Ultrasound-responsive microencapsulated curcumin nanobubbles for treatment of mice rheumatoid arthritis and mechanistic insights based on single-cell Transcriptomics.

BACKGROUND: Curcumin (Cur) inhibits rheumatoid arthritis (RA) progression with few adverse effects, but its hydrophobicity limits clinical use. METHODS: RA fibroblast-like synoviocytes (RA‑FLS) were treated with Cur to assess apoptosis, migration, invasion, and viability. Curcumin-loaded nanobubbles (Cur@NB) were prepared via thin-film hydration and characterized, and their in vitro drug release and serum stability were evaluated. Cellular uptake and the effects of Cur, Cur@NB, and Cur@NB+US on RA-FLS were compared in vitro. An RA mouse model received Cur@NB with ultrasound-targeted microbubble destruction (UTMD), and its biodistribution, inflammatory responses and systemic toxicity were evaluated, followed by single‑cell RNA sequencing. RESULTS: Cur dose‑dependently reduced RA‑FLS viability, migration, and invasion while promoting apoptosis. Cur@NB exhibited favorable physicochemical properties, ultrasound-responsive drug release, and good serum stability. Cur@NB+US most strongly inhibited RA-FLS viability, migration, and invasion and promoted apoptosis in vitro. Ultrasound‑assisted Cur@NB preferentially accumulated in inflamed joints and enhanced anti‑inflammatory and therapeutic effects against RA with good safety. Bioinformatics revealed downregulation of proliferation, migration, and inflammation‑related genes. CONCLUSION: Ultrasound‑assisted Cur@NB inhibits RA‑FLS proliferation, migration, and invasion, induces apoptosis, and alleviates inflammation, offering a novel RA therapy strategy.