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To develop and evaluate oleuropein-loaded hyalurosomes (OLE-HLs) as a unique topical nanocarrier system for wound healing using an experimental diabetic rat model. OLE-HLs were synthesized using a modified thin-film hydration method, and the nano-formulation was characterized by measuring the size and potential, followed by TEM, encapsulation efficiency, FTIR, in vitro release studies, and cell cytotoxicity assay. The wound-healing efficacy was evaluated in vitro, using scratch assay and in vivo, via studying the wound closure rate, oxidative stress markers, pro-inflammatory cytokines,\n                    <jats:italic>TGF\u03b21<\/jats:italic>\n                    gene expression, and histopathological alterations, complemented by immunohistochemical analysis. OLE-HLs exhibited a mean particle size of 254.64\u2009\u00b1\u20099.84\u00a0nm, a zeta potential of \u2212\u200925.12\u2009\u00b1\u20092.18\u00a0mV, and an encapsulation efficiency of 89.61\u2009\u00b1\u20091.82%, while TEM revealed spherical, uniformly sized, and well-dispersed vesicles, confirming stability and homogeneity. FTIR analysis verified successful oleuropein encapsulation and compatibility within the hyalurosomal system. The formulation displayed a biphasic release profile, with 26.47\u2009\u00b1\u20090.86% released in the first hour and 76.72\u2009\u00b1\u20092.45% within 24\u00a0h. Cytotoxicity assays showed enhanced bioactivity (IC\n                    <jats:sub>50<\/jats:sub>\n                    : 269.63\u00a0\u00b5g\/mL) compared with free OLE (644.81\u00a0\u00b5g\/mL). The scratching assay model was validated by the in vivo model, where OLE-HLs significantly promoted wound healing by reducing oxidative stress, as shown by increased GSH and GST levels and decreased MPO activity. It also suppressed inflammatory mediators (IL-6, IL-17, TNF-\u03b1, MMP-13, ADAMTS-5) and enhanced TIMP-3 expression. Additionally, regulation of TGF\u03b21 expression and improved histopathological and immunohistochemical features collectively supported better tissue repair. These data suggest that OLE-HLs notably promote diabetic foot ulcer healing by modulating inflammation, oxidative stress, and cellular regeneration, thereby warranting further clinical investigation.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-42804-5","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T08:27:19Z","timestamp":1774513639000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In vitro and in vivo evaluation of oleuropein loaded hyalurosomes for diabetic foot ulcer healing"],"prefix":"10.1038","volume":"16","author":[{"given":"Ahmed I.","family":"Elgendy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed O.","family":"El-Gendy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba M.","family":"Aboud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma I.","family":"Abo El-Ela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5386-8570","authenticated-orcid":false,"given":"Mohamed I.","family":"Zanaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"issue":"3","key":"42804_CR1","doi-asserted-by":"publisher","DOI":"10.4239\/wjd.v16.i3.100329","volume":"16","author":"K Parveen","year":"2025","unstructured":"Parveen, K., Hussain, M. 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