Curcumin-loaded tetrahedral framework nucleic acids reshape intestinal homeostasis in ulcerative colitis by coordinating barrier repair, microbiota reconstruction, and immune modulation.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) primarily driven by oxidative stress, sustained inflammation, barrier dysfunction, and gut dysbiosis. Current therapeutic drugs face limitations including complex synthetic processes, significant side effects, and suboptimal efficacy. Herein, we propose a simple, safe, and high-efficiency therapeutic strategy using curcumin-loaded tetrahedral framework nucleic acids (tFNAs-Cur) to reshape intestinal homeostasis in UC by coordinating barrier repair, microbiota reconstruction, and antigen presentation modulation. The synthesized tFNAs-Cur demonstrated high Cur loading, stability, water solubility, and biocompatibility. At the cellular level, tFNAs-Cur is efficiently taken up by lipopolysaccharide-stimulated RAW264.7 cells, exerting potent antioxidant and anti-inflammatory effects. In the dextran-sulfate-sodium-induced UC mouse model, tFNAs-Cur shows enhanced colon accumulation, attenuates weight loss and disease activity index, preserves colon length, repairs intact crypt architecture, and thereby restores intestinal barrier function. Further transcriptomic and biochemical analyses reveal that tFNAs-Cur alleviates IBD by upregulating H2-DMb1, potentially enhancing antigen presentation, while concurrently suppressing pro-inflammatory factors (TNF-α, IL-6, NO) and promoting anti-inflammatory cytokine IL-10. Additionally, 16S rRNA sequencing shows that tFNAs-Cur restores a healthy gut microbiota by enriching probiotic Muribaculaceae and suppressing pro-inflammatory bacteria. Collectively, tFNAs-Cur presents a safe, readily translatable, and efficient clinical candidate for UC by coordinating multiple synergistic mechanisms.