Trace Mg-Doped Ultrasmall Iron Oxide Nanoparticles with Boosted T1 Relaxivity for Highly Sensitive MRI of...

Accurate magnetic resonance imaging (MRI) of microvascular occlusive diseases, exemplified by subsegmental pulmonary embolism (SSPE), remains a clinical challenge because of the intrinsic limitations of clinically available Gd-based small molecular contrast agents (CAs). Ultrasmall iron oxide nanoparticles (USIOs)-based CAs have emerged as promising alternatives, offering adjustable MRI T1 relaxivity, favorable pharmacokinetics, and high biocompatibility; however, their performance is critically hampered by inefficient atomic utilization for MR T1 relaxivity enhancement. Herein, we report Mg-doped USIOs MRI CAs with high atomic utilization efficiency, where incorporating a biocompatible Mg dopant into surface octahedral-site Fe vacancies substantially boosts the T1 relaxivity, enabling accurate detection of SSPE-associated structural and perfusion abnormalities. The Mg0.03-USIOs exhibit a 261-fold enhancement of T1 relaxivity contribution by the Mg dopant, achieving an exceptionally high T1 relaxivity of 12.6 mM-1 s-1. Such a high atomic utilization efficiency could stem from the promoted spin polarization and ferromagnetic spin alignment through the surface Mg doping, which considerably boosts the magnetic moment and outer-sphere relaxation contribution. Further in vivo MRI studies in a pig SSPE model demonstrated that the Mg0.03-USIOs enabled visualization of structural and perfusion abnormalities in SSPE, far surpassing the capabilities of Gd-based CAs. In vivo biosafety assessment in the pig model confirmed the high biocompatibility of Mg0.03-USIOs. Our findings provide a highly efficient doping strategy to construct high-performance USIOs-based T1 CAs for sensitive MRI of microvascular structural and functional abnormalities.