ROS-amplifying nanoregulators: Precision thioredoxin reductase-targeted disruption of redox homeostasis overcomes...

Area of Science:

• Biomedical Engineering
• Cancer Therapy
• Redox Biology

Background:

• Malignant tumors develop resistance to oxidative stress therapies via metabolic reprogramming and enhanced redox defenses.
• Thioredoxin reductase (TrxR) is a key regulator of cellular redox homeostasis, making it a strategic target to overcome treatment resistance.

Purpose of the Study:

• To evaluate the hypothesis that TrxR disruption can impair tumor antioxidant capacity and restore therapeutic sensitivity.
• To develop a tumor-selective nanoregulator for targeted delivery and synergistic redox disruption in resistant tumors.

Main Methods:

• Engineered a nanoregulator (P-3@MIL-100@HA) combining a TrxR inhibitor (P-3), an iron-based metal-organic framework (MIL-100), and hyaluronic acid (HA) for CD44-mediated delivery.
• Investigated the nanoregulator's mechanism involving TrxR inhibition, GSH depletion, and Fenton-driven hydroxyl radical generation.
• Assessed the nanoregulator's efficacy in gastric cancer models, evaluating apoptosis, pyroptosis, and systemic toxicity.

Main Results:

• The nanoregulator achieved triple redox disruption: sustained hydrogen peroxide accumulation, crippled antioxidant defenses via GSH depletion, and intensified oxidative damage.
• Stimuli-responsive release of the inhibitor and iron ions triggered dual apoptosis and pyroptosis in the tumor microenvironment.
• Demonstrated superior therapeutic outcomes in gastric cancer models with minimal systemic toxicity.

Conclusions:

• Successfully integrated TrxR inhibition with metal-based chemodynamic therapy (CDT) for the first time, establishing a novel paradigm in oxidative stress-mediated antitumor therapy.
• The developed nanoregulator provides fundamental design principles for oxidative stress-amplifying nanotherapeutics.
• Presents a clinically viable strategy against oxidative stress-resistant malignancies.