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.