From nanoparticles to safe imaging: Cytotoxicity insights for lanthanide-based MRI contrast agents

Magnetic Resonance Imaging (MRI) is a high-resolution, noninvasive imaging method widely used in clinics, with imaging sensitivity enhanced by the contrast agent's ability to modulate proton relaxation times. Over the last few years, lanthanide nanoparticles have emerged as promising MRI contrast agents due to their strong magnetic properties and the convenient nanoscale engineering. Gadolinium-based nanoparticles have been widely utilized as T 1 -weighted contrast agents, while lanthanide-nanoparticles containing lanthanides holmium, dysprosium, and terbium have shown high potential as T 2 -weighted contrast agents. Nanoscale formulations enable enhanced relaxivity, colloidal stability, and surface functionalization, supporting targeted and multimodal imaging capabilities. However, increased interactions between nanoparticles and biological systems at the nanoscale raise particular concerns about cytotoxicity and biocompatibility. This review critically examines the in vitro cytotoxicity evaluation of lanthanide nanoparticles, emphasizing how physicochemical parameters, such as particle size and shape, surface charge, coating type, and cell type, influence biological responses. Various cell viability assays, including metabolism-based assays (MTT, MTS, WST, resazurin), cellular energy status (CellTiter-Glo), and membrane integrity (LDH), were used to observe the cytotoxic effects of nanoparticles. These studies show that rationally designed lanthanide nanoparticles, particularly those surface-functionalized with biocompatible coatings such as PEG, hyaluronic acid, or targeting ligands, exhibit minimal cytotoxicity and maintain high cell viability. Several aspects must be considered to achieve safe and effective nanoparticles as promising MRI contrast agents.