Caspase-3-Instructed Nanosonosensitizer Disassembly for Real-Time NIR-II Feedback of Tumor Sonodynamic Therapy

Sonodynamic therapy (SDT) has emerged as a powerful modality for deep-seated tumor treatment. However, real-time evaluation of its therapeutic efficacy at the molecular level remains elusive. Herein, we report a caspase-3-responsive self-evaluating nanosonosensitizer that enabled precise monitoring of SDT efficacy via near-infrared II (NIR-II) fluorescence feedback. Guided by rational molecular design, we screened diketopyrrolopyrrole (DPP)-based sonosensitizers and developed a julolidine-modulated molecule with extended conjugation (DPP5), which exhibited strong NIR-II emission and efficient ultrasound (US)-activated reactive oxygen species (ROS) generation. DPP5 was then functionalized with a caspase-3-cleavable peptide sequence Cys-Asp-Glu-Val-Asp-Lys-CBT, which self-assembled into fluorescence-quenched nanoparticles (DPP5-CBT NPs) in physiological solutions. Upon US irradiation, DPP5-CBT NPs produced ROS, inducing the apoptosis of tumor cells. This process in turn activated caspase-3 to disassemble nanoparticles, leading to the restoration of bright NIR-II fluorescence. This treatment-apoptosis-feedback cascade establishes a direct correlation among caspase-3 activation, SDT efficacy, and fluorescence restoration, enabling noninvasive and real-time self-assessment of therapeutic outcomes. We foresee that this theranostic molecular engineering platform that integrates treatment and feedback holds the promise of establishing a new paradigm for precise and intelligent SDT.