Rewiring lysosomal redox homeostasis for ferroptosis-amplified sonodynamic cancer therapy

Sonodynamic therapy (SDT) is a promising ROS-mediated antitumor strategy, yet its therapeutic efficacy is frequently restricted by intracellular antioxidant defenses and insufficient ferroptotic amplification. Herein, we developed a multi-stimuli-responsive metal-organic framework (MOF)-based nanoplatform using disulfide-containing imidazole ligands coordinated with zinc ions, in which the sonosensitizer protoporphyrin IX (PpIX) was physically encapsulated (PIssI). Upon ultrasound irradiation, the nanocarrier generated excessive reactive oxygen species (ROS), while intracellular glutathione (GSH) was continuously depleted through thiol-disulfide exchange, resulting in glutathione peroxidase 4 (GPX4) suppression, lipid peroxide accumulation, and amplified ferroptosis. Meanwhile, protonation of imidazole groups in acidic lysosomal compartments induced lysosomal membrane permeabilization and dysfunction, which subsequently blocked autophagic flux and aggravated intracellular oxidative stress. Transcriptomic analysis, ferroptosis rescue experiments, redox biochemical assays, and lysosomal functional evaluation collectively demonstrated that the nanoplatform rewires lysosome-associated redox homeostasis rather than merely inducing transient oxidative injury. In CT-26 tumor-bearing mice, the tailored nanocarrier exhibited markedly enhanced tumor accumulation and antitumor efficacy with minimal systemic toxicity. Unlike conventional ROS nanomedicines that primarily rely on cytosolic oxidative damage, the current system converts lysosomes from metabolic recycling hubs into ferroptotic amplifiers through organelle-level redox regulation. This work highlights lysosomal dysfunction as an additional dimension for ferroptosis-sensitized SDT and provides a new strategy for ROS-amplified cancer therapy. Graphical abstract