A galactose-tethered tetraphenylethene prodrug mediated apoptosis of senescent cells for osteoporosis treatment

Osteoporosis and bone injury healing in elderly patients are major medical challenges, often exacerbated by the accumulation of senescent cells. Herein, we show that TPE-Gal, which contains a tetraphenylethene unit and a galactose moiety, offers a promising molecular therapy designed to light up and eliminate senescent cells through a hydrolysis reaction catalyzed by β-galactosidase, an enzyme overexpressed in senescent cells. The reaction produces TPE-OH, which, in turn, increases reactive oxygen species levels within the senescent cells, leading to noninflammatory apoptosis of senescent cells. This targeted clearance mechanism helps to alleviate osteoporosis symptoms and promotes bone injury healing. Moreover, apoptotic vesicles, which are generated during the process, are partly phagocytosed by macrophages, mimicking physiological metabolic processes. This study opens new avenues for addressing bone health issues through the designed bioclearance of senescent cells, aligning with the body’s natural pathways for maintaining homeostasis.