Ground-State Descriptors Predict ROS Generation Efficiency and Enable Rational Design of Sonosensitizers for PROTAC-Enhanced Sono-Immunotherapy

Abstract Sonodynamic therapy (SDT) offers deep-tissue penetration but is limited by the lack of reliable strategies to predict intersystem crossing efficiency in sonosensitizers. Here, we identify two ground-state electronic descriptors, namely, the orbital center-of-mass distance (DH–L) and the orbital overlap integral (VH–L), that quantitatively correlate with intersystem crossing rates governed by orbital transition characteristics. These descriptors avoid computationally intensive excited-state calculations while maintaining strong predictive power. Guided by this strategy, we developed a series of donor–acceptor sonosensitizers with enhanced reactive oxygen species (ROS) generation under ultrasound (US) irradiation, as validated by both theoretical analysis and experimental measurements. The optimized sonosensitizer was further formulated into DPBRMN NPs that incorporate a hypoxia-responsive, BRD4-targeted PROTAC prodrug. This integrated platform enables tumor-selective ROS production together with in situ protein degradation-mediated immune activation, leading to effective suppression of primary tumors and distant metastases. This work establishes a descriptor-guided framework for sonosensitizer design and provides a molecular strategy for integrating sonodynamic therapy with targeted protein degradation to enhance cancer immunotherapy.