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

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.