A Catalytic Redox-Cycling Nanoreactor Enables Robust Oxidative Stress Amplification for Synergistic Tumor Apoptosis and Ferroptosis.

Abstract

Intervening in the aberrant redox homeostasis of tumors, particularly toward reactive oxygen species (ROS) overload, holds considerable promise for cancer therapy, yet, is severely constrained by the robust compensatory antioxidant defense system (ADS) and the unavoidable disruption of redox homeostasis in normal tissues. Here, we present a catalytic redox-cycling nanoreactor, TEMPO radical-modified cross-linked lipoic acid nanoparticles (T@cLAN), designed to achieve robust oxidative stress amplification for cancer therapy. Lipoic acid (LA) characterized by a cyclic disulfide backbone enables intermolecular thiol-disulfide exchange to from GSH-responsive crosslinked networks, while enabling reversible interconversion with dihydrolipoic acid (DHLA), which can further participate in redox modulation. Mechanistically, T@cLAN depletes intracellular glutathione (GSH) and undergoes depolymerization to generate dihydrolipoic acid (DHLA), which actively participates in redox processes to enhance ROS production. TEMPO, functions as a catalyst rather than a stoichiometric scavenger, directly accelerating the endogenous LA/DHLA redox cycle, thereby further amplifying DHLA generation and sustaining both GSH depletion and ROS amplification. As validated by both in vitro and in vivo results, T@cLAN dismantles the major ADS barrier limiting tumor oxidative stress, achieving an overall 85% GSH depletion and elevating ROS levels by 37-fold compared to untreated tumor cells. Concurrently, it induces both apoptosis and ferroptosis, attaining a tumor inhibition rate of 80% while causing minimal impact on normal cells and tissues, underscoring its substantial potential for cancer therapy. STATEMENT OF SIGNIFICANCE: We engineer a nanoreactor (T@cLAN) as an innovative modality to address a central limitation of oxidative stress-mediated anticancer therapy, that is, the therapeutic attenuation imposed by the highly developed antioxidant defense machinery of tumor cells. T@cLAN is activated by intracellular glutathione, a key redox buffer, to engage two interlinked redox catalytic cycles, enabling sustained glutathione depletion and the amplified accumulation of cytotoxic reactive oxygen species. Through this cooperative redox reprogramming, T@cLAN promotes tumor cell apoptosis and ferroptosis, leading to pronounced anticancer activity. Notably, T@cLAN is activated within the tumor microenvironment while remaining largely quiescent in normal cells, reflecting an active and highly selective intervention mechanism that offers new directions for oxidative stress driven therapeutic innovation.