A Prodrug to Trigger Ferroptosis Based Cell Death in Senescent Cells
Researchers have developed many different approaches to selectively destroy senescent cells based on differences in their biochemistry. The use of prodrugs is one way to activate a cell-killing mechanism more specifically in senescent cells. Most such prodrugs make use of the fact that senescent cells express high levels of β-galactosidase, which removes galactose from molecules. A cell-killing molecule can be rendered inert by adding galactose to its structure, and is only activated to a large degree in senescent cells. Here, the cell-killing molecule acts to trigger ferroptosis in senescent cells, an approach analogous to the various ways that have been shown to trigger apoptosis in senescent cells. Senescent cells are primed for programmed cell death via apoptosis and ferroptosis. The mechanisms holding them back from that fate can be targeted fairly safely, as suppression of those preventative mechanisms will not cause cell death in a normal cell that is not primed for programmed cell death.
Accumulation of senescent cells is associated with aging and age-related diseases. However, current clearance therapies targeting senescent cells are often limited by low efficiency, poor specificity, and insufficient penetration. Here we develop a nano-platform composed of a probe (GD) that can be specifically activated by senescent cells, a photosensitizer (chlorin e6, Ce6), and a kininogen peptide (HK) for targeting ferritin, named HK-PCGC.
We show that upon entering senescent cells, GD is activated by high levels of β-galactosidase, releasing fluorescence to excite Ce6. Ce6 then generates reactive oxygen species to eliminate these cells. Additionally, we find that under the guidance of the peptide HK, our system degrades ferritin to trigger ferroptosis, further eliminating senescent cells. Collectively, we demonstrate that HK-PCGC can effectively eliminate senescent cells, reduce the senescence-associated secretory phenotype, and safely improve the physical fitness of aged mice. This study integrates senescent cell responsiveness, laser-free photodynamic therapy, and induction of ferroptosis, offering a potential approach for delaying aging.