Designed bone-targeting ROS-responsive nanoplatform for precision glycolysis inhibition in postmenopausal osteoporosis

Postmenopausal osteoporosis (PMOP) arises from estrogen deficiency, which disrupts bone remodeling by shifting the balance toward bone resorption over osteogenesis. Glycolytic regulation has emerged as a critical mechanism governing osteoclast differentiation and resorptive activity. Blocking lactate transport through monocarboxylate transporters (MCTs) suppresses glycolysis, thereby attenuating these processes and highlighting MCT inhibition as a potential therapeutic target. The MCT inhibitor AZD3965 blocks lactate transport, thereby downregulating NF-κB/MAPK signaling, increasing intracellular lactate levels, and ultimately suppressing osteoclast formation and bone resorption in vitro. To achieve targeted delivery and reduce off-target effects, a bone-targeted, reactive oxygen species (ROS)-responsive nanocarrier (PH/DPA@A) was engineered by integrating a bone-affinitive DSPE-PEG-Asp₈ (DPA) ligand with a ROS-cleavable phenylboronic acid pinacol ester-hyaluronic acid (PH) shell to encapsulate AZD3965. The nanoparticles exhibited a mean diameter of ∼179 nm, well-defined ROS-triggered drug release kinetics, and high in vivo bone-targeting efficiency. In vitro, PH/DPA@A inhibited osteoclast formation and resorptive activity at levels comparable to free AZD3965, indicating preserved pharmacological potency. In ovariectomized (OVX) mice, systemic PH/DPA@A administration increased femoral bone mineral density and improved trabecular number, thickness, and connectivity, as confirmed by micro-computed tomography. These findings demonstrate that the bone-targeting, ROS-responsive design enables efficient in vivo delivery and metabolic modulation in osteoporotic bone, supporting PH/DPA@A as a multifunctional nanoplatform with translational potential for postmenopausal osteoporosis therapy.