ABSTRACT Objective To develop a photothermal ultrasound contrast agent with C3F8 filled-gold nanoshelled poly(lactide-co-glycolic acid) nanoparticles (C3F8@PLGA@Au NPs) and to investigate its photothermal effect and contrast enhanced ultrasound imaging capability. Methods The nanoscale agent was fabricated through filling C3F8 into PLGA, followed by the formation of gold nanoshell on the surface. The physicochemical properties of C3F8@PLGA@Au NPs were characterized by electronic microscopies and dynamic laser scattering. And its photothermal effect was assessed via monitoring temperature increase under the laser irradiation in vitro. The ultrasonic diagnostic instrument was used to evaluate the ultrasound contrast behavior of C3F8@PLGA@Au NPs. Results The C3F8@PLGA@Au NPs were observed with spherical morphology, good dispersion, and uniform size with average size of 268.2±80.5 nm. The MTT assay indicated the good biocompatibility of our NPs. And the imaging results in vitro and in vivo demonstrated that C3F8@PLGA@Au NPs provided excellent contrast enhancement for ultrasound imaging. Moreover, the NPs also served as efficient photoabsorbers for NIR photothermal therapy. Conclusion The photothermal ultrasound contrast agent has been designed and fabricated. The preliminary studies demonstrate that C3F8@PLGA@Au NPs have excellent photothermal effect in vitro and ultrasound imaging capability in vitro and in vivo.