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

ABSTRACT

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.