{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:18:24Z","timestamp":1788254304272,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"NIH","doi-asserted-by":"publisher","award":["R01NS125413"],"award-info":[{"award-number":["R01NS125413"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Osteoarthritis (OA) is the most prevalent chronic joint disease characterized by the progressive degeneration of articular cartilage leading to debilitating locomotor restrictions and persistent pain. The pathogenesis of OA is driven by a complex cycle of inflammatory mediators, where G protein-coupled receptor protease-activated receptor 2 (PAR2) has emerged as a key driver of both tissue degradation and joint inflammation. PAR2 is expressed on various joint tissues, and on the terminals of nociceptive sensory neurons, providing a direct link to structural joint inflammation and chronic nociception. However, the therapeutic potential of PAR2 antagonists is hampered by the rapid clearance of drugs from the synovial space. Here, we investigate the therapeutic potential of nanoparticle-mediated drug delivery to achieve sustained PAR2 inhibition in OA. OA was induced in C57BL\/6 mice via intra-articular injection of sodium iodoacetate, followed by treatment with the PAR2 antagonist, AZ3451, encapsulated within PAMAM-Chol nanoparticles (PAMAM-Chol-AZ3451). Our results demonstrate that the PAMAM-Chol-AZ3451 nanoparticles blocked cytokine release from synoviocytes and provided a significantly more sustained and effective antinociceptive effect compared to the free AZ3451, with confirmed nanoparticle uptake by neurons and synoviocytes. Furthermore, cell-specific genetic deletion confirmed that PAR2 expressed on Nav1.8 nociceptors is a critical contributor to OA-induced nociception and locomotor deficits. These findings establish that PAR2 signaling in neurons is critical for OA nociception and that nanoparticle delivery of PAR2 antagonists (PAMAM-Chol-AZ3451) represents an effective strategy for sustained inhibition of PAR2 activity, offering a novel approach for managing chronic OA pain.<\/jats:p>","DOI":"10.3390\/nano16171100","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:31:13Z","timestamp":1788251473000},"page":"1100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual-Targeted Inhibition of PAR2 Endosomal Signaling in Synoviocytes and Nociceptors Attenuates Osteoarthritis Pain"],"prefix":"10.3390","volume":"16","author":[{"given":"Marcella de A.","family":"Ferreira","sequence":"first","affiliation":[{"name":"Pain Research Center, College of Dentistry, New York University, New York, NY 10010, USA"},{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8729-8636","authenticated-orcid":false,"given":"Paz","family":"Duran","sequence":"additional","affiliation":[{"name":"Pain Research Center, College of Dentistry, New York University, New York, NY 10010, USA"},{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2175-9804","authenticated-orcid":false,"given":"Raquel","family":"Tonello","sequence":"additional","affiliation":[{"name":"Pain Research Center, College of Dentistry, New York University, New York, NY 10010, USA"},{"name":"Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Veronica Emad","family":"Farag","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mae Stabile","family":"D\u2019Ambra","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9998-7776","authenticated-orcid":false,"given":"Evan Yuhan","family":"Chen","sequence":"additional","affiliation":[{"name":"Pain Research Center, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3733-4648","authenticated-orcid":false,"given":"Sher B.","family":"Poudel","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Kam W.","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6540-2375","authenticated-orcid":false,"given":"Dane D.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Pain Research Center, College of Dentistry, New York University, New York, NY 10010, USA"},{"name":"Translational Research Center, College of Dentistry, New York University, New York, NY 10010, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mohd Noor, N.A., Abdullah Nurul, A., Ahmad Mohd Zain, M.R., Wan Nor Aduni, W.K., and Azlan, M. (2021). Extracellular vesicles from mesenchymal stem cells as potential treatments for osteoarthritis. Cells, 10.","DOI":"10.3390\/cells10061287"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41392-023-01330-w","article-title":"Osteoarthritis: Pathogenic signaling pathways and therapeutic targets","volume":"8","author":"Yao","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/s41598-023-28068-3","article-title":"Human osteoarthritis knee joint synovial fluids cleave and activate Proteinase-Activated Receptor (PAR) mediated signaling","volume":"13","author":"Chandrabalan","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s11914-018-0477-1","article-title":"Mechanisms of Osteoarthritis (OA) Pain","volume":"16","author":"Felson","year":"2018","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1002\/art.42530","article-title":"Age-Associated Changes in Knee Osteoarthritis, Pain-Related Behaviors, and Dorsal Root Ganglia Immunophenotyping of Male and Female Mice","volume":"75","author":"Geraghty","year":"2023","journal-title":"Arthritis Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12532","DOI":"10.18632\/aging.102586","article-title":"Protease-activated receptor 2 (PAR-2) antagonist AZ3451 as a novel therapeutic agent for osteoarthritis","volume":"11","author":"Huang","year":"2019","journal-title":"Aging"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1136\/annrheumdis-2015-208268","article-title":"Proteinase-activated receptor 2 modulates OA-related pain, cartilage and bone pathology","volume":"75","author":"Huesa","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"911","DOI":"10.3899\/jrheum.100710","article-title":"Proteinase-activated receptor-2 gene disruption limits the effect of osteoarthritis on cartilage in mice: A novel target in joint degradation","volume":"38","author":"Amiable","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1016\/j.jpain.2023.06.006","article-title":"Protease-Activated Receptor 2 (PAR2) Expressed in Sensory Neurons Contributes to Signs of Pain and Neuropathy in Paclitaxel Treated Mice","volume":"24","author":"Kume","year":"2023","journal-title":"J. Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.joca.2006.04.015","article-title":"Expression of proteinase-activated receptors (PAR)-2 in articular chondrocytes is modulated by IL-1beta, TNF-alpha and TGF-beta","volume":"14","author":"Xiang","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/art.33323","article-title":"Protease-activated receptor 2, rather than protease-activated receptor 1, contributes to the aggressive properties of synovial fibroblasts in rheumatoid arthritis","volume":"64","author":"Xue","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Habuchi, H., Izumi, M., Dan, J., Ushida, T., Ikeuchi, M., Takeuchi, K., and Habuchi, O. (2021). Bone marrow derived mast cells injected into the osteoarthritic knee joints of mice induced by sodium monoiodoacetate enhanced spontaneous pain through activation of PAR2 and action of extracellular ATP. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252590"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/nrrheum.2018.17","article-title":"Proteinases and their receptors in inflammatory arthritis: An overview","volume":"14","author":"Oikonomopoulou","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/1423-0127-16-97","article-title":"TGF-beta inhibits IL-1beta-activated PAR-2 expression through multiple pathways in human primary synovial cells","volume":"16","author":"Tsai","year":"2009","journal-title":"J. Biomed. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.1002\/anie.201813362","article-title":"Tuned Cationic Dendronized Polymer: Molecular Scavenger for Rheumatoid Arthritis Treatment","volume":"58","author":"Peng","year":"2019","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R121","DOI":"10.1186\/ar2329","article-title":"Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: A basic science study","volume":"9","author":"Boileau","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_18","first-page":"61","article-title":"Proteinase-Activated Receptor-2: Physiological and Pathophysiological Roles","volume":"1","author":"Coelho","year":"2003","journal-title":"Curr. Med. Chem. Cardiovasc. Hematol. Agents"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eaat8800","DOI":"10.1126\/scitranslmed.aat8800","article-title":"Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis","volume":"10","author":"Geiger","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.apmt.2018.05.002","article-title":"PAMAM dendrimers as efficient drug and gene delivery nanosystems for cancer therapy","volume":"12","author":"Dehghan","year":"2018","journal-title":"Appl. Mater. Today"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2112059119","DOI":"10.1073\/pnas.2112059119","article-title":"Mice expressing fluorescent PAR(2) reveal that endocytosis mediates colonic inflammation and pain","volume":"119","author":"Latorre","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2412687122","DOI":"10.1073\/pnas.2412687122","article-title":"Nanomedicines targeting protease-activated receptor 2 in endosomes provide sustained analgesia","volume":"122","author":"Teng","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","first-page":"E7438","article-title":"Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome","volume":"115","author":"Pattison","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaal3447","DOI":"10.1126\/scitranslmed.aal3447","article-title":"Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief","volume":"9","author":"Jensen","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"122874","DOI":"10.1016\/j.biomaterials.2024.122874","article-title":"PAR2 on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451","volume":"314","author":"Bhansali","year":"2025","journal-title":"Biomaterials"},{"key":"ref_26","first-page":"e53746","article-title":"The monoiodoacetate model of osteoarthritis pain in the mouse","volume":"111","author":"Pitcher","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1080\/01621459.1965.10480843","article-title":"The Up-and-Down Method for Small Samples","volume":"60","author":"Dixon","year":"1965","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","article-title":"Quantitative assessment of tactile allodynia in the rat paw","volume":"53","author":"Chaplan","year":"1994","journal-title":"J. Neurosci. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"104664","DOI":"10.1016\/j.jpain.2024.104664","article-title":"Uncoupling the CRMP2-CaV2.2 interaction reduces pain-like behavior in a preclinical joint-pain model","volume":"25","author":"Allen","year":"2024","journal-title":"J. Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jneumeth.2013.12.010","article-title":"Validation and implementation of a novel high-throughput behavioral phenotyping instrument for mice","volume":"224","author":"Brodkin","year":"2014","journal-title":"J. Neurosci. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1097\/j.pain.0000000000002826","article-title":"The contribution of endocytosis to sensitization of nociceptors and synaptic transmission in nociceptive circuits","volume":"164","author":"Tonello","year":"2023","journal-title":"Pain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1365-2818.2006.01706.x","article-title":"A guided tour into subcellular colocalization analysis in light microscopy","volume":"224","author":"Bolte","year":"2006","journal-title":"J. Microsc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1038\/s41565-019-0568-x","article-title":"A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain","volume":"14","author":"Retamal","year":"2019","journal-title":"Nat. Nanotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113909","DOI":"10.1016\/j.colsurfb.2024.113909","article-title":"A minimalist cancer cell membrane-shielded biomimetic nanoparticle for nasopharyngeal carcinoma active-targeting therapy","volume":"238","author":"Sun","year":"2024","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e15588","DOI":"10.1016\/j.heliyon.2023.e15588","article-title":"Anti-inflammatory effect of glycyrrhetinic acid in IL-1beta-induced SW982 cells and adjuvant-induced arthritis","volume":"9","author":"Song","year":"2023","journal-title":"Heliyon"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sommerfelt, R.M., Feuerherm, A.J., Skuland, T., and Johansen, B. (2015). Cytosolic phospholipase A2 modulates TLR2 signaling in synoviocytes. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119088"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1084\/jem.20020205","article-title":"Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis","volume":"196","author":"Grant","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1080\/13684730050515796","article-title":"Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis","volume":"6","author":"Kaneko","year":"2000","journal-title":"Cytokines Cell Mol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Iwaszko, M., Bialy, S., and Bogunia-Kubik, K. (2021). Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis. Cells, 10.","DOI":"10.3390\/cells10113000"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1159\/000538241","article-title":"The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation","volume":"148","author":"Buelli","year":"2024","journal-title":"Nephron"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hornum, L., Hansen, A.J., Tornehave, D., Fjording, M.S., Colmenero, P., Watjen, I.F., Soe Nielsen, N.H., Bliddal, H., and Bartels, E.M. (2017). C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189017"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/nn.4053","article-title":"Different immune cells mediate mechanical pain hypersensitivity in male and female mice","volume":"18","author":"Sorge","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3594","DOI":"10.1111\/bph.16407","article-title":"Pronociceptive role of spinal Ca(v)2.3 (R-type) calcium channels in a mouse model of postoperative pain","volume":"181","author":"Ferreira","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"173168","DOI":"10.1016\/j.pbb.2021.173168","article-title":"Sex differences in the elevated plus-maze test and large open field test in adult Wistar rats","volume":"204","author":"Knight","year":"2021","journal-title":"Pharmacol. Biochem. Behav."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/16\/17\/1100\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T08:49:08Z","timestamp":1788252548000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/16\/17\/1100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":44,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["nano16171100"],"URL":"https:\/\/doi.org\/10.3390\/nano16171100","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}