Dual-Switchable Nanoparticles Resolving the Safety-Efficacy Paradox of Sonodynamic Immunotherapy for Hepatocellular Carcinoma.

Clinical translation of sonodynamic therapy for hepatocellular carcinoma is limited by a safety-efficacy paradox: sonosensitizer activation in healthy tissues poses risks, while tumor efficacy is constrained by hypoxia and redundant antioxidant defenses. To resolve this, dual-switchable core-shell nanoparticles were engineered. Under physiological conditions, a carboxymethyl chitosan shell and a peptide radical scavenger keep the nanoparticles inert, ensuring systemic safety. In the acidic tumor microenvironment, the shell disassembles, and ultrasound exposure triggers a coordinated therapeutic cascade. The linear dumbbell‑shaped piezoelectric core, barium titanate‑gold‑barium titanate heterojunction, generates oxygen, alleviating tumor hypoxia, and simultaneously produces oxyradicals, enabled by a record piezopotential of 4.12 V and its inherent direct water‑splitting capability. Two inhibitors are released to block the AMP‑activated protein kinase and nuclear factor erythroid two-related factor 2 antioxidant pathways, disabling cellular defenses and amplifying oxidative damage. This integrated strategy induces ferroptosis, mitochondrial dysfunction, DNA damage, and immunogenic cell death, as validated by physicochemical characterization, multi-omics, and in vivo studies. In subcutaneous tumor models, inhibition rates reached 98.7% in immunocompetent mice and 91.9% in T‑cell‑deficient mice, with excellent safety. This work establishes a therapeutic paradigm reconciling systemic safety with potency, offering a translatable strategy for HCC.