Hyaluronic Acid-Functionalized Bismuth Sulfide Nanoparticles as Targeted CT Contrast Agents

Nanoparticle (NP)-based contrast agents offer a promising alternative to conventional iodinated compounds for computed tomography (CT) imaging. Here, we report hyaluronic acid (HA) –functionalized bismuth sulfide–loaded bovine serum albumin NPs (Bi₂S₃@BSA-HA) that combine high X-ray attenuation with CD44 receptor–mediated targeting. Bi₂S₃@BSA cores (~ 9 nm) were synthesized via BSA–Bi³⁺ coordination and in-situ sulfide precipitation, followed by surface functionalization with HA to improve colloidal stability, reduce NP aggregation, and enhance negative surface charge. Compared with unmodified Bi₂S₃@BSA and the clinical iodinated contrast agent Omnipaque, Bi₂S₃@BSA-HA exhibited significantly enhanced X-ray attenuation and contrast-to-noise ratios across multiple concentrations and tube voltages. Cytotoxicity assays demonstrated excellent biocompatibility, maintaining over 90% viability in HT-29 human colorectal cancer cells at bismuth concentrations up to 1000 µg mL ^− 1 . In vitro CT imaging further confirmed markedly higher cellular attenuation for Bi₂S₃@BSA-HA, consistent with CD44-mediated NP uptake. These findings highlight Bi₂S₃@BSA-HA as a promising candidate for targeted CT imaging, combining robust X-ray attenuation, receptor-specific internalization, and excellent cytocompatibility, and provide a foundation for future in vivo studies on its pharmacokinetics, biodistribution, clearance, and longer-term therapeutic safety.