Protein‐Coated Biodegradable Gas‐Stabilizing Nanoparticles for Cancer Therapy and Diagnosis Using Focused Ultrasound

Surface‐engineered hydrophobic nanoparticles that can stabilize small gas pockets on their surfaces (i.e., gas‐stabilizing nanoparticles, GSNs) have been recently shown to be excellent contrast and cavitation agents for ultrasound theranostics. However, previously developed GSNs are not biodegradable, which limits their clinical translation potential. Here the development of biodegradable GSNs is shown by coating hydrophobically modified mesoporous silica nanoparticles with different protein solutions. It is found that these novel GSNs retain strong cavitation activity while rapidly degrading in simulated body fluid (SBF) or in vivo in days or a few weeks, respectively. Interestingly, GSNs coated with other stabilizing layers, Pluronic F127 polymer or phospholipids, demonstrated significantly slower degradation rates with only partial degradation even after a month of incubation in SBF. Next, it is shown that these biodegradable GSNs can be used to ablate tumor xenografts at lower ultrasound intensities, thus avoiding the side effects of high‐intensity ultrasound. Finally, it is shown that only tumors treated with GSNs and ultrasound can specifically enrich for circulating tumor DNA, which will improve liquid biopsies for understanding tumor heterogeneity and treatment response. Overall, this study details a simple yet effective method for preparing biodegradable GSNs with broad potential for applications in cancer diagnosis and therapy. Biodegradable gas‐stabilizing nanoparticles are developed for ultrasound theranostics by coating hydrophobic mesoporous silica nanoparticles with different protein solutions. These biodegradable nanoparticles enhance the mechanical effects of focused ultrasound to ablate tumor xenografts in mice at low ultrasound intensities. The nanoparticle‐enhanced tumor ablation also enhances the concentration of circulating tumor DNA to enable a more sensitive liquid biopsy of cancer.