{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T11:46:23Z","timestamp":1775216783606,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Research Support Program for Excellent Young Teachers in Heilongjiang Province","award":["YQJH2023216"],"award-info":[{"award-number":["YQJH2023216"]}]},{"DOI":"10.13039\/501100005046","name":"Heilongjiang Province Natural Science Foundation","doi-asserted-by":"crossref","award":["LH2024H003"],"award-info":[{"award-number":["LH2024H003"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study developed a transdermal drug delivery system for Rheumatoid Arthritis (RA) using a dual-network hydrogel microneedle patch loaded with methotrexate nanocrystals (DHMN@MTX-NCs), and explored its synergistic therapy with Adalimumab (ADA) for a painless, long-acting, and targeted RA treatment. This study synthesized Methacrylated Hyaluronic Acid and Methacrylated Gelatin. MTX-NCs were prepared by solvent-antisolvent precipitation and incorporated into a dual-network hydrogel microneedle patch via centrifugal molding. Evaluations included pharmaceutical properties, mechanical strength, drug release, in vitro anti-inflammatory effects on RAW 264.7 cells, and therapeutic efficacy in a rat RA model. The experimental results show that the prepared MTX-NCs present a spherical shape, an average size of 325.72 nm, a PDI of 0.154, and a drug-loading capacity of 61.3%. The microneedle patch exhibited high puncture efficiency and suitable swelling. In vitro, DHMN@MTX-NCs combined with ADA most strongly inhibited macrophage migration, upregulated IL-10, and downregulated TNF-\u03b1, IL-1\u03b2, NO, iNOS, and COX-2. In vivo, both monotherapy and combination therapy reduced joint swelling, bone erosion, and histopathological damage. Ultimately, the study demonstrated the synergistic anti-inflammatory efficacy of DHMN@MTX-NCs combined with ADA, providing a novel, non-invasive, and targeted therapeutic strategy for RA.<\/jats:p>","DOI":"10.3390\/ijms27042075","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T14:05:11Z","timestamp":1771855511000},"page":"2075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Study on the Treatment of Rheumatoid Arthritis Using a Novel GelMA-HAMA Dual-Network Hydrogel Microneedle Loaded with MTX-NCs in Combination with Adalimumab"],"prefix":"10.3390","volume":"27","author":[{"given":"Jianing","family":"Tian","sequence":"first","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhang","family":"Shi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyu","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mu","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusi","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huilin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Su","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Ping","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Jiamusi University, Jiamusi 154007, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e15376","DOI":"10.1111\/1756-185X.15376","article-title":"The role of non-coding RNAs in fibroblast-like synoviocytes in rheumatoid arthritis","volume":"27","author":"Zheng","year":"2024","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"827","DOI":"10.2147\/IJGM.S444056","article-title":"Combining Traditional Chinese Herbs and csDMARDs for the Treatment of Rheumatoid Arthritis Involves Tapering and Discontinuing Glucocorticoids: Protocol for a Two-Stage Non-Randomized Controlled Trial","volume":"17","author":"Wang","year":"2024","journal-title":"Int. J. Gen. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/BOR.0000000000001142","article-title":"Epidemiology and outcomes of rheumatoid arthritis","volume":"38","author":"Klingemann","year":"2026","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"An, P., Ma, Z., Tian, T., Zhang, S., Wang, J., and Tian, Z. (2026). Global burden and genetic insights of RA and JIA in ages 0-19 years: GBD 2021 and MR analysis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1661461"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s13075-023-03174-9","article-title":"Comprehensive analysis of serum exosome-derived lncRNAs and mRNAs from patients with rheumatoid arthritis","volume":"25","author":"Li","year":"2023","journal-title":"Arthritis Res. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rom\u00e3o, V.C., and Fonseca, J.E. (2021). Etiology and Risk Factors for Rheumatoid Arthritis: A State-of-the-Art Review. Front. Med., 8.","DOI":"10.3389\/fmed.2021.689698"},{"key":"ref_7","first-page":"21","article-title":"Cytokine pathways driving diverse tissue pathologies in rheumatoid arthritis","volume":"35","author":"Najm","year":"2025","journal-title":"Arthritis Rheumatol."},{"key":"ref_8","first-page":"55","article-title":"Effects of concomitant methotrexate and predictors of remission in Janus kinase inhibitor therapy for rheumatoid arthritis","volume":"31","author":"Asai","year":"2025","journal-title":"Jt. Bone Spine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.ard.2025.03.002","article-title":"Treatment with methotrexate plus oral prednisolone versus triple therapy (methotrexate\/sulfasalazine\/hydroxychloroquine) plus intra-articular glucocorticoids in early rheumatoid arthritis: A prespecified nonrandomised subgroup analysis of clinical and radiographic data at 48 weeks from the NORD-STAR trial\u2019s conventional treatment arm","volume":"84","author":"Hetland","year":"2025","journal-title":"Ann. Rheum. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Radu, A.F., and Bungau, S.G. (2021). Management of Rheumatoid Arthritis: An Overview. Cells, 10.","DOI":"10.3390\/cells10112857"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1681\/ASN.0000000000000245","article-title":"Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE)","volume":"35","author":"Pergola","year":"2024","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"116326","DOI":"10.1016\/j.bios.2024.116326","article-title":"Sensing patches for biomarker identification in skin-derived biofluids","volume":"258","author":"Wei","year":"2024","journal-title":"Biosens. Bioelectron."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2000307","DOI":"10.1002\/mabi.202000307","article-title":"Hydrogel-Forming Microneedles: Current Advancements and Future Trends","volume":"21","author":"Turner","year":"2021","journal-title":"Macromol. Biosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"40491","DOI":"10.1021\/acsami.2c05352","article-title":"Galunisertib-Loaded Gelatin Methacryloyl Hydrogel Microneedle Patch for Cardiac Repair after Myocardial Infarction","volume":"14","author":"Chen","year":"2022","journal-title":"ACS. Appl. Mater. Interfaces"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1208\/s12249-022-02462-y","article-title":"Combinatorial Approach of Thermosensitive Hydrogels and Solid Microneedles to Improve Transdermal Delivery of Valsartan: An In Vivo Proof of Concept Study","volume":"24","author":"Nirmayanti","year":"2022","journal-title":"AAPS PharmSciTech"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1021\/acs.molpharmaceut.0c00954","article-title":"Novel DEK-Targeting Aptamer Delivered by a Hydrogel Microneedle Attenuates Collagen-Induced Arthritis","volume":"18","author":"Cao","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"0485","DOI":"10.34133\/research.0485","article-title":"Bioinspired Wet Adhesive Proanthocyanidins Microneedles for Ocular Wound Healing","volume":"7","author":"Kong","year":"2024","journal-title":"Research"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1039\/D2BM01937J","article-title":"A mechanically tough and ultra-swellable microneedle for acute gout arthritis","volume":"11","author":"Jiang","year":"2023","journal-title":"Biomater. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12076","DOI":"10.1021\/acsomega.2c00335","article-title":"Three-Dimensional Printing Self-Healing Dynamic\/Photocrosslinking Gelatin-Hyaluronic Acid Double-Network Hydrogel for Tissue Engineering","volume":"7","author":"Wang","year":"2022","journal-title":"ACS. Omega"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"214064","DOI":"10.1016\/j.bioadv.2024.214064","article-title":"PI3K\/Akt pathway-mediated enhancement of bone and vascular regeneration by gelatin\/hyaluronic acid\/exosome composite scaffold in bone tissue engineering","volume":"166","author":"Wan","year":"2025","journal-title":"Biomater. Adv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109027","DOI":"10.1016\/j.exer.2022.109027","article-title":"Photo-crosslinked hydrogels for tissue engineering of corneal epithelium","volume":"218","author":"Sang","year":"2022","journal-title":"Exp. Eye. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1166\/jbn.2021.3088","article-title":"A Gelatin-Hyaluronic Acid Double Cross-Linked Hydrogel for Regulating the Growth and Dual Dimensional Cartilage Differentiation of Bone Marrow Mesenchymal Stem Cells","volume":"17","author":"Ren","year":"2021","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.2174\/0115680266346339250328153358","article-title":"Rheumatoid Arthritis: Pathogenesis, Therapeutic Strategies, Advances, and Structural Activity Relationships of Synthesized Agents","volume":"25","author":"Jan","year":"2025","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yu, X., Zhong, J., Zhuang, X., Lin, Z., Fu, H., and Zhang, Y. (2025). Drug-associated infections and infestations in older adults with tumor necrosis factor-alpha inhibitors: A real-world retrospective and pharmacovigilance study. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1533902"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1021\/acs.biomac.1c01063","article-title":"In Situ Forming Cellulose Nanofibril-Reinforced Hyaluronic Acid Hydrogel for Cartilage Regeneration","volume":"22","author":"Zhao","year":"2021","journal-title":"Biomacromolecules"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"110163","DOI":"10.1016\/j.compositesb.2022.110163","article-title":"DLP fabricating of precision GelMA\/HAp porous composite scaffold for bone tissue engineering application","volume":"244","author":"Song","year":"2022","journal-title":"Composites Part B"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ijbiomac.2020.12.204","article-title":"Hyaluronate-functionalized hydroxyapatite nanoparticles laden with methotrexate and teriflunomide for the treatment of rheumatoid arthritis","volume":"171","author":"Pandey","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17251","DOI":"10.1021\/acsnano.4c04816","article-title":"A Double Network Composite Hydrogel with Self-Regulating Cu2+\/Luteolin Release and Mechanical Modulation for Enhanced Wound Healing","volume":"18","author":"Li","year":"2024","journal-title":"ACS. Nano"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.actbio.2023.10.016","article-title":"Development of hyaluronic acid-silica composites via in situ precipitation for improved penetration efficiency in fast-dissolving microneedle systems","volume":"172","author":"Tay","year":"2023","journal-title":"Acta. Biomater."},{"key":"ref_30","unstructured":"(2009). Biological evaluation of medical devices\u2014Part 5: Tests for in vitro cytotoxicity (Standard No. ISO 10993-5)."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"822","DOI":"10.4014\/jmb.1911.11042","article-title":"Smilax guianensis Vitman extract prevents LPS-induced inflammation by inhibiting the NF-\u03baB pathway in RAW 264.7 cells","volume":"30","author":"Kim","year":"2020","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"153712","DOI":"10.1016\/j.phymed.2021.153712","article-title":"Cascade of immune mechanism and consequences of inflammatory disorders","volume":"91","author":"Megha","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"112482","DOI":"10.1016\/j.intimp.2024.112482","article-title":"Suaeda maritima polysaccharides attenuate LPS-induced inflammation of RAW264.7 cells and antioxidative activity","volume":"137","author":"You","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"154967","DOI":"10.1016\/j.phymed.2023.154967","article-title":"Guizhi Shaoyao Zhimu granules attenuate bone destruction in mice with collagen-induced arthritis by promoting mitophagy of osteoclast precursors to inhibit osteoclastogenesis","volume":"118","author":"Yao","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2305116","DOI":"10.1002\/advs.202305116","article-title":"Mesenchymal Stem Cells-Involved Strategies for Rheumatoid Arthritis Therapy","volume":"11","author":"Li","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"102422","DOI":"10.1016\/j.tice.2024.102422","article-title":"The role of TNF-\u03b1 in osteoporosis, bone repair and inflammatory bone diseases: A review","volume":"89","author":"Yao","year":"2024","journal-title":"Tissue. Cell."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41584-023-00969-7","article-title":"Shared inflammatory pathways of rheumatoid arthritis and atherosclerotic cardiovascular disease","volume":"19","author":"Weber","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eabq4419","DOI":"10.1126\/scitranslmed.abq4419","article-title":"Additive efficacy of a bispecific anti-TNF\/IL-6 nanobody compound in translational models of rheumatoid arthritis","volume":"15","author":"Biesemann","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s13770-021-00336-1","article-title":"Effect of TNF-\u03b1 and IL-6 on Compact Bone-Derived Cells","volume":"18","author":"Zhang","year":"2021","journal-title":"Tissue. Eng. Regen. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12967-025-06174-2","article-title":"Wnt signaling as a translational target in rheumatoid and psoriatic arthritis","volume":"23","author":"Riitano","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Riitano, G., Recalchi, S., Capozzi, A., Manganelli, V., Misasi, R., Garofalo, T., Sorice, M., and Longo, A. (2023). The Role of Autophagy as a Trigger of Post-Translational Modifications of Proteins and Extracellular Vesicles in the Pathogenesis of Rheumatoid Arthritis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612764"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"136773","DOI":"10.1016\/j.ijbiomac.2024.136773","article-title":"A multi-purpose dressing based on resveratrol-loaded ionic liquids\/gelatin methacryloyl hydrogel for enhancing diabetic wound healing","volume":"16","author":"Xu","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1021\/acsbiomaterials.3c01641","article-title":"Application of Biomaterials in the Development of Hydrogel-Forming Microneedles Integrated with a Cyclodextrin Drug Reservoir for Improved Pharmacokinetic Profiles of Telmisartan","volume":"10","author":"Enggi","year":"2024","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"123883","DOI":"10.1016\/j.ijpharm.2024.123883","article-title":"Industrializable approach for preparing hydrogel microneedles and their application in melanoma treatment","volume":"653","author":"Xing","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lin, W., Lin, S., Zhou, X., Yang, F., Lin, Z., Li, S., Zhang, H., Ouyang, Y., Zhu, J., and Sun, W. (2023). Biodegradable double-network GelMA-ACNM hydrogel microneedles for transdermal drug delivery. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1110604"},{"key":"ref_46","first-page":"355","article-title":"Impact of Formulation and Microneedle Length on Transdermal Metronidazole Permeation through Microneedle-Treated Skin","volume":"41","author":"Kumar","year":"2023","journal-title":"Pharmaceutical. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.2147\/DMSO.S317096","article-title":"Advances in Biological Functions and Clinical Studies of FGF21","volume":"14","author":"Lin","year":"2021","journal-title":"Diabetes. Metab. Syndr. Obes."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cclet.2020.11.048","article-title":"Nanotechnology for diagnosis and therapy of theumatoid arthritis:Evolution towards theranostic approaches","volume":"32","author":"Zhao","year":"2021","journal-title":"Chinese Chemical Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2075\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T05:26:56Z","timestamp":1771997216000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27042075"],"URL":"https:\/\/doi.org\/10.3390\/ijms27042075","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]}}}