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Dual-Switchable Nanoparticles Resolving the Safety-Efficacy Paradox of Sonodynamic Immunotherapy for Hepatocellular
Xiujun Gao1, Yao Wang2, Mingyuan Wang1
1School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China.
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.
Insights
Dual-switchable nanoparticles overcome safety and efficacy issues in sonodynamic therapy for liver cancer (HCC). These nanoparticles generate oxygen and induce tumor cell death while remaining safe in healthy tissues.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Sonodynamic therapy (SDT) for hepatocellular carcinoma (HCC) faces challenges with safety and efficacy due to off-target sonosensitizer activation and tumor microenvironment factors like hypoxia and antioxidant defenses.
- Current SDT approaches struggle to balance systemic safety with potent tumoricidal activity.
Purpose of the Study:
- To engineer dual-switchable core-shell nanoparticles to resolve the safety-efficacy paradox in SDT for HCC.
- To develop a nanoparticle system that is inert under physiological conditions but becomes active in the tumor microenvironment upon ultrasound exposure.
Main Methods:
- Fabrication of core-shell nanoparticles with a carboxymethyl chitosan shell and a peptide radical scavenger for systemic safety.
- Design of a linear dumbbell-shaped piezoelectric core (barium titanate-gold-barium titanate heterojunction) for oxygen generation and oxyradical production.
- Incorporation of inhibitors targeting AMP-activated protein kinase and nuclear factor erythroid two-related factor 2 antioxidant pathways.
- In vitro and in vivo validation using physicochemical characterization, multi-omics, and subcutaneous tumor models in mice.
Main Results:
- The engineered nanoparticles demonstrated controlled disassembly in the acidic tumor microenvironment and activation upon ultrasound exposure.
- The piezoelectric core generated a record piezopotential (4.12 V), producing oxygen to alleviate tumor hypoxia and generating oxyradicals.
- Inhibition of antioxidant pathways sensitized tumors to oxidative damage, leading to ferroptosis, mitochondrial dysfunction, DNA damage, and immunogenic cell death.
- Tumor inhibition rates of 98.7% in immunocompetent mice and 91.9% in T-cell-deficient mice were achieved with excellent safety profiles.
Conclusions:
- The dual-switchable nanoparticles establish a novel therapeutic paradigm for HCC by reconciling systemic safety with enhanced therapeutic potency.
- This integrated nanoplatform offers a translatable strategy for overcoming the limitations of current sonodynamic therapies for liver cancer.
