Ultrasmall Superparamagnetic Iron Oxide Nanoparticles as Positive Contrast Agents in Low‐Field Magnetic Resonance Imaging

ABSTRACT Ultrasmall superparamagnetic iron oxide nanoparticles (usSPIONs) are promising alternatives to gadolinium‐based contrast agents for positive contrast enhancement in magnetic resonance imaging (MRI). Unlike larger SPIONs that primarily function as T2/T2* negative contrast agents, usSPIONs with core diameters below 5 nm can effectively shorten T1 relaxation times, producing bright signals in T1‐weighted images. This distinct behavior stems from their unique magnetic properties, including single‐domain configurations, surface spin canting, and rapid Néel relaxation dynamics, which are particularly enhanced at low magnetic field strengths. The biocompatibility of iron oxide, efficient renal clearance pathways, and versatility for surface functionalization offer potential advantages over gadolinium‐based agents, especially regarding safety concerns related to nephrogenic systemic fibrosis and gadolinium deposition. These nanoparticles show particular promise for applications in low‐field MRI, vascular imaging, targeted molecular imaging, and theranostic platforms. Although challenges remain in optimizing synthesis methods for consistent production of monodisperse usSPIONs with tailored surface chemistry, ongoing research continues to advance their potential for clinical translation. This review explores the mechanisms, synthesis approaches, applications, and future perspectives of usSPIONs as positive contrast agents in MRI.