Objective Osteopontin (OPN) is highly expressed in vulnerable atherosclerotic plaques and suggested to be a good bio-marker and imaging target. This study was aimed at designing poly lactic acid (PLA) nanoparticles coupled with OPN antibodies for OPN-targeted ultrasonic molecular imaging. Methods PLA-perfluorooctyl bromide nanoparticles (PLA-PFOB NPs) were prepared by oil-in-water emulsion process. Subsequently, amino polyethylene glycol carboxyl (NH2-PEG-COOH) was attached to PLA through carbodiimide method. OPN antibody was conjugated with PEG-PLA-PFOB NPs by amide bonds to obtain OPN-targeted nanoprobe for ultrasound imaging. The biocompatibility of PLA NPs was evaluated in RAW264.7 cells by CCK-8 assay. Morphological characterizations of the probes were detected by transmission electron microscopy and particle size analyzer. Sensibility of the probes was evaluated by cellular uptake assay under laser scanning confocal microscope. Ultrasonic imaging was conducted with enhanced ultrasonography with PLA NPs as contrast agent. Results The PLA NPs were sphere or spherical in shape, with a hydrodynamic size of(267.60±82.40)nm. CCK-8 assay revealed that the nanoprobes showed negligible cytotoxicity at a dose from 0.00 to 0.50 mg/ml in foam cells, and no significant difference was observed in cell viability in different groups of cells (P>0.05). Cellular uptake assay also showed there were obviously large amount of the nanoparticle in the foam cells (P<0.05). Ultrasound imaging showed the probes presented fine punctuate hyper echo with no attenuation for the rear echo in the latex tubes on the pulse inversion harmonic image. Conclusion Our prepared OPN-targeted ultrasound contrast nanoprobes are of high biocompatibility, and can specifically bind to OPN highly expressed foam cells, and have excellent ultrasound signals in contrast-enhanced ultrasound imaging.