Ferritin-encapsulated iron oxide nanoparticles for dual-mode MRI contrast enhancement and targeted cancer imaging

Background: Magnetic Resonance Imaging (MRI) is a crucial non-invasive diagnostic tool, yet its inherent contrast limitations often necessitate the use of exogenous agents. Conventional gadolinium-based contrast agents suffer from toxicity and limited specificity. Results: In this study, we present Fe₃O₄@HFn, an ultrasensitive MRI contrast agent composed of human ferritin (HFn) encapsulating iron oxide nanoparticles. Fe₃O₄@HFn enables dual-mode longitudinal relaxation time (T₁) and transverse relaxation time (T₂) contrast enhancement, significantly outperforming Gd-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a commonly used clinical MRI contrast agent, at both 3.0 T and 11.7 T. At 3.0 T, Fe₃O₄@HFn exhibits 1.56-fold and 40.1-fold higher longitudinal relaxation rate (r₁ = 5.20 s⁻¹mM⁻¹) and transverse relaxation rate (r₂ = 147.6 s⁻¹mM⁻¹), respectively. At 11.7 T, it maintains superior relaxation rates (r₁ = 0.85 s⁻¹mM⁻¹, r₂ = 178.0 s⁻¹mM⁻¹). Mechanistic studies demonstrated efficient tumor targeting via TfR1 receptor-mediated endocytosis in U87 glioma and HL60 leukemia cells. In vivo, Fe₃O₄@HFn exhibited high selectivity, excellent biocompatibility, and promising potential for early cancer detection and therapeutic monitoring. Significance: This work pioneers the integration of human ferritin nanocages with magnetic nanocores for precise, non-invasive cancer imaging, offering a transformative approach to early tumor detection and monitoring, and addressing critical safety and sensitivity limitations of existing MRI contrast agents.