New Paradigm of anti-Aging with Self-Assembled Senolytic via the Intracellular Oligomerization
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Senolytics is an emerging therapeutic strategy for the treatment of various age-related diseases. However, the majority of current senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, thereby limiting its specificity and inducing severe side effects. To overcome this limitation, we utilized an intracellular oligomerization system that specifically targets senescent cells for the construction of self-assembling senolytics. The intracellular oligomerization of aryl-dithiol-containing peptide only occurs inside the mitochondria of senescent cells due to their utilization of elevated reactive oxygen species levels as a chemical fuel for the disulfide-forming reaction. The resultant artificial protein-like nano-assembly with the stable α-helix secondary structure could disrupt the mitochondrial membrane via multivalent interactions, consequently resulting in mitochondrial destruction. The therapeutic efficacy was further investigated in mouse models of age-related macular degeneration, showing amelioration of retinal degeneration. This system provides a novel strategy to treat age-related diseases through the use of supramolecular senolytics.