Elimination of Senescent Osteocytes by Bone‐Targeting Delivery of β‐Galactose‐Modified Maytansinoid Prevents Age‐Related Bone Loss

The accumulation of senescent cells in bone during aging contributes to senile osteoporosis, and clearance of senescent cells by senolytics could effectively alleviate bone loss. However, the applications of senolytics are limited due to their potential toxicities. Herein, small extracellular vesicles (sEVs) have been modified by incorporating bone-targeting peptide, specifically (AspSerSer)₆, to encapsulate galactose-modified Maytansinoids (DM1). These modified vesicles are referred to as (AspSerSer)₆-sEVs/DM1-Gal, and they have been designed to specifically clear the senescent osteocytes in bone tissue. In addition, the elevated activity of lysosomal β-galactosidase in senescent osteocytes, but not normal cells in bone tissue, could break down DM1-Gal to release free DM1 for selective elimination of senescent osteocytes. Mechanically, DM1 could disrupt tubulin polymerization, subsequently inducing senescent osteocytes apoptosis. Further, administration of bone-targeting senolytics to aged mice could alleviate aged-related bone loss without non-obvious toxicity. Overall, this bone-targeting senolytics could act as a novel candidate for specific clearance of senescent osteocytes, ameliorating age-related bone loss, with a promising therapeutic potential for senile osteoporosis.