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Because of the multifactorial pathogenesis of DFUs, there is a pressing demand for novel drug delivery approaches capable of enhancing treatment effectiveness. This study aimed to enhance topical drug delivery for DFU management through the formulation and optimization of a Quercetin-loaded hyaluosome gel (QCN-HS). The nanoformulation was prepared and characterized, followed by in vitro and in vivo evaluations. The optimized QCN-HS demonstrated an entrapment efficiency of 88.1%, a mean particle size of 122.42\u00a0nm, and a zeta potential of \u2212\u200924 mV. Morphological assessment by transmission electron microscopy revealed a uniform cuboidal-to-rounded square architecture without aggregation, further validated by FTIR spectroscopy. QCN-HS significantly reduced the expression of pro-inflammatory cytokines (TGF-\u03b2, TNF-\u03b1, IL-17, and IL-6) and lowered MPO activity, while markedly increasing GST and GSH levels. Moreover, QCN-HS downregulated ADAMTS-5 and MMP-13 while upregulating TIMP-3, findings corroborated by scratch assay and IC50 data, confirming effective regulation of extracellular matrix turnover. Histological and immunohistochemical analyses further demonstrated significant suppression of NF-\u03baB expression in skin tissue. The quercetin-loaded hyaluosome gel, with favorable physicochemical properties and high entrapment efficiency, showed strong therapeutic potential for DFU treatment. Both in vitro and in vivo results underscore its ability to attenuate inflammation, enhance antioxidant defenses, and promote extracellular matrix remodeling; these outcomes strengthen the rationale for QCN-HS as an effective targeted treatment for DFUs.<\/jats:p>","DOI":"10.1038\/s41598-026-37537-4","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:35:21Z","timestamp":1771335321000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Topical treatment of diabetic foot ulcers using a novel quercetin-loaded hyaluosome gel nanoformulation"],"prefix":"10.1038","volume":"16","author":[{"given":"Mohamed S.","family":"Amer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid A.","family":"El-Nesr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma I. 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