A Targeting Senescence and Recycling Intracellular Nicotinamide Adenine Dinucleotide Strategy for Attenuation of Senescence-Associated Phenotypes

Cellular senescence is a critical factor in organismal aging and age-related diseases. Nicotinamide adenine dinucleotide (NAD⁺) has been shown to be closely related to the cellular senescence process and holds potential as a senotherapeutic agent. However, its clinical application has been hindered by challenges such as its inability to be directly absorbed by cells, instability, and lack of targeting specificity. To address these issues, a senescent cell targeting and intracellular NAD⁺ recycling strategy for attenuation of senescence-associated phenotypes has been developed. As a proof of concept, we demonstrate that the Cu-NAD@CM system can target and recognize senescent cells while restoring the NADH to NAD⁺ cycle and inhibiting senescence-associated secretory phenotype (SASP) expression. Our study reveals the significant therapeutic potential of the Cu-NAD@CM system in managing atherosclerosis (a disease involving multiple senescent cell types) and in doxorubicin-induced and d-galactose-induced senescent mouse models.