Indoleamine 2,3-dioxygenase 1-targeted redox remodeling by a mesoporous medium-entropy alloy nanozyme promotes ferroptosis and cuproptosis for tumor therapy.

Abstract

Tumor cells exhibit robust redox adaptive capacity, limiting the effectiveness of ROS amplification alone in inducing persistent and irreversible oxidative damage. Accordingly, simultaneously enhancing oxidative stress and disrupting antioxidant defenses represents an effective strategy for improving catalytic cancer therapy. Here, we developed hyaluronic acid-functionalized NLG-919-loaded mesoporous PtPdRhCu medium-entropy alloy colloidal nanoparticles (PPRCNH), an interface-engineered platform integrating porous architecture, multimetallic electronic coupling, surface functionalization, and metabolic regulation. The mesoporous framework exposes abundant low-coordination catalytic sites, while interactions among Pt, Pd, Rh, and Cu promote H2O2 activation and sustained ROS production. HA functionalization facilitates the uptake of PPRCNH by CD44-overexpressing osteosarcoma cells, whereas NLG-919 inhibits indoleamine 2,3-dioxygenase 1 (IDO1)-dependent tryptophan-to-kynurenine conversion, consequently impairing G6PD-mediated nicotinamide adenine dinucleotide phosphate (NADPH) regeneration. The acidic tumor microenvironment further accelerates Cu release and perturbs mitochondrial lipoylated protein homeostasis. Mechanistic studies demonstrated that PPRCNH enhanced ROS generation and suppressed antioxidant compensation dependent on glutathione (GSH) and NADPH, resulting in mitochondrial dysfunction and the simultaneous induction of ferroptosis and cuproptosis. In the osteosarcoma model, PPRCNH achieved a tumor growth inhibition rate of approximately 77.2%. This study establishes a catalytic-metabolic regulatory paradigm by integrating mesoporous medium-entropy alloy interfaces with metabolic checkpoint modulation to achieve sustained oxidative stress amplification.

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