Cattaneo Marco, Guerriero Giulia, Shakya Gazendra, Krattiger Lisa A, G Paganella Lorenza, Narciso Maria L, Supponen Outi
Institute of Fluid Dynamics, ETH Zürich, Zürich, Switzerland.
Department of Obstetrics, University Hospital Zürich, University of Zürich, Zürich, Switzerland.
Nat Phys. 2025;21(4):590-598. doi: 10.1038/s41567-025-02785-0. Epub 2025 Feb 21.
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.
对能够克服包括血脑屏障在内的生物屏障的靶向疗法的追求，激发了对可改善治疗效果并减少不良副作用的刺激响应性微制剂的研究。静脉注射的超声响应性微泡是很有前景的制剂，在临床试验中已显示出潜力，但药物吸收的潜在机制仍不清楚。在这里，我们表明超声驱动的单个微泡会刺穿细胞膜并通过稳定的循环微射流诱导药物摄取。我们的理论模型成功地再现了观察到的气泡和细胞动态响应。我们发现循环射流源于形状不稳定性，这与由压力梯度驱动的经典惯性射流不同，能够在低于100kPa的温和超声压力下形成微射流。我们还确定了气泡径向膨胀的阈值，超过该阈值微射流形成并促进细胞渗透，并表明微射流产生的应力比先前提出的机制至少强一个数量级。总体而言，这项工作阐明了微泡介导的靶向药物递送背后的物理原理，并为其有效和安全应用提供了标准。
