Selective Modulation of Th1‐Mediated Inflammation and T Cell Metabolism via Shikonin‐Loaded Nanogels

ABSTRACT Chronic inflammatory and autoimmune diseases are characterised by dysregulated Th1 and Th17 immune responses, leading to excessive production of proinflammatory cytokines. Shikonin (SK) is a natural anti‐inflammatory compound whose therapeutic use is limited by poor solubility and bioavailability. Here, we evaluated SK‐loaded hyaluronic acid‐zein (HA‐Zein) nanogels as a targeted strategy to modulate inflammatory CD4 + T‐cell responses in vitro and in vivo. HA‐Zein nanogels were designed to preferentially target CD44 + activated/effector T cells, key mediators of inflammation in Th1‐ or Th17‐associated diseases. SK‐HA‐Zein nanogels preferentially interacted with CD44 + activated CD4 + T cells and reduced IFN‐γ production and Th1‐associated polarisation while preserving Th17‐associated readouts. At higher concentrations, SK enhanced FoxP3/IL‐10‐associated regulatory features. Metabolomic analysis revealed that SK‐HA‐Zein nanogels inhibited key metabolic activities of Th1 cells, including glutamine and glucose consumption, thereby reducing overall cellular activity. In an acute in vivo inflammation model, SK‐HA‐Zein nanogels reduced local IFN‐γ levels and inflammatory cell infiltration. These findings support SK‐HA‐Zein nanogels as a targeted immunometabolic strategy to dampen inflammatory CD4+ T‐cell responses and promote regulatory features in chronic inflammatory settings.