Multimodal Photodynamic Therapy by Inhibiting the Nrf2/ARE Signaling Pathway in Tumors

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Photodynamic therapy (PDT) is effective for superficial tumors but limited by tumor hypoxia and the Nrf2 antioxidant system.
• Overcoming these challenges is crucial for improving PDT efficacy.

Purpose of the Study:

• To design a cascade-responsive "oxidative stress amplifier" (EZ@TD) to enhance PDT by addressing tumor hypoxia and Nrf2-mediated resistance.
• To investigate the synergistic effects of EZ@TD on tumor growth inhibition and antitumor immune response.

Main Methods:

• Encapsulation of manganese-doped carbon dots (photosensitizer) and catalase (CAT)-like nanozyme within pH-sensitive ZIF-8.
• Incorporation of Zn²⁺-activated DNAzyme for Nrf2 gene disruption.
• Evaluation of EZ@TD's performance in relieving hypoxia, enhancing oxidative stress, and inhibiting the Nrf2/ARE signaling pathway.

Main Results:

• EZ@TD effectively relieved tumor hypoxia and disrupted the Nrf2/ARE signaling pathway.
• The system demonstrated synergistic inhibition of tumor growth.
• EZ@TD treatment activated a robust antitumor immune response.

Conclusions:

• EZ@TD represents a novel strategy for amplifying intracellular oxidative stress to overcome PDT resistance.
• This approach offers a new paradigm for cancer therapy by interfering with key tumor survival pathways.