Grapefruit-derived nanovesicles: a promising nanoplatform for enhancing the therapeutic efficacy of andrographolide against ulcerative colitis.

Andrographolide (AGP) is a promising bioactive candidate for treating ulcerative colitis (UC), but its clinical application is severely hindered by poor water solubility and low oral bioavailability. Plant-derived nanovesicles have emerged as attractive oral delivery systems due to their biocompatibility, inherent bioactivity, cost-effectiveness, and ability to improve the bioavailability and therapeutic efficacy of anti-UC agents. Herein, we developed bioactive and biocompatible grapefruit-derived nanovesicles (GDNs) as an efficient delivery system for AGP to treat UC. GDNs were prepared via PEG8000 precipitation combined with ultracentrifugation, and AGP was loaded into GDNs through reproducible ultrasonic incubation, achieving a drug loading capacity of 9.50 ± 0.48% (w/w). Pharmacokinetic assays in rats demonstrated that oral administration of AGP-loaded GDNs (GDNs-AGP) increased plasma AGP concentration by 2.75-fold and prolonged its retention time compared with free AGP. In a dextran sulfate sodium (DSS)-induced UC mouse model, GDNs-AGP outperformed free AGP and GDNs alone in attenuating disease severity, as evidenced by improved colon length, reduced histological damage, and downregulated pro-inflammatory cytokines expression. Mechanistically, GDNs-AGP exerted anti-UC effect by restoring intestinal microbiota homeostasis and regulating unsaturated fatty acid biosynthesis pathways. These results indicate that GDNs serve as a versatile and efficient delivery system for hydrophobic natural products such as AGP, offering a promising strategy to enhance their therapeutic efficacy in UC treatment.