nanoparticles, namely gas-stabilizing nanoparticles (GSNs), produce micron-sized bubbles when activated with sufficiently intense ultrasound pulses delivered using focused ultrasound (FUS) or standard ultrasound imaging transducers. The bubbles generated by GSNs enhance the contrast of ultrasound images as they are strong scatterers of ultrasound beams. [7][8][9][10][11] In addition, the non-stabilized bubbles rapidly collapse (i.e., inertial cavitation) to release intense mechanical energy and induce various biological effects in the tissue, from permeabilization of cell membranes to ablation of cells. [4,5,12] Thus, GSNs have also been used to enhance the outcomes of therapeutic ultrasound applications such as drug delivery, antivascular therapy, and thrombolysis. [1,[13][14][15][16][17][18][19][20][21] Conventional ultrasound contrast/cavitation agents include lipid-, protein-, or polymer-stabilized gas microbubbles and micro/nanodroplets of low-boiling point perfluorocarbons, which can be vaporized to form acoustically active microbubbles. [4,[22][23][24] Compared with these more conventional ultrasound contrast agents, GSNs pose several advantages: small size (down to ≈50 nm), excellent storage and in vivo stability, and high and durable cavitation activity. [2,9,[13][14][15]25] However, the non-degradable nature of GSNs is a concern as such nanoparticles can accumulate and potentially induce toxicity in the liver, spleen, and bone marrow. [26][27][28][29] 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.