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

Malignant tumors often develop resistance to oxidative stress therapies through metabolic reprogramming and reinforcing redox defense mechanisms. To overcome this challenge, we strategically targeted thioredoxin reductase (TrxR), a master regulator of cellular redox homeostasis. The hypothesis that TrxR disruption could impair the antioxidant capacity and restore the therapeutic sensitivity of tumors was evaluated. A tumor-selective nanoregulator, P-3@MIL-100@HA (PMH), was engineered, which combines a natural product-derived TrxR inhibitor (P-3) with an iron-based metal-organic framework (MIL-100), and features a hyaluronic acid (HA) coating to enable CD44-mediated delivery. The core component, P-3, was identified through systematic pharmacological screening and structural optimization as a promising TrxR inhibitor. PMH orchestrates triple redox disruption in resistant tumors: (1) effective TrxR inhibition by P-3 induces sustained hydrogen peroxide accumulation, amplifying oxidative stress; (2) GSH depletion via iron-mediated redox cycling cripples antioxidant defenses; and (3) Fenton-driven hydroxyl radical (·OH) generation further intensifies oxidative damage. Under the reductive tumor microenvironment, PMH exhibits stimuli-responsive release of P-3 and Fe2+, triggering dual apoptosis and pyroptosis. In gastric cancer models, PMH achieves superior therapeutic outcomes with minimal systemic toxicity. This study establishes a novel paradigm in oxidative stress-mediated antitumor therapy by successfully integrating TrxR inhibition with metal-based chemodynamic therapy (CDT) for the first time. Our work provides fundamental design principles for developing oxidative stress-amplifying nanotherapeutics and presents a clinically viable strategy against oxidative stress-resistant malignancies.