Multi-interfacial microbubbles controlled sequential cavitation for synergistic vascular destruction/chemotherapeutic therapy

Microbubbles have emerged as versatile theranostic platforms in biomedicine. In addition to being used as ultrasound contrast agents, capitalizing on cavitation-mediated physical effects, microbubbles now enable targeted drug delivery and precision tumor ablation. In this study, we engineer doxorubicin (DOX)-loaded multi-interfacial microbubbles (DOX-MIMBs) through interfacial self-assembly of hydrophobic mesoporous silica nanoparticles (hMSNs), establishing a hierarchically structured MIMBs with the sustained acoustic activity. Strong affinity between hMSNs and the gas-liquid interface facilitates cavitation effect transmission. Under low intensity ultrasound (<3 W/cm²) irradiation, primary MIMBs collapse generates secondary daughter bubbles that rapidly stabilize via hMSNs-mediated gas-liquid interface reconstruction and are able to cavitate again. This process enables energy-cascaded cavitation-successive bubble generations persisting until acoustic energy dissipation, achieving prolonged cavitation duration versus conventional lipid-shelled microbubbles. The sequential acoustomechanical perturbation generated by DOX-MIMBs induced synergistic tumor therapy: selective vascular destruction for mechanically collapsed immature tumor vasculature and enhanced chemotherapy for wider distribution and deeper penetration of DOX in tumors. Utilizing sequential bubble cavitation-induced shockwave and microstreaming, by integrating tumor vasculature mechanical disruption and deep tumor DOX penetration chemotherapy, DOX-MIMBs achieved tumor volume appropriate 90 % reduction in renal cell carcinoma models. Such elaborated DOX-MIMBs mechano-pharmaceutical delivery system achieve a paradigm shift from systemic drug bombardment to local mechanochemical tumor suppression and provide a powerful strategy for tumor precision therapy.