Advances in iron-storage protein-based MRI reporter genes: from molecular mechanisms to translational imaging...

Non-invasive monitoring of cellular and molecular events is essential for advancing precision medicine. While exogenous probes often suffer from signal dilution, iron-storage protein-based MRI reporter genes offer an alternative for longitudinal tracking, because contrast is regenerated by the cells themselves. Especially ferritin and its engineered variants have attracted growing interest due to their ability to regulate intracellular iron and generate endogenous T2/T2* contrast. This review summarizes the molecular mechanisms and design principles of iron-based MRI reporter genes, and examines recent developments including CRISPR-mediated integration and manganese-dependent "Bright Ferritin" platforms, which generate positive T1 contrast but require repeated administration of exogenous manganese. Preclinical studies have tracked cellular dynamics in vivo and monitored transgene expression after viral gene delivery, although the evidence base remains almost entirely preclinical. Nevertheless, a persistent challenge lies in generating sufficiently strong MRI contrast while maintaining the delicate balance of intracellular iron metabolism on which these reporters depend. By linking molecular design to imaging performance, this review distinguishes what has been demonstrated experimentally from what remains prospective, and identifies the quantitative and safety questions that stand between the current evidence and clinical use.