Self-Reinforcing ROS Nanodrug and Ferritin-Based LYTACs Advance Tumor-Targeted Therapy
A self-reinforcing ROS-generating nanodrug and a modular ferritin-based LYTAC platform represent two new nanoparticle strategies for tumor-targeted therapy, with high drug loading, efficient protein degradation, and tumor growth inhibition in vivo.
Two recent studies describe novel nanoparticle-based strategies for tumor-targeted therapy. One presents a self-reinforcing full-active pharmaceutical ingredient nanodrug that generates reactive oxygen species without external excitation or oxygen, while the other reports a modular ferritin-based lysosome-targeting chimera platform that degrades membrane proteins to inhibit tumor growth.
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. To address this, researchers developed 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 in situ cascade reactions for perturbing redox homeostasis. 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. Both downstream metabolites HClO and Fe2+ further react with LAOOH through the Russell mechanism to produce singlet oxygen (1O2), achieving stimuli- and oxygen-free formation of multiple ROS (HClO-•OH–1O2) that synergistically amplify oxidative stress. The 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.
In a separate study, researchers developed a modular LYTAC platform based on human heavy chain ferritin (HFn), leveraging its peptide-display function and TfR1-mediated lysosomal endocytosis. Lysosome-targeting chimeras (LYTACs) hold therapeutic potential by degrading pathogenesis-associated proteins, but current LYTAC systems often require considerable effort for case-by-case construction and are devoid of a convenient modular platform. The system comprises a bioengineered HFn scaffold with enhanced TfR1 affinity and target-specific affibodies conjugated to the HFn via SpyTag-SpyCatcher system. Using this approach, HFn-LYTACs efficiently degrade epidermal growth factor receptor, epidermal growth factor receptor-2 and programmed death-ligand 1. Mechanistic studies indicate that the HFn-LYTAC platform mediates degradation via two distinct mechanisms: a TfR1-dependent endocytic pathway as well as the nanoparticle size and multivalent ligand effect. In vivo, HFn-LYTACs inhibit tumor growth with favorable safety.