{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:36:37Z","timestamp":1787646997131,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013845","name":"Foundation Against Cancer","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100013845","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ERA-NET TRANSCAN-3","award":["SmartCAR-T"],"award-info":[{"award-number":["SmartCAR-T"]}]},{"name":"Fonds National de la Recherche Scientifique"},{"name":"T\u00e9l\u00e9vie-FNRS"},{"name":"Fonds Sp\u00e9ciaux de la Recherche"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Multiple myeloma (MM) is an incurable hematologic malignancy arising from clonal plasma cells, with poor long-term outcomes due to inevitable relapse after conventional therapies. Chimeric antigen receptor (CAR) T-cell immunotherapy targeting B-cell maturation antigen (BCMA) has shown remarkable efficacy in relapsed patients. Conventional CARs employ single-chain variable fragments (scFvs), whereas single-domain antibodies (sdAb or VHHs) offer advantages such as small size, high stability, and potentially reduced immunogenicity. We designed and evaluated a novel anti-BCMA nanoCAR-T based on the VHH Nb17, compared with the conventional scFv-based CAR-T CT103a. Nb17 demonstrated strong BCMA binding and was incorporated into a CAR construct. Both nanoCAR-T and CT103a were generated via lentiviral transduction of primary T cells. Their cytotoxicity, cytokine secretion, degranulation, memory phenotype, and gene expression were assessed in vitro, along with antitumor activity in vivo. Nb17-nanoCAR-T demonstrated specific cytotoxicity, cytokine release (IL-2, TFNa, IFNg), and CD107a degranulation comparable to CT103a. Transcriptomic analysis revealed overlapping pathways between both CARs. Upon rechallenge, both CARs showed enhanced proliferation compared with untransduced T cells. In vivo, Nb17-nanoCAR-T and CT103a eradicated tumors in NSG mice. These findings demonstrate Nb17-nanoCAR-T exhibits potent anti-myeloma efficacy comparable to scFv-based CAR-T, supporting its potential as a promising therapeutic alternative.<\/jats:p>","DOI":"10.3390\/cells14241944","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:52:24Z","timestamp":1765205544000},"page":"1944","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparing a Novel Anti-BCMA NanoCAR with a Conventional ScFv-Based CAR for the Treatment of Multiple Myeloma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3508-6065","authenticated-orcid":false,"given":"M\u00e9gane","family":"Jassin","sequence":"first","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"Onkelinx","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Bocuzzi","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8663-1804","authenticated-orcid":false,"given":"Bianca","family":"E Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2088-857X","authenticated-orcid":false,"given":"Oswin","family":"Kwan","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix","family":"Block","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"},{"name":"Department of Clinical Hematology, University Hospital Center (CHU) of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Dubois","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coline","family":"Daulne","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Marcion","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Ormenese","sequence":"additional","affiliation":[{"name":"Cell Imaging & Flow Cytometry Platform, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5287-7950","authenticated-orcid":false,"given":"Emmanuel","family":"Di Valentin","sequence":"additional","affiliation":[{"name":"Viral Vectors Platform, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Baron","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"},{"name":"Department of Clinical Hematology, University Hospital Center (CHU) of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Gr\u00e9goire","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"},{"name":"Department of Clinical Hematology, University Hospital Center (CHU) of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7018-1770","authenticated-orcid":false,"given":"Gr\u00e9gory","family":"Ehx","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"},{"name":"Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, 1300 Wavre, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tham Thi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Caers","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, GIGA Institute, University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"},{"name":"Department of Clinical Hematology, University Hospital Center (CHU) of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev-med-070209-175325","article-title":"Multiple Myeloma","volume":"62","author":"Laubach","year":"2011","journal-title":"Annu. Rev. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-024-50932-7","article-title":"Deciphering the genetics and mechanisms of predisposition to multiple myeloma","volume":"15","author":"Went","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1002\/jha2.906","article-title":"\u201cFast but not so furious\u201d: A condensed step-up dosing schedule of teclistamab for relapsed\/refractory multiple myeloma","volume":"5","author":"Graf","year":"2024","journal-title":"eJHaem"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s11899-024-00740-z","article-title":"Management of Toxicities Associated with BCMA, GPRC5D, and FcRH5-Targeting Bispecific Antibodies in Multiple Myeloma","volume":"19","author":"Pan","year":"2024","journal-title":"Curr. Hematol. Malign-Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-immunol-042718-041407","article-title":"Emerging Cellular Therapies for Cancer","volume":"37","author":"Guedan","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1007\/s12094-023-03368-2","article-title":"CAR-T cell therapy: A game-changer in cancer treatment and beyond","volume":"26","author":"Utkarsh","year":"2024","journal-title":"Clin. Transl. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"American Association for Cancer Research (2017). First-Ever CAR T-cell Therapy Approved in U.S. Cancer Discov., 7, 10.","DOI":"10.1158\/2159-8290.CD-NB2017-126"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41408-021-00507-2","article-title":"KarMMa-RW: Comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma","volume":"11","author":"Jagannath","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mu, W., Long, X., Cai, H., Chen, C., Hu, G., Lou, Y., Xing, S., Wang, D., Wang, J., and Xiao, M. (2022). A Model Perspective Explanation of the Long-Term Sustainability of a Fully Human BCMA-Targeting CAR (CT103A) T-Cell Immunotherapy. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.803693"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e005403","DOI":"10.1136\/jitc-2022-005403","article-title":"Anti-BCMA CAR-T cells therapy for a patient with extremely high membrane BCMA expression: A case report","volume":"10","author":"Li","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1097\/BS9.0000000000000068","article-title":"CT103A, a forward step in multiple myeloma immunotherapies","volume":"3","author":"Xu","year":"2021","journal-title":"Blood Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41417-023-00712-0","article-title":"An alternative fully human anti-BCMA CAR-T shows response for relapsed or refractory multiple myeloma with anti-BCMA CAR-T exposures previously","volume":"31","author":"Wang","year":"2023","journal-title":"Cancer Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8025","DOI":"10.1200\/JCO.2023.41.16_suppl.8025","article-title":"CT103A, a novel fully human BCMA-targeting CAR-T cells, in patients with relapsed\/refractory multiple myeloma: Updated results of phase 1b\/2 study (FUMANBA-1)","volume":"41","author":"Li","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtm.2019.09.007","article-title":"Rapid Transduction and Expansion of Transduced T Cells with Maintenance of Central Memory Populations","volume":"16","author":"Pampusch","year":"2020","journal-title":"Mol. Ther.-Methods Clin. Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.jcyt.2024.03.003","article-title":"CAR-T cell expansion platforms yield distinct T cell differentiation states","volume":"26","author":"Song","year":"2024","journal-title":"Cytotherapy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1752592","DOI":"10.1080\/2162402X.2020.1752592","article-title":"Development of CAR-T cell therapy for B-ALL using a point-of-care approach","volume":"9","author":"Abdo","year":"2020","journal-title":"OncoImmunology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1146\/annurev-biochem-063011-092449","article-title":"Nanobodies: Natural Single-Domain Antibodies","volume":"82","author":"Muyldermans","year":"2013","journal-title":"Annu. Rev. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s40291-021-00533-7","article-title":"Camelid Single-Domain Antibodies for the Development of Potent Diagnosis Platforms","volume":"25","author":"Sousa","year":"2021","journal-title":"Mol. Diagn. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s13045-021-01171-6","article-title":"A non-internalised CD38-binding radiolabelled single-domain antibody fragment to monitor and treat multiple myeloma","volume":"14","author":"Duray","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Abebe, E.C., Shiferaw, M.Y., Admasu, F.T., and Dejenie, T.A. (2022). Ciltacabtagene autoleucel: The second anti-BCMA CAR T-cell therapeutic armamentarium of relapsed or refractory multiple myeloma. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.991092"},{"key":"ref_21","first-page":"225","article-title":"Bringing cell therapy to tumors: Considerations for optimal CAR binder design","volume":"6","author":"Smith","year":"2023","journal-title":"Antib. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hanssens, H., Meeus, F., Gesquiere, E.L., Puttemans, J., De Vlaeminck, Y., De Veirman, K., Breckpot, K., and Devoogdt, N. (2024). Anti-Idiotypic VHHs and VHH-CAR-T Cells to Tackle Multiple Myeloma: Different Applications Call for Different Antigen-Binding Moieties. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115634"},{"key":"ref_23","unstructured":"Zhou, J., Liu, J., Hu, G., Yang, Y., Meng, G., Gao, W., Wang, Y., and Niu, P. (2020). Chimeric Antigen Receptor (CAR) Binding to BCMA, and Uses Thereof. (US20200376030A1)."},{"key":"ref_24","unstructured":"Fan, X., Zhuang, Q., Zhao, Y., Yang, L., Fang, X., and Xu, C. (2021). Single Domain Antibodies and Chimeric Antigen Receptors Targeting BCMA and Methods of Use Thereof. (WO2021121228A1)."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4614","DOI":"10.1038\/s41467-022-32423-9","article-title":"A 33-residue peptide tag increases solubility and stability of Escherichia coli produced single-chain antibody fragments","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zeghal, M., Matte, K., Venes, A., Patel, S., Laroche, G., Sarvan, S., Joshi, M., Rain, J.-C., Couture, J.-F., and Gigu\u00e8re, P.M. (2023). Development of a V5-tag\u2013directed nanobody and its implementation as an intracellular biosensor of GPCR signaling. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.105107"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Beghein, E., and Gettemans, J. (2017). Nanobody Technology: A Versatile Toolkit for Microscopic Imaging, Protein\u2013Protein Interaction Analysis, and Protein Function Exploration. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00771"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3334","DOI":"10.1182\/blood-2018-99-111576","article-title":"Improved Expansion and Function of CAR T Cell Products from Cultures Initiated at Defined CD4:CD8 Ratios","volume":"132","author":"Lee","year":"2018","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nasiri, F., Kozani, P.S., and Rahbarizadeh, F. (2023). T-cells engineered with a novel VHH-based chimeric antigen receptor against CD19 exhibit comparable tumoricidal efficacy to their FMC63-based counterparts. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1063838"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1007\/s00262-023-03422-6","article-title":"Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia","volume":"72","author":"Cheng","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1186\/s12967-024-05101-1","article-title":"The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment","volume":"22","author":"Xiong","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hanssens, H., Meeus, F., De Vlaeminck, Y., Lecocq, Q., Puttemans, J., Debie, P., De Groof, T.W.M., Goyvaerts, C., De Veirman, K., and Breckpot, K. (2024). Scrutiny of chimeric antigen receptor activation by the extracellular domain: Experience with single domain antibodies targeting multiple myeloma cells highlights the need for case-by-case optimization. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1389018"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e006985","DOI":"10.1136\/jitc-2023-006985","article-title":"Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies","volume":"11","author":"Temple","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"De Munter, S., Ingels, J., Goetgeluk, G., Bonte, S., Pille, M., Weening, K., Kerre, T., Abken, H., and Vandekerckhove, B. (2018). Nanobody Based Dual Specific CARs. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020403"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1056\/NEJMoa1407222","article-title":"Chimeric antigen receptor T cells for sustained remissions in leukemia","volume":"371","author":"Maude","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1182\/blood-2017-02-769208","article-title":"Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults","volume":"129","author":"Gardner","year":"2017","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fischer, J.W., and Bhattarai, N. (2021). CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.693016"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1365-2249.2009.03933.x","article-title":"Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex","volume":"157","author":"King","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/j.1365-2249.2011.04462.x","article-title":"Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2r\u03b3\u00a0null H2-Ab1 tm1Gru Tg (human leucocyte antigen D-related 4) mice: A mouse model of human allogeneic graft-versus-host disease","volume":"166","author":"Covassin","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1111\/bjh.19631","article-title":"Development of novel humanized CD19\/BAFFR bicistronic chimeric antigen receptor T cells with potent antitumor activity against B-cell lineage neoplasms","volume":"205","author":"Wu","year":"2024","journal-title":"Br. J. Haematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.omto.2023.07.007","article-title":"Nanobody-derived bispecific CAR-T cell therapy enhances the anti-tumor efficacy of T cell lymphoma treatment","volume":"30","author":"Xia","year":"2023","journal-title":"Mol. Ther.-Oncolytics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40425-017-0216-7","article-title":"CCR7+ selected gene-modified T cells maintain a central memory phenotype and display enhanced persistence in peripheral blood in vivo","volume":"5","author":"Kueberuwa","year":"2017","journal-title":"J. Immunother. Cancer"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/1944\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T05:29:24Z","timestamp":1765344564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/1944"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,8]]},"references-count":42,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14241944"],"URL":"https:\/\/doi.org\/10.3390\/cells14241944","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,8]]}}}