Autophagy-enhanced nanosonosensitizer mediated sonodynamic therapy for post-myocardial infarction neuromodulation and arrhythmia prevention

Rationale: Sympathetic hyperactivation and neuroinflammation are the main triggers of malignant ventricular arrhythmias (VAs) after myocardial infarction (MI). Previous studies proved that photothermal therapy (PTT) and photodynamic therapy (PDT) could reduce MI-induced VAs by inhibiting neuroinflammation. However, the limited penetration depth and potential phototoxicity of phototherapy impose constraints on its further application. As a treatment strategy derived from phototherapy, sonodynamic therapy (SDT) offers exceptional advantages, including excellent penetration capability, temporal-spatial controllability, superior efficacy and minimal side effects. Therefore, it is worthwhile to investigate the effects of sonodynamic modulation on neuroinflammation and arrhythmia prevention. Methods: We designed a long-wavelength emissive sonosensitizer (named BBTD-TPA) based on donor-acceptor-donor scaffold. Subsequently, the compound was encapsulated in DSPE-PEG5000 to form BBTD-TPA nanoparticles (NPs). In vitro experiments were conducted to determine the optimal concentration of BBTD-TPA NPs-mediated SDT and to verify the effects and pathways on autophagy in BV2 cells. The distribution and metabolism of BBTD-TPA NPs in vivo were assessed by NIR-II fluorescence imaging. Finally, in vivo studies were performed to assess the effect of BBTD-TPA NPs-mediated SDT on post-MI sympathetic neuroinflammation and the occurrence of VAs. Results: In vitro studies demonstrated that BBTD-TPA NPs combined with LIFU could promote microglial autophagy via the ROS-AMPK-mTOR pathway. BBTD-TPA NPs were further microinjected into the paraventricular nucleus (PVN), real-time NIR-II fluorescence imaging showed that BBTD-TPA NPs could remain in the PVN for up to 12 h and be metabolized through the liver and kidney. Further in vivo results verified that BBTD-TPA NPs-mediated SDT could inhibit sympathetic nervous activity, and inflammatory responses, thus preventing MI-induced VAs. Conclusion: BBTD-TPA NPs-mediated SDT can promote microglial autophagy and inhibit sympathetic neuroinflammation, thus reducing MI-induced VAs. The current research may inspire a novel strategy for neuromodulation and arrhythmia prevention, providing broader prospects for clinical translation of nanomedical technology.