Dynamic HA/D-mannose dual-ligand nanomedicine reprograms macrophage-epithelial crosstalk for precision therapy of colitis.

Ulcerative colitis (UC) is characterized by complex spatiotemporal heterogeneity, which poses significant challenges for effective treatment. Herein, we constructed DS-HDLTQs, a core-shell nanodelivery platform with dynamic dual-targeting capabilities. This platform utilizes hyaluronic acid (HA) and D-mannose (D-Man) to target acute inflammation and promote repair. It also features a dopamine-alginate (DA-SA, or DS) shell to achieve pH-responsive release specifically at colonic lesions. In animal experiments, DS-HDLTQs achieved 83.3% mucosal healing in just 7 days, significantly outperforming single-targeting systems. The DA-SA protective layer ensures pH-responsive release in the colon with an efficiency of up to 92.7%. Such therapeutic enhancement is driven by three synergistic mechanisms: molecular functional synergy (restoring antioxidants), spatiotemporal targeting-pathological process synergy (accelerating barrier reconstruction), and immune-epithelial repair synergy (promoting macrophage polarization and epithelial regeneration). DS-HDLTQs demonstrated a 12.7-fold increase in drug concentration at the lesion site. This design resolves the core contradiction between dynamic pathology and oral delivery efficiency, providing a new paradigm for UC treatment and potential applications in other inflammatory diseases.