SSK1‐Loaded Neurotransmitter‐Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells

Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging‐associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti‐AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by β‐gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of β‐gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1‐loaded neurotransmitter ‐derived lipid nanoparticles are herein developed (SSK1‐NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1‐NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid‐beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1‐NPs, a novel nanomedicine displaying potent anti‐AD activity and excellent safety profile, provides a promising strategy for AD therapy. In this study, a novel nanomedicine is generated, SSK1‐NPs, that efficiently delivers SSK1 into the brain, at where SSK1 is then specifically cleaved by lysosomal β‐gal that is expressed at higher levels in aged cells, followed by the release of its active form, gemcitabine, which in turn induces the apoptosis of senescent cells leading to the reduction of amyloid‐beta accumulation and improvement of cognitive function in aged AD mice.