An Ultrasound‐Activated Supramolecular Modulator Enhancing Autophagy to Prevent Ventricular Arrhythmias Post‐Myocardial Infarction

Abstract Ventricular arrhythmias (VAs) triggered by myocardial infarction (MI) are the leading cause of sudden cardiac mortality worldwide. Current therapeutic strategies for managing MI‐induced VAs, such as left stellate ganglion resection and ablation, are suboptimal, highlighting the need to explore safer and more effective intervention strategies. Herein, we rationally designed two supramolecular sonosensitizers RuA and RuB , engineered through acceptor modification to generate moderate reactive oxygen species (ROS) to modulate VAs. Both RuA and RuB demonstrated high ultrasound (US)‐activated ROS production efficiency, with singlet oxygen ( 1 O 2 ) quantum yield (Φ Δ ) of 0.70 and 0.88, respectively, surpassing ligand IR1105 and the conventional sonosensitizer ICG (Φ Δ =0.40). In vitro, RuB , at a modest concentration and under US intensity notably boosts pro‐survival autophagy in microglia BV2 cell. To improve in vivo stability and biocompatibility, RuB was further encapsulated into DSPE‐PEG 5000 to prepare RuB nanoparticles ( RuB NPs). In vivo studies after microinjection of RuB NPs into the paraventricular nucleus (PVN) and subsequent US exposure, demonstrated that RuB NPs‐mediated US modulation effectively suppresses sympathetic nervous activity (SNA) and inflammatory responses, thereby preventing VAs. Importantly, no tissue injury was observed post RuB NPs‐mediated US modulation. This work pioneers the design of long‐wave emission supramolecular sonosensitizers, offering new insights into regulating cardiovascular diseases.