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

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.