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To resolve this, dual\u2010switchable core\u2010shell 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\u2011shaped piezoelectric core, barium titanate\u2011gold\u2011barium titanate heterojunction, generates oxygen, alleviating tumor hypoxia, and simultaneously produces oxyradicals, enabled by a record piezopotential of 4.12\u00a0V and its inherent direct water\u2011splitting capability. Two inhibitors are released to block the AMP\u2011activated protein kinase and nuclear factor erythroid two\u2010related 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\u2010omics, and in vivo studies. In subcutaneous tumor models, inhibition rates reached 98.7% in immunocompetent mice and 91.9% in T\u2011cell\u2011deficient mice, with excellent safety. This work establishes a therapeutic paradigm reconciling systemic safety with potency, offering a translatable strategy for HCC.<\/jats:p>","DOI":"10.1002\/adhm.71562","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T03:23:17Z","timestamp":1786159397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual\u2010Switchable Nanoparticles Resolving the Safety\u2010Efficacy Paradox of Sonodynamic Immunotherapy for Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Xiujun","family":"Gao","sequence":"first","affiliation":[{"name":"School of Biomedical Engineering and Technology Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Therapeutic Ultrasonography, National Clinical Research Center of Cancer, Key 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