{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T19:17:30Z","timestamp":1787944650051,"version":"build-2784847793"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2023M731023"],"award-info":[{"award-number":["2023M731023"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2023M731023"],"award-info":[{"award-number":["2023M731023"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Henan Province\u2019s Science and Technology Research and Development","award":["242102311212"],"award-info":[{"award-number":["242102311212"]}]},{"name":"Henan Province\u2019s Science and Technology Research and Development","award":["262102310545"],"award-info":[{"award-number":["262102310545"]}]},{"name":"Key Research and Development Special Project of Henan Province","award":["241111311200"],"award-info":[{"award-number":["241111311200"]}]},{"name":"Joint Funds of Science and Technology Research and Development Project of Henan Province","award":["232301420070"],"award-info":[{"award-number":["232301420070"]}]},{"name":"Joint Funds of Science and Technology Research and Development Project of Henan Province","award":["235200810046"],"award-info":[{"award-number":["235200810046"]}]},{"name":"Joint Funds of Science and Technology Research and Development Project of Henan Province","award":["235200810108"],"award-info":[{"award-number":["235200810108"]}]},{"name":"Key Research Projects of Henan Provincial Colleges and Universities","award":["25A310008"],"award-info":[{"award-number":["25A310008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Methotrexate (MTX) is a well-established therapeutic agent for psoriasis owing to its anti-inflammatory and immunomodulatory effects. However, its clinical use is limited by insufficient local accumulation in skin lesions and the potential risk of systemic exposure. Dunaliella salina-derived exosome (DsEXO) has favorable biocompatibility, low immunogenicity and potential skin delivery capacity, making it a promising natural nanocarrier for topical MTX delivery. This study aimed to construct Dunaliella salina-derived exosome loaded with methotrexate (DsEXO@MTX) and evaluate its therapeutic efficacy and potential mechanisms in psoriasis-like skin inflammation. Methods: DsEXO@MTX was prepared and characterized in terms of morphology, particle size, surface charge and drug-loading capacity. Cellular uptake, skin retention and tissue distribution were evaluated using fluorescence imaging and skin section analysis. Therapeutic efficacy was evaluated in an imiquimod-induced psoriasis-like mouse model by clinical scoring, histopathological examination, spleen index measurement and Ki-67 immunofluorescence staining. STAT3 phosphorylation and Th17\/Treg differentiation were further examined to explore the potential immunomodulatory mechanism. Results: DsEXO@MTX exhibited a relatively uniform particle size distribution and drug-loading capacity. In vivo fluorescence imaging and skin section analysis showed that DsEXO@MTX enhanced local skin retention and promoted fluorescence distribution in epidermal and dermal regions. It significantly alleviated IMQ-induced erythema, scaling, epidermal thickening, inflammatory infiltration, splenomegaly and abnormal keratinocyte proliferation in psoriasis-like mice. Mechanistically, DsEXO@MTX reduced STAT3 phosphorylation and modulated Th17\/Treg differentiation, suggesting restoration of immune balance in psoriatic inflammation. Conclusions: DsEXO@MTX represents a natural exosome-like nanovesicle-mediated topical MTX delivery system that improves local drug delivery and enhances therapeutic efficacy in IMQ-induced psoriasis-like skin inflammation, particularly when administered topically. These findings provide a potential strategy for safer and more efficient local treatment of psoriasis.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091085","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:33:52Z","timestamp":1787942032000},"page":"1085","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical Dunaliella salina-Derived Exosome Loaded with Methotrexate Alleviates Psoriasis-like Inflammation via STAT3-Dependent Th17\/Treg Balance"],"prefix":"10.3390","volume":"18","author":[{"given":"Yitong","family":"Yang","sequence":"first","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Guo","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"},{"name":"Henan Engineering Research Center for Chinese Medicine Foods for Special Medical Purpose, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binbin","family":"Sun","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Dou","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanjiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Medical Plant Garden of Guangxi Zhuang Autonomous Region, Nanning 530023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2466-4912","authenticated-orcid":false,"given":"Shuying","family":"Feng","sequence":"additional","affiliation":[{"name":"Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, China"},{"name":"Henan Engineering Research Center for Chinese Medicine Foods for Special Medical Purpose, Zhengzhou 450046, China"},{"name":"Medical Plant Garden of Guangxi Zhuang Autonomous Region, Nanning 530023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-025-00630-5","article-title":"Psoriasis","volume":"11","author":"Armstrong","year":"2025","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(20)32549-6","article-title":"Psoriasis","volume":"397","author":"Griffiths","year":"2021","journal-title":"Lancet"},{"key":"ref_3","first-page":"467","article-title":"Psoriasis as a systemic disease","volume":"121","author":"Mrowietz","year":"2024","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Li, Z., Gu, Z., Xiang, J., and Zhang, X. (2025). The incidence of metabolic syndrome in psoriasis patients and its correlation with disease activity: A systematic review and meta-analysis. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1593003"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41419-022-04523-3","article-title":"Advances in the pathogenesis of psoriasis: From keratinocyte perspective","volume":"13","author":"Zhou","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s12016-024-08991-7","article-title":"The immunology of psoriasis-current concepts in pathogenesis","volume":"66","author":"Sieminska","year":"2024","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Brembilla, N.C., and Boehncke, W.H. (2023). Revisiting the interleukin 17 family of cytokines in psoriasis: Pathogenesis and potential targets for innovative therapies. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1186455"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zdanowska, N., Kasprowicz-Furmanczyk, M., Placek, W., and Owczarczyk-Saczonek, A. (2021). The role of chemokines in psoriasis-an overview. Medicina, 57.","DOI":"10.3390\/medicina57080754"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41419-025-07358-w","article-title":"S1PR3-driven positive feedback loop sustains STAT3 activation and keratinocyte hyperproliferation in psoriasis","volume":"16","author":"Lian","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s40001-023-01144-0","article-title":"Transcriptional regulation on effector T cells in the pathogenesis of psoriasis","volume":"28","author":"Qu","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1186\/s12967-023-04427-6","article-title":"MicroRNA-125a-5p regulates the effect of Tregs on Th1 and Th17 through targeting ETS-1\/STAT3 in psoriasis","volume":"21","author":"Yan","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kim, J., Moreno, A., and Krueger, J.G. (2022). The imbalance between type 17 T-cells and regulatory immune cell subsets in psoriasis vulgaris. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1005115"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1080\/09546634.2022.2117539","article-title":"Methotrexate dosing regimen for plaque-type psoriasis: An update of a systematic review","volume":"33","author":"Sikkel","year":"2022","journal-title":"J. Dermatol. Treat."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mocanu, M., Procopciuc, D., Gheuca-Solovastru, D.F., Popescu, I.A., Olinici, D.T., Patrascu, A.I., Vata, D., and Gheuca-Solovastru, L. (2024). An overview of methotrexate indications in skin diseases. Medicina, 60.","DOI":"10.3390\/medicina60071024"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.jaad.2020.07.087","article-title":"Joint AAD-NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures","volume":"84","author":"Elmets","year":"2021","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bodnar, K., Feher, P., Ujhelyi, Z., Bacskay, I., and Jozsa, L. (2024). Recent approaches for the topical treatment of psoriasis using nanoparticles. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16040449"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"122535","DOI":"10.1016\/j.ijpharm.2022.122535","article-title":"Nanotechnology-based alternatives for the topical delivery of immunosuppressive agents in psoriasis","volume":"631","author":"Gomes","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kocsis, D., Horvath, S., Kemeny, A., Varga-Medveczky, Z., Pongor, C., Molnar, R., Mihaly, A., Farkas, D., Naszlady, B.M., and Fulop, A. (2022). Drug delivery through the psoriatic epidermal barrier-a \u201cskin-on-a-chip\u201d permeability study and ex vivo optical imaging. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084237"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Orsmond, A., Bereza-Malcolm, L., Lynch, T., March, L., and Xue, M. (2021). Skin barrier dysregulation in psoriasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910841"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, M., Hong, S., Sun, X., Zhou, Y., Luo, Y., Liu, L., Wang, J., Wang, C., Lin, N., and Li, X. (2022). Exploration of and insights into advanced topical nanocarrier systems for the treatment of psoriasis. Front. Med., 9.","DOI":"10.3389\/fmed.2022.1017126"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Thery","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/s41565-021-00931-2","article-title":"Extracellular vesicles as a next-generation drug delivery platform","volume":"16","author":"Herrmann","year":"2021","journal-title":"Nat. Nanotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"20417314251319474","DOI":"10.1177\/20417314251319474","article-title":"Extracellular vesicles: From large-scale production and engineering to clinical applications","volume":"16","author":"Wang","year":"2025","journal-title":"J. Tissue Eng."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12081","DOI":"10.1002\/jev2.12081","article-title":"Nanoalgosomes: Introducing extracellular vesicles produced by microalgae","volume":"10","author":"Adamo","year":"2021","journal-title":"J. Extracell. Vesicles"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tang, B., Bi, Y., Zheng, X., Yang, Y., Huang, X., Yang, K., Zhong, H., Han, L., Lu, C., and Chen, H. (2024). The role of extracellular vesicles in the development and treatment of psoriasis: Narrative review. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16121586"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ncrna.2025.08.007","article-title":"Exosome-like nanovesicles from Dunaliella salina efficient sequential co-delivery of anti-PDL1 and miR-375 for enhancing gene\/immune therapy","volume":"14","author":"Wei","year":"2025","journal-title":"Non-Coding RNA Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12645-026-00382-1","article-title":"Preparation of oridonin-loaded microalgae-derived small extracellular vesicles and their anti-colorectal cancer efficacy evaluation","volume":"17","author":"Wang","year":"2026","journal-title":"Cancer Nanotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12341","DOI":"10.1021\/acsami.7b18135","article-title":"Methotrexate-loaded extracellular vesicles functionalized with therapeutic and targeted peptides for the treatment of glioblastoma multiforme","volume":"10","author":"Ye","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e12238","DOI":"10.1002\/jev2.12238","article-title":"Identification of storage conditions stabilizing extracellular vesicles preparations","volume":"11","author":"Gorgens","year":"2022","journal-title":"J. Extracell. Vesicles"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1186\/s12964-024-01548-3","article-title":"Strategies for labelling of exogenous and endogenous extracellular vesicles and their application for in vitro and in vivo functional studies","volume":"22","author":"Boudna","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.4049\/jimmunol.0802999","article-title":"Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23\/IL-17 axis","volume":"182","author":"Mourits","year":"2009","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/s42003-022-03129-x","article-title":"Rap1 prevents colitogenic Th17 cell expansion and facilitates Treg cell differentiation and distal TCR signaling","volume":"5","author":"Ishihara","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature04753","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells","volume":"441","author":"Bettelli","year":"2006","journal-title":"Nature"},{"key":"ref_37","first-page":"100888","article-title":"Fourier-Transform InfraRed (FT-IR) spectroscopy to show alterations in molecular composition of EV subpopulations from melanoma cell lines in different malignancy","volume":"25","author":"Stepien","year":"2021","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_38","first-page":"e18761429361884","article-title":"The role of complement component 3 (C3) in Psoriasis","volume":"17","author":"Cao","year":"2024","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s40262-023-01341-4","article-title":"Clinical pharmacokinetic and pharmacodynamic considerations in the treatment of moderate-to-severe psoriasis","volume":"63","author":"Greenzaid","year":"2024","journal-title":"Clin. Pharmacokinet."},{"key":"ref_40","first-page":"327","article-title":"Development and evaluation of methotrexate and baicalin-loaded nanolipid carriers for psoriasis treatment","volume":"21","author":"Sohail","year":"2024","journal-title":"Turk. J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Shinde, S., Singh, A.K., Chidrawar, V.R., Rajput, A., and Singh, S. (2025). Enhanced topical delivery of methotrexate via transferosome-loaded microneedle array patch: Formulation, optimization, and in vitro-in vivo assessment. Pharmaceuticals, 18.","DOI":"10.3390\/ph18040594"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1080\/03639045.2022.2117373","article-title":"Development and evaluation of a novel methotrexate-loaded electrospun patch to alleviate psoriasis plaques","volume":"48","author":"Hashemi","year":"2022","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/j.jid.2021.06.019","article-title":"Mouse models of psoriasis: A comprehensive review","volume":"142","author":"Gangwar","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.jid.2025.09.005","article-title":"Reevaluating the imiquimod model: A barrier to translational progress in psoriasis","volume":"146","author":"Smith","year":"2026","journal-title":"J. Investig. Dermatol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1085\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:35:12Z","timestamp":1787942112000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/9\/1085"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["pharmaceutics18091085"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18091085","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}