Cascade-targeting strategy with UTMD for noninvasive transendothelial delivery of TBK1-PROTAC for enhancing anti-inflammatory efficacy in abdominal aortic aneurysm

Restricted by high shear stress and the arterial endothelial barrier, effective delivery of anti-inflammatory drugs into the aortic media remains a major challenge. We found that the inflammatory microenvironment in the medial layer of human abdominal aortic aneurysm (AAA) tissues was closely associated with aberrant activation of the STING pathway. To enhance transendothelial delivery of the proteolysis-targeting chimera (PROTAC) that inhibits the STING pathway to alleviate the inflammatory microenvironment, we designed a cascade-targeting strategy based on ultrasound-targeted microbubble destruction. Magnetic nanoparticles and macrophage membrane were integrated into the shell of microbubbles to enhance PROTAC accumulation at AAA by magnetic guidance and inflammation-mediated targeting. By tuning the acoustic pressure of low-frequency focused ultrasound, cascade-targeted microbubbles reversibly open the aortic endothelial barrier, resulting in a 10.4-fold increase in PROTAC concentration in the medial layer. This approach effectively suppressed AAA progression while maintaining favorable biosafety. Overall, this strategy offers a potentially generalizable approach to enhance transendothelial delivery of anti-inflammatory drugs to the aortic medial layer in inflammatory aortic diseases by overcoming the constraints imposed by high shear stress and the endothelial barrier.