Ultrasound-activated dual-targeted liposomes for visualized precise neuromodulation against myocardial ischemia-reperfusion injury

Myocardial ischemia-reperfusion (I/R) injury remains a critical clinical challenge with limited effective treatments. Sympathetic hyperactivation and microglia-mediated neuroinflammation in the paraventricular nucleus exacerbate myocardial I/R injury. Whilst previous studies suggest that sonodynamic neuromodulation has the potential to impede neuroinflammation and confer cardioprotective effect, existing sonosensitizers employed in neuromodulation demonstrate deficiencies in terms of cellular targeting specificity and the capacity to facilitate functional imaging of neuroinflammation. Herein, a sonosensitizer (BT) was designed based on a donor-acceptor-donor scaffold exhibiting emission in the near-infrared (NIR)-II window, and it was further engineered into a neuroinflammatory dual-targeted sonosensitizer through antibody-modified liposomes (named BT@Lip-TN). <i>In vitro</i> studies demonstrated that BT@Lip-TN under ultrasound irradiation significantly enhanced reactive oxygen species generation compared to commercial sonosensitizers. More importantly, BT@Lip-TN was selectively internalized by sympathetic neurons and microglia, localized to mitochondria, and promoted mitophagy via the PINK1-Parkin pathway, thereby modulating neuroinflammation. <i>In vivo</i> studies confirmed that BT@Lip-TN enabled functional NIR-II imaging and real-time monitoring of neuroinflammatory activity. Furthermore, BT@Lip-TN-mediated targeted sonodynamic neuromodulation suppressed sympathetic neuroinflammation and ameliorating myocardial I/R injury. This study pioneers the design of neuroinflammatory dual-targeted sonosensitizer and establishes an integrated theranostic platform, offering novel insights into visualized precise neuromodulation and the treatment of myocardial I/R injury.