Counterion modulation of aza-BODIPY aggregation behaviour for boosted sonodynamic therapy

Small-molecule based sonosensitizers hold great promise for deep-seated tumor therapy, yet their structure-activity relationships (SARs) remained largely unexplored, hindering their further biomedical applications. Herein, we propose a counterion-engineering strategy to modulate the aggregation behaviour of aza-BODIPY dyes, thereby achieving high-performance sonodynamic therapy (SDT). We demonstrated that Cl^--paired aza-BODIPY dye (BT-Cl) formed nanoparticles with the smallest hydrodynamic diameter and yielded the highest levels of reactive oxygen species (ROS). BT-Cl NPs also displayed potent sonodynamic cytotoxicity toward both 4T1 and U87-MG cells. Consequently, BT-Cl exhibited excellent tumor growth inhibition with minimal side effects. Overall, this work underscored the critical role of noncovalent ion-pairing interactions in governing small-molecule sonosensitizer aggregation and provided a facile approach for the rational design of high-efficiency sonosensitizers.