Water-Soluble Chemically Precise Fluorinated Molecular Clusters for Interference-Free Multiplex ¹⁹F MRI in Living Mice

Fluorine-19 magnetic resonance imaging ( 19 F MRI) is gaining widespread interest from the fields of biomolecule detection, cell tracking, and diagnosis, benefiting from its negligible background, deep tissue penetration, and multispectral capacity. However, a wide range of 19 F MRI probes are in great demand for the development of multispectral 19 F MRI due to the limited number of high-performance 19 F MRI probes. Herein, we report a type of water-soluble molecular 19 F MRI nanoprobe by conjugating fluorine-containing moieties with a polyhedral oligomeric silsesquioxane (POSS) cluster for multispectral color-coded 19 F MRI. These chemically precise fluorinated molecular clusters are of excellent aqueous solubility with relatively high 19 F contents and of single 19 F resonance frequency with suitable longitudinal and transverse relaxation times for high-performance 19 F MRI. We construct three POSS-based molecular nanoprobes with distinct 19 F chemical shifts at −71.91, −123.23, and −60.18 ppm and achieve interference-free multispectral color-coded 19 F MRI of labeled cells in vitro and in vivo . Moreover, in vivo 19 F MRI reveals that these molecular nanoprobes could selectively accumulate in tumors and undergo rapid renal clearance afterward, illustrating their favorable in vivo behavior for biomedical applications. This study provides an efficient strategy to expand the 19 F probe libraries for multispectral 19 F MRI in biomedical research.