Ultrasound-actuated drug delivery with acoustic percolation switches

Devices that can be remote-controlled under image guidance to precisely deliver biomedicines to sites of disease are a major goal of biomedical research. However, most existing externally triggered delivery systems are based on complex micromachines that are controlled with electromagnetic waves and require custom external instrumentation. Here we present a drug delivery platform comprising a simple protein-containing hydrogel that can be both imaged and triggered to release drugs at specific locations using widely available ultrasound imaging devices. This technology is based on the addition of air-filled protein nanostructures called gas vesicles (GVs) to hydrogel delivery vehicles. While intact, GVs sterically block the release of drug payloads and allow the vehicle to be imaged with ultrasound. An increase in ultrasound pressure causes the collapse of GVs within hydrogels present at the desired anatomical location, instantly creating percolation channels and triggering rapid drug release. Both the imaging and release are performed using a common diagnostic ultrasound probe. We implement this concept by establishing ultrasound-controlled drug diffusion and release from hydrogels in vitro and demonstrating targeted image-guided protein delivery in vivo following oral administration. We use this approach to deliver anti-inflammatory antibodies to treat gastrointestinal inflammation in a rat model of colitis. Targeted acoustic percolation switches (TAPS) open a conduit for local, image-guided drug delivery with a simple formulation and commonplace ultrasound equipment. ### Competing Interest Statement MPA and MGS are co-inventors on a patent application describing this technology (US17/092,215) assigned to the California Institute of Technology. The authors declare that they have no other competing financial interests.