Self-Accelerating Bimetallic Peroxide Nanozymes for Cascade-Amplified Pyroptosis-Immunotherapy

Area of Science:

• Nanomedicine
• Cancer Therapy
• Immunotherapy

Background:

• Hydrogen peroxide (H2O2)-mediated cancer therapy faces challenges due to low H2O2 levels and immunosuppressive tumor microenvironments (TME).
• Developing novel nanoplatforms is crucial to enhance H2O2-based therapies and overcome TME-mediated resistance.

Purpose of the Study:

• To design a TME-responsive bimetallic peroxide nanosystem (CuZnONPs) for synergistic cancer treatment.
• To investigate the triple-combination therapeutic strategy involving H2O2 generation, reactive oxygen species (ROS) production, and pyroptosis induction.

Main Methods:

• Synthesis and characterization of CuZnONPs.
• In vitro and in vivo evaluation of CuZnONPs' therapeutic efficacy.
• Density functional theory (DFT) calculations to elucidate the catalytic mechanisms.
• Assessment of ROS generation, pyroptosis activation, and immune microenvironment modulation.

Main Results:

• CuZnONPs effectively self-supply H2O2 and catalyze its conversion into toxic ROS (·OH, ·O2⁻) and O2 in the TME.
• Single Cu atoms in CuZnONPs are critical for peroxidase-like, catalase-like, and oxidase-like activities.
• The generated ROS burst disrupts redox homeostasis and damages cellular components.
• Zn2+ release from CuZnONPs activates pyroptosis, promoting dendritic cell maturation and converting cold tumors to hot tumors.

Conclusions:

• CuZnONPs establish a TME-responsive nanoplatform for synergistic cancer therapy.
• The integrated approach of catalytic therapy and pyroptosis-enhanced immunotherapy offers a promising strategy for cancer treatment.
• This work provides new insights into nanomedicine design for overcoming TME-related therapeutic limitations.