Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells

The accumulation
of senescent cells, a hallmark of aging
and age-related
diseases, is also considered as a side effect of anticancer therapies,
promoting drug resistance and leading to treatment failure. The use
of senolytics, selective inducers of cell death in senescent cells,
is a promising pharmacological antiaging and anticancer approach.
However, more studies are needed to overcome the limitations of first-generation
senolytics by the design of targeted senolytics and nanosenolytics
and the validation of their usefulness in biological systems. In the
present study, we have designed a nanoplatform composed of iron oxide
nanoparticles functionalized with an antibody against a cell surface
marker of senescent cells (CD26), and loaded with the senolytic drug
HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action
against oxidative stress-induced senescent human fibroblasts, WI-38
and BJ cells, and anticancer drug-induced senescent cutaneous squamous
cell carcinoma A431 cells, demonstrating for the first time that CD26
is a valid marker of senescence in cancer cells. A dual response to
MNP@CD26@17D stimulation in senescent cells was revealed, namely,
apoptosis-based early response (2 h treatment) and ferroptosis-based
late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis
might be executed by ferritinophagy as judged by elevated levels of
the ferritinophagy marker NCOA4 and a decreased pool of ferritin.
As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human
erythrocytes in vitro, this newly designed nanoplatform
could be considered as an optimal multifunctional tool to target and
eliminate senescent cells of skin origin, overcoming their apoptosis
resistance.