Development of Sub‐50 nm Core–Shell Silica Nanoparticles With Controlled In Vivo Behavior for ¹⁹ F Magnetic Resonance Imaging

ABSTRACT 19 F magnetic resonance imaging ( 19 F MRI) enables quantitative and background‐free detection, but its inherently low sensitivity demands probes with high fluorine density and favorable pharmacokinetics. Perfluorocarbon (PFC)‐encapsulated nanoparticles are a promising class of 19 F MRI probes that demonstrate high 19 F MR sensitivity. However, their relatively large size (usually over 70 nm) results in slow hepatic clearance and limited tumor accumulation. Herein, we developed sub‐50 nm perfluoro‐15‐crown‐5‐ether (PFCE)‐loaded core–shell silica nanoparticles (s‐FLAME), which combine high 19 F signal intensity with reduced size distribution. The established one‐pot double‐emulsion‐based synthesis shortened the silica shell formation time, suppressed droplet coalescence, and kinetically fixed PFCE emulsions at smaller sizes, resulting in the preparation of uniform core–shell nanoparticles (s‐FLAME‐OH) with a core diameter of 30 nm—significantly smaller than previously reported liquid‐core systems. A co‐condensation approach yielded carboxyl‐functionalized nanoparticles (s‐FLAME‐COOH), which reduced cytotoxicity and improved colloidal stability. The resulting nanoparticles exhibited strong, concentration‐dependent 19 F MRI signals. In vivo 19 F MRI revealed accelerated hepatic clearance and tumor‐associated signals, indicating size‐dependent biodistribution. This study establishes a versatile strategy for tuning the size and surface chemistry of silica‐based 19 F MRI nanoprobes to achieve controlled in vivo behaviors, providing a promising platform for future molecular imaging applications.