Intracellular in-situ activated enzyme/prodrug strategy based on tris(triazole)-Cu+ complex for cooperative catalytic cancer therapy

Abstract

Simultaneously delivering enzymes and prodrugs to the target sites is an attractive anticancer strategy. In this work, we demonstrate that triskelion lysine containing a tris(triazole)-Cu⁺ complex (TLTC) can be employed to concurrently load horseradish peroxidase (HRP) and a prodrug (indole-3-acetic acid, IAA) within a single TLTC nanoparticle. This design utilizes Cu⁺-mediated HRP inhibition to prevent premature activation of IAA, addressing a critical limitation in conventional HRP/IAA systems. Due to the responsion of Cu⁺ to H₂O₂, the HRP/IAA system is activated by the high-concentration H₂O₂ in tumors to generate reactive oxygen species (ROS) for killing tumor cells. The controlled activation of the HRP/IAA system within the tumor microenvironment, mediated by Cu⁺/H₂O₂ interaction, represents a significant advancement over conventional enzyme/prodrug therapies. Moreover, the self-supply of H₂O₂ from the HRP/IAA reaction and the Fenton reaction mediated by Cu⁺/Cu²⁺ redox cycling further amplifies the therapeutic effect, creating a self-sustaining cycle of ROS production. This dual mechanism of ROS generation, combining enzyme/prodrug activation and Fenton effect, significantly improves therapeutic outcomes. Thus, our triskelion-based architectures offer the opportunity to activate the enzyme/prodrug therapy (EPT) within the tumor mass while evading systemic toxicity, which represents a promising strategy for developing novel EPT based on triskelion peptide self-assembly.