xiao","year":"2024","unstructured":"Xiao, J. et al. CD248-expressing cancer-associated fibroblasts induce epithelial-mesenchymal transition of non-small cell lung cancer via inducing M2-polarized macrophages. Sci. Rep. 14, 14343\u201314343. https:\/\/doi.org\/10.1038\/s41598-024-65435-0 (2024).","journal-title":"Sci. Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-79069-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-79069-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-79069-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T13:03:20Z","timestamp":1731157400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-79069-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,9]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["79069"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-79069-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,9]]},"assertion":[{"value":"17 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The animal experiments conducted in the study was approved by the Animal Care and Committee of Jilin University (Jilin, China). The animal study was conducted in accordance with the local legislation and institutional requirements. All experiments were performed in accordance with ARRIVE guidelines.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical statement"}}],"article-number":"27395"}}