Layered Double Hydroxide-Based Sonosensitizer Triggers "Paraptosis+" Multidimensional Cell Death Network for...

Area of Science:

• Biomaterials Science
• Cancer Therapy
• Immunology

Background:

• Paraptosis, a caspase-independent cell death, offers an alternative to overcome apoptosis resistance in cancer.
• Current paraptosis inducers face limitations due to low reactive oxygen species (ROS) generation and insufficient anti-tumor efficacy.
• Developing novel strategies to enhance paraptosis induction and anti-tumor activity is crucial for clinical translation.

Purpose of the Study:

• To develop a novel inducer for paraptosis-mediated sono-immunotherapy to overcome limitations of existing treatments.
• To investigate the synergistic effects of multi-modal cell death induced by the novel nanosheets.
• To evaluate the efficacy of the developed sono-immunotherapy in inhibiting primary and distant tumor growth.

Main Methods:

• Synthesis of defective nickel-doped ZnMo-layered double hydroxide nanosheets (DR-Ni-ZnMo-LDH).
• Evaluation of DR-Ni-ZnMo-LDH as a sonosensitizer for ROS generation under ultrasound irradiation.
• In vitro and in vivo studies to assess multi-modal cell death induction, immunogenic cell death, and tumor inhibition.

Main Results:

• DR-Ni-ZnMo-LDH demonstrated superior singlet oxygen generation activity under ultrasound irradiation.
• The ROS burst effectively induced paraptosis, apoptosis, and ferroptosis, synergistically eliminating apoptosis-resistant tumor cells.
• Significant inhibition of primary (98.44%) and distant (88.53%) tumor growth was observed, alongside remodeling of the immunosuppressive tumor microenvironment.

Conclusions:

• DR-Ni-ZnMo-LDH serves as an effective inducer for paraptosis-mediated sono-immunotherapy.
• The multi-modal cell death strategy overcomes tumor resistance and immunosuppression.
• This study presents a new material design paradigm for enhanced ROS-mediated sono-immunotherapy.