Gram‐Scale Production of Iron Oxide Rubik‐Cube Nanoparticles: New Tools for the Clinical Translation of Magnetic Hyperthermia and Magnetic Particle Imaging

ABSTRACT This work presents the first gram‐scale solvothermal synthesis of a novel class of anisotropic nanoparticles with a distinctive architecture, termed “Rubik's cube nanoparticles.” These nanostructures combine an overall cubic morphology with a dendritic multi‐core structure, resulting in a unique morphology with record magnetic heating performance. Their formation is achieved by a carefully engineered mixture of shape‐directing agents, including a subclass of vinyl ketones and aromatic aldehydes. By adjusting the ketone/iron molar ratio or the reaction time, the nanoparticle size was tuned between 19 and 45 nm. Structural characterization confirms their single domain nature and identifies the Ƴ‐Fe 2 O 3 magnetic phase with cubic structure (space group Fd‐3m). Despite their large size, they exhibit low coercivity with high saturation magnetization, leading to record magnetic heat losses under clinically relevant radiofrequency excitation. Furthermore, Rubik's cube nanoparticles up to 27 nm show a medium viscosity‐independent magnetic heat efficiency. Particles with edge lengths of 27 and 42 nm exhibit enhanced performance in magnetic particle imaging compared to VivoTrax standard. Furthermore, the application of a magnetic field gradient during magnetic hyperthermia allows for spatial localization of heat generation. These properties position Rubik's cube nanoparticles as promising candidates for clinical translation with therapeutic efficacy and diagnostic precision in oncology.