<i>In Situ</i> Self-Reinforcing Fully Active Nanodrugs: Excitation/Oxygen-Free Redox Disruption Therapy through Metabolite-Driven Reactive Oxygen Species Cascades.

Abstract

Reactive oxygen species (ROS) have emerged as promising therapeutic agents in tumor treatment. However, conventional ROS-based therapies often suffer from diminished or complete loss of antineoplastic efficacy due to insufficient oxidative stress damage, primarily stemming from limited ROS generation capacity and reliance on excitation and oxygen. Herein, we present a self-reinforcing full-active pharmaceutical ingredient (API) nanodrug (CFL FAND), assembled of chloroperoxidase (CPO), Fe³⁺, and linoleic acid hydroperoxide (LAOOH). This nanoplatform leverages endogenous products to reactivate the API, enabling <i>in situ</i> cascade reactions for perturbing redox homeostasis. Specifically, CPO catalyzes intracellular H₂O₂ into hypochlorous acid (HClO), while Fe³⁺ is reduced by glutathione to Fe²⁺, facilitating hydroxyl radical (•OH) generation via the Fenton reaction. Crucially, both downstream metabolites HClO and Fe²⁺ further react with LAOOH through the Russell mechanism to produce singlet oxygen (¹O₂), thereby achieving stimuli- and oxygen-free formation of multiple ROS (HClO-•OH-¹O₂) that synergistically amplify oxidative stress. Furthermore, the as-fabricated FANDs possess an exceptionally high API loading content (100 wt %) and a tumor-acidity-triggered degradation profile, which inherently enhances therapeutic efficacy while minimizing systemic toxicity. This work showcases a robust strategy to augment the potency and sustainability of ROS-mediated cancer therapies, offering a paradigm shift in precision oncology.