Tuning Core Fluidity in Emulsion Nanoparticles for Stable and Transition-Metal-Free Responsive 19F MRI Probes.

19F magnetic resonance imaging (19F MRI) enables the visualization of probes containing 19F nuclei without background signals and has been widely applied to the in vivo imaging of target tissues and biochemical processes. In the design of 19F MRI probes, nanoparticles containing liquid fluorinated molecules, such as nanoemulsions, have been developed to increase the local 19F concentration and MR signal intensity by incorporating mobile 19F nuclei; however, their limited stability remains a major challenge. While conventional stabilization strategies rely on surface coating with silica or polymers, their surface elasticity, which influences delivery efficiency and long-term in vivo accumulation, cannot be readily controlled. Additionally, responsive probe designs often rely on paramagnetic metals, raising concerns regarding toxicity. To solve these problems, we report emulsion-based 19F MRI probes that incorporate solid lipids into their core, thereby enhancing emulsion stability while providing responsiveness through the regulation of internal fluidity. In this approach, simultaneous control of emulsion stability and internal fluidity was achieved without using rigid external coatings, resulting in stable probes that were clearly visualized by in vivo19F MRI and exhibited minimal accumulation, with clearance occurring within 1 day. Furthermore, incorporation of ROS-responsive solid lipids led to the development of a probe in which reaction-induced changes in fluidity activate the 19F MR signal, enabling the visualization of biomarker responses without the use of paramagnetic metals. This strategy provides a new design paradigm in which the physicochemical properties of 19F MRI probes are tuned through internal structural regulation, offering a versatile platform for controlling probe behavior and developing responsive imaging agents.