Cyclic jetting enables microbubble-mediated drug delivery

Abstract: The pursuit of targeted therapies capable of overcoming biological barriers, including the tenacious blood-brain barrier, has spurred the investigation into stimuli-responsive microagents. This approach could improve therapeutic efficacy, reduce undesirable side effects, and open avenues for treating previously incurable diseases. Intravenously-administered ultrasound-responsive microbubbles are one of the most promising agents, having demonstrated potential in several clinical trials. However, the mechanism by which microbubbles enhance drug absorption remains unclear. Here, we reveal through unprecedented time-resolved side-view visualisations that single microbubbles, upon microsecond-long ultrasound driving, puncture the cell membrane and induce drug uptake via stable cyclic microjets. Our theoretical models successfully reproduce the observed bubble and cell dynamic responses. We find that cyclic jets arise from shape instabilities, warranting recognition as a novel class of jets in bubbles, distinct from classical inertial jets driven by pressure gradients. We also establish a threshold for bubble radial expansion beyond which microjets form and facilitate cellular permeation. Remarkably, these microjets occur at ultrasound pressures below 100 kPa due to their unique formation mechanism. We show that the stress generated by microjetting surpasses all previously suggested mechanisms by at least an order of magnitude. In summary, this work elucidates the physics behind microbubble-mediated targeted drug delivery and provides criteria for its effective yet safe application.