Redox-imbalance amplification via BODIPY sonosensitizer: A cysteine-depleting oxygen-independent strategy for spatiotemporal deep tumor sonodynamic therapy.

Sonodynamic therapy (SDT) is a non-invasive cancer treatment that uses ultrasound to activate sonosensitizers and generate reactive oxygen species (ROS), offering the distinct advantage of penetrating deep tumor tissues. However, SDT efficacy is hindered by tumor hypoxia and strong antioxidant defenses. Glutathione (GSH), the central ROS scavenger, depends on cysteine (Cys) for synthesis, and tumor cells elevate Cys uptake to preserve redox balance and counter oxidative stress, thereby weakening SDT responsiveness. To address these challenges, we present a multifunctional nanoplatform, NBD-B-T/TiO2@Lip, integrating organic and inorganic sonosensitizers within liposomes to optimize solubility, biocompatibility, and ROS production for enhanced sonodynamic therapy. The BODIPY-based NBD-B-T generates oxygen-independent ROS and selectively binds intracellular cysteine, enabling real-time fluorescence imaging while depleting cysteine, disrupting GSH biosynthesis, and perturbing redox homeostasis to trigger ferroptosis. Upon ultrasound activation, the platform synergistically amplifies ROS generation and cysteine depletion, intensifying oxidative stress and ferroptotic cell death in the tumor microenvironment. In vivo, it achieves potent tumor suppression, durable therapeutic efficacy, and minimal systemic toxicity. This strategy establishes a precise, high-efficacy SDT paradigm by uniting oxygen-independent ROS production with targeted redox modulation.