Mechanistic understanding the bioeffects of ultrasound-driven microbubbles to enhance macromolecule delivery

Ultrasound-driven microbubbles can trigger reversible membrane perforation (sonoporation), open inter-endothelial junctions and stimulate endocytosis, thereby providing a temporary and reversible time-window for the delivery of macromolecules across biological membranes and endothelial barriers. This time-window is related not only to cavitation events, but also to biological regulatory mechanisms. Mechanistic understanding of the interaction between cavitation events and cells and tissues, as well as the subsequent cellular and molecular responses will lead to new design strategies with improved efficacy and minimized side effects. Recent important progress on the spatiotemporal characteristics of sonoporation, cavitation-induced interendothelial gap and endocytosis, and the spatiotemporal bioeffects and the preliminary biological mechanisms in cavitation-enhanced permeability, has been made. On the basis of the summary of this research progress, this Review outlines the underlying bioeffects and the related biological regulatory mechanisms involved in cavitation-enhanced permeability; provides a critical commentary on the future tasks and directions in this field, including developing a standardized methodology to reveal mechanism-based bioeffects in depth, and designing biology-based treatment strategies to improve efficacy and safety. Such mechanistic understanding the bioeffects that contribute to cavitation-enhanced delivery will accelerate the translation of this approach to the clinic.