Stimulus-responsive nanomedicine mediated by metabolic intervention mechanisms to amplify redox anticancer therapy

Metabolic reprogramming and altered redox balance are two common hallmarks of cancer. Redox homeostasis is intricately intertwined with tumor energy metabolism, but the potential for metabolic intervention mechanisms to disrupt redox balance has been consistently underestimated. In this study, we present a stimulus-responsive nanocarrier (NC) designed to leverage metabolic intervention mechanisms to enhance redox-based anticancer therapy. These nanoparticles are composed of zeolitic imidazolate framework-90 (ZIF-90) as the ATP- and pH-responsive porous core, enveloped in an amphiphilic pluronic 407 (poloxamer F127) coating to ensure steric stabilization. Within the core of these hybrid NCs, we co-loaded active cargos 3-bromopyruvate (3-BrPA) and metformin (MET). Serving as a multifaceted inhibitor of both aerobic glycolysis and respiration, 3-BrPA impedes the activities of hexokinase II, leading to reduced glucose consumption and an increase in ROS levels. This synergistic effect, in conjunction with MET, results in a decrease in the levels of reducing substances, sensitizing 3-BrPA-induced apoptosis in cancer cells. At both the cellular and animal levels, these hybrid NCs have demonstrated superior anticancer activity by inhibiting metabolism and disrupting redox homeostasis. This study introduces a novel approach targeting the metabolism-redox interplay for tumor treatment, potentially broadening the scope of available antitumor strategies.