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.