Uptake Mechanism of Riboflavin-Functionalized Superparamagnetic Iron Oxide Nanoparticles in Triple-Negative Breast Cancer Cells

Superparamagnetic iron oxide nanoparticles (SPIONs), which are widely used as contrast agents in magnetic resonance imaging and as magnetic hyperthermia agents in cancer therapy, can be functionalized with biological molecules to enhance their specificity, stability, and cellular interaction. Riboflavin (Rf), a crucial biomolecule in cellular metabolism, is a potentially effective targeting moiety that can be selectively transported via riboflavin transporters (RFVTs), which are often overexpressed in cancer cells, including breast cancer cells. Here, we synthesize Rf-functionalized SPIONs (Rf-SPIONs) with high colloidal stability and stronger cellular interaction with breast cancer cells (MCF-7, and MDA-MB-231) than with normal breast cells (MCF-10A). Notably, the uptake is highest in triple-negative breast cancer cells (MDA-MB-231), a highly aggressive and treatment-resistant subtype. A mechanistic study revealed that RFVT is expressed in breast cancer cells and plays an important role in Rf-SPIONs uptake via the RFVT-mediated pathway. These findings identify riboflavin-functionalized nanoparticles as a promising platform for targeted delivery, diagnostic imaging, and cancer therapeutics. Rf-based nanomaterials could also pave the way for precision targeting of Rf-dependent metabolic pathways in cancer and other diseases.