New Frontiers in Contrast-Enhanced Ultrasound for Cancer Imaging

Nanobubbles (NBs) are increasingly recognized as the next generation of ultrasound contrast agents that can provide alternate avenues for the advancement of cancer imaging and therapy. Compared to currently clinically viable microbubbles that are limited to the vasculature because of their size, nanobubbles with diameters ranging from 200 to 500 nm can potentially target the perivascular and possibly extravascular compartments. Their polymeric, lipid, or hybrid shells can be engineered to tune stability, increase circulation time, and support surface functionalization with ligands to facilitate receptor-directed binding. Preclinical studies show that NBs can extend ultrasound imaging windows, improve sensitivity, and increase tumor-to-background contrast across different types of cancers. NBs can also be formulated with secondary reporters that allow their combination with other imaging modalities, such as optical (photoacoustic and fluorescence) and magnetic resonance imaging. However, several challenges need to be overcome to allow the clinical translation of NBs, such as acoustic optimization and standardization, formulation and manufacturing reproducibility, and comprehensive safety characterization. Addressing these barriers will be essential to establishing NBs as clinically viable agents. Here, we summarize recent advances in NB design and functionalization, review key preclinical oncology applications, and discuss translational priorities to support their integration into precision oncology clinical workflows.