FIGURE 3 (A) Schematic illustration of nonporous GOx@[Cu(tz)]. (B) Cell vitality after different treatments. (C) Cell viabilities treated with different concentrations of GOx@[Cu(tz)]. (D) Oligomerization analysis of DLAT after different treatments. (E) Tumor volume in mice after different treatments. (A-E) Reproduced with permission.41 Copyright 2022, Wiley-VCH.
Recently, a variety of endogenous stimulus-responsive nanomaterials have been designed to respond to certain unique features in the tumor microenvironment, such as hypoxia, acidic pH, high ROS, overexpressed enzyme, and enriched GSH for improving the selectivity and specificity of cancer treatment.42,43 For example, Zhang et al . developed a pH-responsive nano-delivery system (HFn-Cu-REGO NPs) consisting of human H-ferritin (HFn), chemotherapeutic agent regorafenib and Cu2+ to induce autophagy and cuproptosis for glioblastoma treatment (Figure 4A ).44Benefiting from the modification of HFn, HFn-Cu-REGO NPs showed good blood-brain barrier (BBB) permeation, tumor-site accumulation, and pH-responsive disassembly capability. Upon treatment with HFn-Cu-REGO NPs, the pH-responsive nano-delivery system was responsive disassembled and released regorafenib and Cu2+ in response to the acidic pH, causing concentrations of regorafenib and Cu2+ was locally elevated in tumor region. On the one hand, excessive intracellular Cu2+ activated the copper homeostasis system, leading to upregulation of copper efflux receptors and downregulation of copper uptake receptors (Figure 4B ); on the other hand, Cu2+ bound to DLAT, causing the aggregation of lipoacylated DLAT (Figure 4C ) and triggering cuproptosis. In addition, the released regorafenib induced lethal autophagy arrest to exert the therapeutic effect through preventing autophagy lysosomal fusion. Based on the Cu2+-induced cuproptosis and regorafenib-mediated lethal autophagy arrest, HFn-Cu-REGO NP-treated tumor-bearing mice showed delayed tumor growth and the lowest bioluminescence among all groups, indicating the optimal anti-cancer effect of HFn-Cu-REGO NP (Figure 4D ). This study provided new insights into the treatment of cancer via targeting the delivery of copper ions in response to endogenous stimulation to induce cuproptosis in cancer cells.