Cyclic jetting enables microbubble-mediated drug delivery

Abstract The pursuit of targeted therapies capable of overcoming biological barriers, including the blood–brain barrier, has spurred the investigation of stimuli-responsive microagents that can improve therapeutic efficacy and reduce undesirable side effects. Intravenously administered, ultrasound-responsive microbubbles are promising agents with demonstrated potential in clinical trials, but the mechanism underlying drug absorption remains unclear. Here we show that ultrasound-driven single microbubbles puncture the cell membrane and induce drug uptake through stable cyclic microjets. Our theoretical models successfully reproduce the observed bubble and cell dynamic responses. We find that cyclic jets arise from shape instabilities, as opposed to classical inertial jets that are driven by pressure gradients, enabling microjet formation at mild ultrasound pressures below 100 kPa. We also establish a threshold for bubble radial expansion beyond which microjets form and facilitate cellular permeation and show that the stress generated by microjetting outperforms previously suggested mechanisms by at least an order of magnitude. Overall, this work elucidates the physics behind microbubble-mediated targeted drug delivery and provides the criteria for its effective and safe application.