Long-Acting Fractionated Sonodynamic Therapy Enabled by Fused-Trianthracene Nanoparticles with Ultra-Bright Ultrasound-Induced Afterglow Luminescence

Sonodynamic therapy (SDT) enables noninvasive treatment of deep-seated tumors, yet its clinical translation is hindered by inefficient and transient reactive oxygen species (ROS) generation and the absence of real-time treatment feedback. Here, we report a long-acting, fractionated sonodynamic platform that integrates long-persistent ROS release with deep-tissue imaging guidance. The platform is enabled by an ultrasound-charged organic energy storage system based on engineered fused-trianthracene nanoparticles (FTA NPs). As a novel class of organic sonosensitizers, FTA NPs can store mechanical energy in the form of endoperoxides and subsequently release it as long-persistent ROS, enabling sustained "OFF-state" ROS production in the absence of ultrasound excitation. This system leverages an ultrasound-triggered electron transfer pathway to boost ROS output 3.0 times more ROS than typical afterglow nanoparticles poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEHPPV). Ultrasound activation forms unstable endoperoxide intermediates that slowly sustain ROS production and ultrabright ultrasound-induced afterglow luminescence for over 15 min postsonication, achieving afterglow intensity 1971.6 times higher than MEHPPV NPs. This persistent activity enables a fractionated ultrasound regimen─five low-power pulses over a fixed total dose─that enhances cumulative ROS generation by 3.1× and cytotoxicity by 2.2× compared to continuous irradiation. Even when separated by 5 cm of chicken tissue, ultrasound could still induce afterglow luminescence from FTA NPs; this afterglow exhibited a quantitative correlation with ROS levels, allowing real-time optimization of irradiation intervals and pulse frequency in vivo. Applied to subcutaneous and orthotopic pancreatic tumors, this strategy delivers potent antitumor efficacy. Our results establish an ultrasound-driven energy storage, delayed ROS release, ultrasound-induced luminescence imaging guidance and long-acting SDT modality as a versatile and clinically promising approach for precision treatment of deep-seated malignancies.