Multielement Doping Engineered Iron Oxide Nanoparticles: Enabling the Shift from Negative to Positive MRI Contrast for Enhanced Diagnostic Precision

Abstract Contrast‐enhanced magnetic resonance imaging (CE‐MRI) is a crucial tool for the diagnosis and management of various diseases globally. Iron oxide nanoparticles with sizes less than 5 nm are expected to address the long‐term toxicity and brain accumulation issues associated with clinical gadolinium‐based T 1 contrast agents (GBCAs) due to their non‐toxicity and biodegradability. However, synthesizing sub‐5‐nanometer particles presents significant challenges that complicate their clinical translation. Herein, traditional iron oxide‐based negative ( T 2 ) agents into positive ( T 1 ) agents are transformed and an all‐in‐one multielement doping strategy is developed. Multiple elements into iron oxide crystals are introduced to form multielement doping engineered iron oxide nanoparticles (MDE‐IONPs) and their surfaces with flexible hydrophilic ligands are subsequently modified. It is shown that Ni (II) and Gd (III) doping engineered nanoparticles can effectively enhance imaging efficacy, reducing clearance rates, and enabling controlled synthesis. Ultimately, the implementation of Ni (II) and Gd (III) co‐engineering yield longitudinal relaxivity of up to 14.7 mM −1 s −1 even for particles as large as 9 nm, an improvement of approximately 300% over GBCAs. Combined with the stability, biosafety, both in vitro and in vivo results suggest that all‐in‐one multielement doping is a favorable strategy for advancing the development of next‐generation safe MRI contrast agents.