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Shikonin (SK) is a natural anti\u2010inflammatory compound whose therapeutic use is limited by poor solubility and bioavailability. Here, we evaluated SK\u2010loaded hyaluronic acid\u2010zein (HA\u2010Zein) nanogels as a targeted strategy to modulate inflammatory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell responses in\u00a0vitro and in\u00a0vivo. HA\u2010Zein nanogels were designed to preferentially target CD44\n                    <jats:sup>+<\/jats:sup>\n                    activated\/effector T cells, key mediators of inflammation in Th1\u2010 or Th17\u2010associated diseases. SK\u2010HA\u2010Zein nanogels preferentially interacted with CD44\n                    <jats:sup>+<\/jats:sup>\n                    activated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and reduced IFN\u2010\u03b3 production and Th1\u2010associated polarisation while preserving Th17\u2010associated readouts. At higher concentrations, SK enhanced FoxP3\/IL\u201010\u2010associated regulatory features. Metabolomic analysis revealed that SK\u2010HA\u2010Zein nanogels inhibited key metabolic activities of Th1 cells, including glutamine and glucose consumption, thereby reducing overall cellular activity. In an acute in\u00a0vivo inflammation model, SK\u2010HA\u2010Zein nanogels reduced local IFN\u2010\u03b3 levels and inflammatory cell infiltration. These findings support SK\u2010HA\u2010Zein nanogels as a targeted immunometabolic strategy to dampen inflammatory CD4+ T\u2010cell responses and promote regulatory features in chronic inflammatory settings.\n                  <\/jats:p>","DOI":"10.1111\/imm.70169","type":"journal-article","created":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T13:53:32Z","timestamp":1785074012000},"page":"406-417","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Modulation of Th1\u2010Mediated Inflammation and T Cell Metabolism via Shikonin\u2010Loaded Nanogels"],"prefix":"10.1111","volume":"179","author":[{"given":"Matias","family":"Cardoso","sequence":"first","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry University of Aveiro  Aveiro Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8021-0451","authenticated-orcid":false,"given":"Marta","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho  Braga Portugal"},{"name":"ICVS\/3B's\u2014PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mendes\u2010Frias","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho  Braga Portugal"},{"name":"ICVS\/3B's\u2014PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Jo\u00e3o","family":"Peixoto","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho  Braga Portugal"},{"name":"ICVS\/3B's\u2014PT Government Associate Laboratory  Braga\/Guimar\u00e3es Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0372-2493","authenticated-orcid":false,"given":"V\u00edtor M.","family":"Gaspar","sequence":"additional","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry University of Aveiro  Aveiro Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2342-3765","authenticated-orcid":false,"given":"Jo\u00e3o F.","family":"Mano","sequence":"additional","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of Chemistry University of Aveiro  Aveiro Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iola F.","family":"Duarte","sequence":"additional","affiliation":[{"name":"CICECO\u2014Aveiro Institute of Materials, Department of 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