3 CONCLUSION AND PERSPECTIVES
​Cancer is already the second most lethal disease after cardiovascular
disease, and this grave situation has led to the search for effective
control and intervention techniques.50-52 Cuproptosis
is a new form of PCD proposed in 2022 in which copper ions play an
important role.29 Since then, the cellular regulatory
mechanisms and signaling pathways involving cuproptosis have been
investigated extensively, which propelled the movement toward
cuproptosis inducers represented by copper-based nanomaterials for the
eradication of malignant tumors. Copper-based nanomaterials can not only
achieve targeted delivery of copper ions through surface modification,
but also nicely circumvent the deficiencies of traditional cancer
therapy, such as short blood circulation, poor solubility, low
bioavailability, off-target effects, and nonspecific
distribution.53,54 In this minireview, we first
comprehensively expounded the regulatory mechanism of cuproptosis in the
introduction section, and then introduced the application of cuproptosis
mechanism in the field of nanomedicine, which may provide new insights
into designing copper-based nanomaterials for cancer therapy.
Although the rapid development of studies on cuproptosis-based cancer
therapy, challenges remain to be addressed, along with tremendous
opportunities. Firstly, the understanding of the complicated molecular
mechanism and associated regulatory pathways of cuproptosis are still in
its infancy. Knowledge of the mechanism of cuproptosis may help in
designing a more effective anti-cancer
nanomaterial.15,55 Secondly, cuproptosis is a process
closely related to cellular copper metabolism, so it is very important
to reasonably control intracellular copper ion concentration in bothin vitro and in vivo studies. Regarding cancer,
cuproptosis is a double-edged sword because it can not only kill cancer
cells, but also induce copper toxicosis to destroy normal
cells.56,57 Therefore, particular attention should be
paid to the parameters such as type, dosage, timing, to obtain an
optimal relationship between efficacy and side effects in practical
application.58,59 Thirdly, copper-based nanomaterials
might exert a cytotoxic effect via a cuproptosis-independent
pathway. For example, copper ions may treat cancer through the Fenton
reaction.60 Thus, a clear understanding of the action
mechanism could aid the rational design of highly selective and specific
copper-based nanosystems. Meanwhile, this also suggests that combining
crosstalk between different cell death phenotypes may be an effective
therapeutic regimen and possess potential clinical application in cancer
treatment.61,62 Fourthly, the existing nanomaterials
are weak in the responsive release of copper ions because of the small
difference in enzyme activity or acidity between the tumor and normal
tissue resulting from the diversity and heterogeneity of the
tumor.7 Hence, there is a pressing demand for
designing ultra-sensitive nanomaterials which can be activated within a
very narrow threshold.63,64 Fifthly, during the
circulation process, the dissolution of copper in copper-based
nanomaterials seriously affects the therapeutic efficacy and cycle
stability. Supramolecular nanomaterials exhibit strong stability due to
their dynamic characteristics and high correlation constant between
matching groups, and may be a promising cuproptosis
inducer.65,66 Lastly, it is highly anticipated that
cuproptosis can be extended to the treatment of other diseases. In
addition to chemotherapy, nano-drug-based cell cuproptosis therapies are
also expected to be widely combined with other treatments, which can
further improve the treatment efficiency of tumor therapies based on
cell cuproptosis.
In conclusion, with the deepening of our understanding in cuproptosis
and its relationship with nanomaterials, cancer therapeutic outcome
would be continuously improved through the design and development of
copper-based nanomaterials.