Development of Sub-50 nm Core-Shell Silica Nanoparticles With Controlled In Vivo Behavior for ¹⁹F Magnetic Resonance...

¹⁹F magnetic resonance imaging (¹⁹F 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 ¹⁹F MRI probes that demonstrate high ¹⁹F 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 ¹⁹F 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 ¹⁹F MRI signals. In vivo ¹⁹F 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 ¹⁹F MRI nanoprobes to achieve controlled in vivo behaviors, providing a promising platform for future molecular imaging applications.