(a) A schematic showing how the polarity-sensitive fluorophores encapsulated in the pH- and thermo-sensitive nanoparticle are switched on in an environment with a low pH value and a high temperature in USF imaging. When a nanoparticle is in an environment with a pH value lower than the pKa of acidic comonomer (such as in the tumor environment), the particle shrinks and water molecules are expelled. The polarity in the nanoparticle reduces, which leads to the fluorophores partially switching on. Upon applying the HIFU, the temperature increases above the LCST of the particle within the ultrasound focal zone. This further expels water molecules and reduces the polarity in the particle and, therefore, more fluorophores are switched on. (b) A schematic of the pKa of the comonomers. 9-decenoic acid has the highest pKa among the partially soluble carboxylic acids. (A color version of this figure is available in the online journal.)