{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:39:17Z","timestamp":1785418757649,"version":"3.56.0"},"reference-count":96,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006701","name":"Umm al-Qura University","doi-asserted-by":"publisher","award":["26UQU4350639GSSR01"],"award-info":[{"award-number":["26UQU4350639GSSR01"]}],"id":[{"id":"10.13039\/501100006701","id-type":"DOI","asserted-by":"publisher"}]},{"award":["26UQU4350639GSSR01"],"award-info":[{"award-number":["26UQU4350639GSSR01"]}],"id":[{"id":"https:\/\/ror.org\/01xjqrm90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Skin aging is driven by oxidative stress and ultraviolet (UV) exposure, leading to extracellular matrix degradation and loss of skin elasticity. This study aimed to identify the most biologically active Citrus species using a bioassay-guided approach and evaluate its potential for dermal applications. Methods: Hydroalcohol extracts and ethyl acetate fractions of Citrus sinensis, Citrus aurantifolia, and Citrus reticulata leaves were screened for antioxidant, enzyme-inhibitory, and polyphenol content. The most active fraction was characterized by UPLC-PDA and LC\u2013MS\/MS, formulated into Span-based nanovesicles, and evaluated for physicochemical properties and drug release. Biological activity was assessed using an in vitro scratch wound-healing assay on human dermal fibroblasts and a UVA-induced photoaging mouse model, supported by molecular dynamics simulations. Results: The ethyl acetate fraction of C. aurantifolia (CAE) exhibited the highest biological activity among the tested samples. This fraction showed potent antioxidant activity (DPPH IC50 = 3.53 \u00b1 0.05 \u00b5g\/mL), marked inhibition of elastase (91.3%), collagenase (92.0%), and tyrosinase (80.2%), and a high total flavonoid content (110.49 mg rutin equivalents\/g). Phytochemical profiling of CAE tentatively identified fourteen compounds, predominantly flavonoids, with hesperidin (30.4 mg\/g) as a major constituent. The optimized nanovesicles (184 \u00b1 0.9 nm, PDI 0.10, EE% 75.0%) enabled sustained hesperidin release. CAE and CAEnp enhanced fibroblast migration and accelerated wound closure at 24 h (p &lt; 0.05). In vivo, CAEnp improved UVA-induced histopathological alterations and modulated oxidative stress-related markers by reducing p62\/SQSTM1 by 28.7%, Keap1 expression to 21% compared with the CAE-treated group, and enhancing Nrf2, ARE, and NQO1 expression by 54.1%, 28.3%, and 57%, respectively. Molecular dynamics simulations supported stable hesperidin binding to elastase and suggested possible modulation of collagenase flexibility. Conclusions: The polyphenol-rich leaf fraction from C. aurantifolia, identified through comparative bioassay-guided fractionation, demonstrated antioxidant, enzyme-inhibitory, wound-healing, and photoprotective effects, particularly after nanoformulation. These findings support its potential for further development as a natural topical anti-aging candidate.<\/jats:p>","DOI":"10.3390\/nu18132130","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T10:41:01Z","timestamp":1782902461000},"page":"2130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Bioassay-Guided Fractionation of Citrus Species: Phytochemical Characterization and Nanoformulation of a Polyphenol-Rich Leaf Fraction from Citrus aurantifolia for Skin Anti-Aging Applications"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1846-2265","authenticated-orcid":false,"given":"Noha","family":"Swilam","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled A.","family":"Nematallah","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3021-8767","authenticated-orcid":false,"given":"Amgad","family":"Albohy","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3823-5804","authenticated-orcid":false,"given":"Noha M.","family":"Badawi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1876-0548","authenticated-orcid":false,"given":"Sameh S.","family":"Gad","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences, and Arts MSA, 6th October City 12451, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1254-2504","authenticated-orcid":false,"given":"Maha M.","family":"Shouman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences, and Arts MSA, 6th October City 12451, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeed S.","family":"Al-Ghamdi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7782-0574","authenticated-orcid":false,"given":"Abdullah R.","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-889X","authenticated-orcid":false,"given":"Nahla","family":"Ayoub","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3390\/biom5020545","article-title":"Oxidative Stress in Aging Human Skin","volume":"5","author":"Rinnerthaler","year":"2015","journal-title":"Biomolecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3793\/jaam.6.46","article-title":"Photoaging of the skin","volume":"6","author":"Ichihashi","year":"2009","journal-title":"Anti-Aging Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Azevedo Martins, T.E., Sales De Oliveira Pinto, C.A., Costa De Oliveira, A., Robles Velasco, M.V., Gorriti Guiti\u00e9rrez, A.R., Cosquillo Rafael, M.F., Tarazona, J.P.H., and Retuerto-Figueroa, M.G. 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