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Microbubbles are widely used as contrast agents to improve the diagnostic capability of conventional, highly speckled, low-contrast ultrasound imaging. However, while microbubbles can be used for molecular imaging, these agents are limited to the vascular space due to their large size (&gt; 1 μm). Smaller microbubbles are desired but their ultrasound visualization is limited due to lower echogenicity or higher resonant frequencies. Here we present nanometer scale, phase changing, blinking nanocapsules (BLInCs), which can be repeatedly optically triggered to provide transient contrast and enable background-free ultrasound imaging. In response to irradiation by near-infrared laser pulses, the BLInCs undergo cycles of rapid vaporization followed by recondensation into their native liquid state at body temperature. High frame rate ultrasound imaging measures the dynamic echogenicity changes associated with these controllable, periodic phase transitions. Using a newly developed image processing algorithm, the blinking particles are distinguished from tissue, providing a background-free image of the BLInCs while the underlying B-mode ultrasound image is used as an anatomical reference of the tissue. We demonstrate the function of BLInCs and the associated imaging technique in a tissue-mimicking phantom and in vivo for the identification of the sentinel lymph node. Our studies indicate that BLInCs may become a powerful tool to identify biological targets using a conventional ultrasound imaging system.

Blinking Phase-Change Nanocapsules Enable Background-Free Ultrasound Imaging