A Novel Reactive Oxygen Species‐Responsive Bone‐Targeted Nanoplatform Based on Cloperastine Attenuates Ovariectomy‐Induced Bone Loss by Inhibiting Osteoclast Oxidative Phosphorylation

Postmenopausal osteoporosis is caused by excessive osteoclast‐mediated bone resorption. This study identifies mitochondrial oxidative phosphorylation (OXPHOS) as a tractable metabolic target for antiresorptive therapy. A literature‐guided drug repurposing screen focused on compounds reported to affect OXPHOS or related energy metabolism identified cloperastine (Clo) as a potent suppressor of receptor activator of nuclear factor κB ligand‐induced osteoclastogenesis. Clo reduces mitochondrial respiration, downregulates OXPHOS complex proteins, decreases mitochondrial reactive oxygen species (ROS), dissipates the mitochondrial membrane potential, disrupts mitochondrial dynamics, and collectively impairs osteoclast differentiation and bone resorption in vitro. Asp8‐modified methionine/lysine‐based ROS‐responsive polyethylene glycol micelles encapsulating Clo (Clo/Asp8‐PMK‐MCs) were developed for potential bone‐directed delivery. These micelles (∼220 nm; −3.60 ± 0.09 mV) exhibit ROS‐triggered disassembly and accelerated Clo release under oxidative conditions. Fluorescence tracking of DID‐labeled micelles shows stronger skeletal signals with Asp8 modification than without it. Clo/Asp8‐PMK‐MCs inhibit osteoclast differentiation and bone resorption, whereas bioactive Asp8‐PMK‐MCs simultaneously promote osteoblast differentiation and matrix mineralization. In ovariectomized mice, Clo/Asp8‐PMK‐MCs attenuate ovariectomy‐induced bone loss, preserve trabecular bone microarchitecture, reduce osteoclast‐related parameters and serum bone resorption markers, and enhance bone formation. These findings support Clo/Asp8‐PMK‐MCs as a potential OXPHOS‐targeted nanomedicine integrating Clo‐mediated antiresorptive activity with carrier‐mediated osteogenic activity to attenuate estrogen deficiency‐induced bone loss.