{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:54:40Z","timestamp":1792184080871,"version":"4.4.0"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82174074"],"award-info":[{"award-number":["82174074"]}]},{"name":"National Natural Science Foundation of China","award":["2023ZY031"],"award-info":[{"award-number":["2023ZY031"]}]},{"name":"Air Force Medical Center, Air Force Medical University, PLA, Beijing","award":["82174074"],"award-info":[{"award-number":["82174074"]}]},{"name":"Air Force Medical Center, Air Force Medical University, PLA, Beijing","award":["2023ZY031"],"award-info":[{"award-number":["2023ZY031"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Purpose: Androgenetic alopecia (AGA) is a common, chronic, non-cicatricial dermatological condition characterized by progressive miniaturization of hair follicles. Although AGA is a benign disorder, it has a considerable impact on patients\u2019 quality of life and psychological health. The current treatment options often demonstrate limited efficacy and are frequently associated with undesirable side effects. This study aimed to co-mill two natural compounds, quercetin (QT) and glycyrrhizic acid (GL), to develop follicle-targeted nanocrystals (NCs), thereby enhancing local accumulation, improving the pathological follicular microenvironment associated with AGA, and promoting hair regrowth. Methods: QT nanocrystals (QT-NCs) were fabricated using a top\u2013down wet media milling technique with GL as a bioactive stabilizer. The resulting QT-NCs were characterized regarding their particle size, crystallinity, morphology, and stability. The skin permeation properties of the QT-NCs were further evaluated in vitro, and their therapeutic efficacy was assessed in a dihydrotestosterone (DHT)-induced AGA mouse model. Results: The QT-NCs exhibited an irregular structure with a particle size ranging from 200 to 300 nm, demonstrating uniform dimensions and excellent storage stability. In vitro permeation studies revealed a 2.27-fold increase in cumulative penetration and a 2.47-fold enhancement in skin retention compared to raw QT. In the DHT-induced AGA mouse model, QT-NCs significantly reduced local DHT levels while concurrently modulating the follicular microenvironment, resulting in markedly improved therapeutic outcomes. Notably, when co-administered, QT and GL demonstrated synergistic pharmacological effects, suggesting potential combinatory benefits. Conclusions: This study presents the first demonstration of QT-NCs for AGA treatment, establishing a novel therapeutic strategy with substantial potential for clinical translation.<\/jats:p>","DOI":"10.3390\/pharmaceutics17091188","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T13:43:02Z","timestamp":1757684582000},"page":"1188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Quercetin Nanocrystal Gel: A Novel Topical Therapeutic Strategy for Androgenetic Alopecia"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0029-2871","authenticated-orcid":false,"given":"Yaya","family":"Su","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6328-8150","authenticated-orcid":false,"given":"Yuwen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Air Force Medical Center, PLA, Air Force Medical University, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","first-page":"112","article-title":"Bioinspired engineering ADSC nanovesicles thermosensitive hydrogel enhance autophagy of dermal papilla cells for androgenetic alopecia treatment","volume":"36","author":"Xiong","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jdin.2023.07.005","article-title":"Androgenetic alopecia: An update","volume":"13","author":"Ntshingila","year":"2023","journal-title":"JAAD Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.2147\/CCID.S385861","article-title":"Treatment of Androgenetic Alopecia: Current Guidance and Unmet Needs","volume":"16","author":"Kaiser","year":"2023","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"85","DOI":"10.4103\/npmj.npmj_47_24","article-title":"Androgenetic Alopecia: A Review","volume":"31","author":"Oiwoh","year":"2024","journal-title":"Niger. Postgrad. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Choi, J.Y., Boo, M.Y., and Boo, Y.C. (2024). Can Plant Extracts Help Prevent Hair Loss or Promote Hair Growth? A Review Comparing Their Therapeutic Efficacies, Phytochemical Components, and Modulatory Targets. Molecules, 29.","DOI":"10.3390\/molecules29102288"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"154887","DOI":"10.1016\/j.phymed.2023.154887","article-title":"Quercetin: A promising therapy for diabetic encephalopathy through inhibition of hippocampal ferroptosis","volume":"126","author":"Cheng","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_7","first-page":"398","article-title":"Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration","volume":"14","author":"Zhao","year":"2023","journal-title":"Protein Cell"},{"key":"ref_8","first-page":"81","article-title":"A combination therapy for androgenic alopecia based on quercetin and zinc\/copper dual-doped mesoporous silica nanocomposite microneedle patch","volume":"24","author":"Zhang","year":"2023","journal-title":"Bioact. Mater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.ijpharm.2010.11.009","article-title":"Preparation of a chemically stable quercetin formulation using nanosuspension technology","volume":"404","author":"Gao","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xiang, H., Xu, S., Zhang, W.X., Li, Y., Zhou, Y.X., and Miao, X.Q. (2023). Skin permeation of curcumin nanocrystals: Effect of particle size, delivery vehicles, and permeation enhancer. Colloids Surf. B-Biointerfaces, 224.","DOI":"10.1016\/j.colsurfb.2023.113203"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1080\/17425247.2022.2110579","article-title":"Nanocrystals for controlled delivery: State of the art and approved drug products","volume":"19","author":"Kalhapure","year":"2022","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ijpharm.2011.08.026","article-title":"Lutein nanocrystals as antioxidant formulation for oral and dermal delivery","volume":"420","author":"Mitri","year":"2011","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1016\/j.drudis.2021.07.010","article-title":"Pharmaceutical nanocrystals: A promising approach for improved topical drug delivery","volume":"26","author":"Parmar","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1039\/D3CP04835G","article-title":"Glycyrrhizic acid aggregates seen from a synthetic surfactant perspective","volume":"26","author":"Fischer","year":"2024","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"122109","DOI":"10.1016\/j.ijpharm.2022.122109","article-title":"Glycyrrhizin micellar nanocarriers for topical delivery of baicalin to the hair follicles: A targeted approach tailored for alopecia treatment","volume":"625","author":"Zeng","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8814","DOI":"10.1021\/acs.nanolett.4c05420","article-title":"Co-Assembled Cryptotanshinone Derivative and Glycyrrhizic Acid Carrier-Free Hydrogel: A Synergistic Approach to Acne Treatment","volume":"25","author":"Zeng","year":"2025","journal-title":"Nano Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"140347","DOI":"10.1016\/j.foodchem.2024.140347","article-title":"Aspects of quercetin stability and its liposomal enhancement in yellow onion skin extracts","volume":"459","author":"Osojnik","year":"2024","journal-title":"Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.2147\/IJN.S459788","article-title":"Hair Follicle-Targeted Delivery of Azelaic Acid Micro\/Nanocrystals Promote the Treatment of Acne Vulgaris","volume":"19","author":"Ji","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1007\/s13346-023-01418-4","article-title":"Preparation of luteolin loaded nanostructured lipid carrier based gel and effect on psoriasis of mice","volume":"14","author":"Xu","year":"2024","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.2147\/IJN.S44924","article-title":"Process optimization and evaluation of novel baicalin solid nanocrystals","volume":"8","author":"Yue","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Alshaer, W., Alsotari, S., Aladaileh, N., Rifai, A., Khalaf, A., AlQuaissi, B., Sabbah, B., Nsairat, H., and Odeh, F. (2025). Clarithromycin-Loaded Albumin-Based Nanoparticles for Improved Antibacterial and Anticancer Performance. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17060729"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sheng, Y.Z., Yu, Q., Huang, Y.P., Zhu, Q.A., Chen, Z.J., Wu, W., Yi, T., and Lu, Y. (2023). Pickering Emulsions Enhance Oral Bioavailability of Curcumin Nanocrystals: The Effect of Oil Types. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051341"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105489","DOI":"10.1016\/j.jdent.2024.105489","article-title":"Remineralization and bacterial inhibition of early enamel caries surfaces by carboxymethyl chitosan lysozyme nanogels loaded with antibacterial drugs","volume":"152","author":"Zhou","year":"2025","journal-title":"J. Dent."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110707","DOI":"10.1016\/j.cclet.2024.110707","article-title":"A novel N-stable Co2P nano-catalyst for the synthesis of quinoxalines by annulation of alkynes and 1,2-diaminobenzenes","volume":"36","author":"Liu","year":"2025","journal-title":"Chin. Chem. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"125722","DOI":"10.1016\/j.ijpharm.2025.125722","article-title":"Development and characterisation of co-axial electrosprayed curcumin-loaded mesoporous silica and polymer composite coated microneedles","volume":"678","author":"Ali","year":"2025","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1016\/j.ijbiomac.2020.10.164","article-title":"Shear sensitive injectable hydrogels of cross-linked tragacanthic acid for ocular drug delivery: Rheological and biological evaluation","volume":"165","author":"Chegini","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"104458","DOI":"10.1016\/j.jddst.2023.104458","article-title":"The preparation of high minoxidil loaded transfersomes and its gel for effective topical treatment of alopecia","volume":"84","author":"Sun","year":"2023","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s42114-025-01287-0","article-title":"Glutamic acid-loaded separable microneedle composite for long-acting hair regeneration treatment","volume":"8","author":"Mbituyimana","year":"2025","journal-title":"Adv. Compos. Hybrid Mater."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"140751","DOI":"10.1016\/j.ijbiomac.2025.140751","article-title":"Near-infrared light-triggered nitric oxide-releasing hyaluronic acid hydrogel for precision transdermal therapy of androgenic alopecia","volume":"304","author":"Xing","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13759","DOI":"10.1021\/acsnano.1c05272","article-title":"Ceria Nanozyme-Integrated Microneedles Reshape the Perifollicular Microenvironment for Androgenetic Alopecia Treatment","volume":"15","author":"Yuan","year":"2021","journal-title":"ACS Nano"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"124863","DOI":"10.1016\/j.ijpharm.2024.124863","article-title":"Formulation and optimization of transferrin-modified genistein nanocrystals: In vitro anti-cancer assessment and pharmacokinetic evaluation","volume":"667","author":"Iqbal","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"121862","DOI":"10.1016\/j.ijpharm.2022.121862","article-title":"Review of nanosuspension formulation and process analysis in wet media milling using microhydrodynamic model and emerging characterization methods","volume":"623","author":"Tian","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1021\/acs.jafc.4c08659","article-title":"Encapsulation and Sustained Release of Quercetin-Loaded pH-Responsive Intelligent Nanovehicles Based on the Coassembly of Pea Protein Isolate and Hyaluronic Acid","volume":"73","author":"Wang","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_34","first-page":"100246","article-title":"Fabrication and in vitro\/vivo evaluation of quercetin nanocrystals stabilized by glycyrrhizic acid for liver targeted drug delivery","volume":"7","author":"Shen","year":"2024","journal-title":"Int. J. Pharm. X"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.36468\/pharmaceutical-sciences.500","article-title":"Enhancing Solubility of Candesartan Cilexetil by Co-milling; Preparation of Candesartan Cilexetil-glycyrrhizic Acid Composite","volume":"81","author":"Lu","year":"2019","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120546","DOI":"10.1016\/j.ijpharm.2021.120546","article-title":"Preparation, optimization, characterization and in vitro release of baicalein-solubilizing glycyrrhizic acid nano-micelles","volume":"601","author":"You","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"123197","DOI":"10.1016\/j.ijbiomac.2023.123197","article-title":"Chitosan\/glycyrrhizic acid hydrogel: Preparation, characterization, and its potential for controlled release of gallic acid","volume":"231","author":"Saeedi","year":"2023","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2412581","DOI":"10.1002\/advs.202412581","article-title":"Bioactive Glycyrrhizic Acid Ionic Liquid Self-Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti-Photoaging Signal Peptides","volume":"12","author":"Wang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1586924","DOI":"10.3389\/fbioe.2025.1586924","article-title":"Nanotechnology-driven nanoemulsion gel for enhanced transdermal delivery of Sophora alopecuroides L. empyreumatic oil: Formulation optimization, and anti-biofilm efficacy","volume":"13","author":"Cheng","year":"2025","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110163","DOI":"10.1016\/j.foodhyd.2024.110163","article-title":"Construction of oleogels based on emulsion gels stabilized by glycyrrhizic acid and chitosan","volume":"155","author":"Lin","year":"2024","journal-title":"Food Hydrocoll."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/jdv.20000","article-title":"Retinoic acid drives hair follicle stem cell activation via Wnt\/\u03b2-catenin signalling in androgenetic alopecia","volume":"39","author":"Wen","year":"2025","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"118227","DOI":"10.1016\/j.jep.2024.118227","article-title":"Ellagic acid inhibits dihydrotestosterone-induced ferroptosis and promotes hair regeneration by activating the wnt\/\u03b2-catenin signaling pathway","volume":"330","author":"Fu","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"142114","DOI":"10.1016\/j.molstruc.2025.142114","article-title":"ZnS\/MnO2 nanocomposite electrodes: A dual approach for superior supercapacitor and safety open structure lithium-ion battery","volume":"1336","author":"Godlaveeti","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2303095","DOI":"10.1002\/adhm.202303095","article-title":"Traditional Scraping (Gua Sha) Combined with Copper-Curcumin Nanoparticle Oleogel for Accurate and Multi-Effective Therapy of Androgenic Alopecia","volume":"13","author":"Gao","year":"2024","journal-title":"Adv. Healthc. Mater."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6174","DOI":"10.1021\/acs.nanolett.4c01843","article-title":"Polydopamine Synergizes with Quercetin Nanosystem to Reshape the Perifollicular Microenvironment for Accelerating Hair Regrowth in Androgenetic Alopecia","volume":"24","author":"Yang","year":"2024","journal-title":"Nano Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.det.2012.08.003","article-title":"Pattern Hair Loss in Men Diagnosis and Medical Treatment","volume":"31","author":"Banka","year":"2013","journal-title":"Dermatol. Clin."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kesika, P., Sivamaruthi, B.S., Thangaleela, S., Bharathi, M., and Chaiyasut, C. (2023). Role and Mechanisms of Phytochemicals in Hair Growth and Health. Pharmaceuticals, 16.","DOI":"10.3390\/ph16020206"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s12668-025-01828-3","article-title":"QbD-Enabled Development of Quercetin Dihydrate-Loaded Nanostructured Lipid Carriers: In vitro Characterization, Safety and Efficacy Assessment in Androgenetic Alopecia Mice Model","volume":"15","author":"Sayyed","year":"2025","journal-title":"BioNanoScience"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1080\/03639045.2019.1652635","article-title":"Phospholipid-polymer hybrid nanoparticle-mediated transfollicular delivery of quercetin: Prospective implement for the treatment of androgenic alopecia","volume":"45","author":"Das","year":"2019","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"114068","DOI":"10.1016\/j.colsurfb.2024.114068","article-title":"A carrier-free, injectable, and self-assembling hydrogel based on carvacrol and glycyrrhizin exhibits high antibacterial activity and enhances healing of MRSA-infected wounds","volume":"241","author":"Cui","year":"2024","journal-title":"Colloids Surf. B-Biointerfaces"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"40228","DOI":"10.1021\/acsami.3c07582","article-title":"Cyclodextrin-Coordinated Liposome-in-Gel for Transcutaneous Quercetin Delivery for Psoriasis Treatment","volume":"15","author":"Zhang","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/9\/1188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:44:46Z","timestamp":1760035486000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/9\/1188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,12]]},"references-count":51,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["pharmaceutics17091188"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17091188","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,12]]}}}