Breaking the Redox Homeostasis: an Albumin‐Based Multifunctional Nanoagent for GSH Depletion‐Assisted Chemo‐/Chemodynamic Combination Therapy

Redox homeostasis is vital for cell survival. Nowadays, developing novel nanoagents that can efficiently break the redox homeostasis, which includes improving the reactive oxygen species level while reducing the glutathione (GSH) level, has emerged as a promising but challenging strategy for tumor therapy. In this work, a novel albumin-based multifunctional nanoagent is developed for GSH-depletion assisted chemo-/chemodynamic combination therapy. Briefly, CuO and MnOX are in situ co-grown inside the albumin molecules through a facile biomineralization process, followed by the conjugation of Pt (IV) prodrug to obtain the final nanoagent. Thereinto, copper species can produce center dot OH with optimal efficiency under weakly acidic conditions (pH = 6.5), while MnOX can react with GSH, leading to the GSH depletion, which reduces the formation of GSH-Pt adducts and center dot OH consumption, thus favoring a better chemotherapy and chemodynamic therapy effect, respectively. Significantly, both GSH depletion and center dot OH generation contributes to the inhibited expression of GPX-4, which further increases the oxidative stress. Moreover, during the reaction between MnOX and GSH or H2O2, Mn2+ ions are released for MR imaging while O-2 is produced for hypoxia relief. It is believed that the proposed strategy can provide a new perspective on effective tumor therapy.