Prodrug nanoplatform for triggering ferroptosis to eliminate senescent cells in age-associated pathologies

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 (Ce6), and a 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.