A hypoxia-responsive calixarene supramolecular system enables redox-regulated matrix remodeling for postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) is characterized by progressive bone loss driven by excessive osteoclast activity, impaired osteogenesis, and maladaptive remodeling of the bone microenvironment. Although raloxifene (RLX) is clinically approved for PMOP, its therapeutic potential is constrained by limited bone selectivity and systemic adverse effects. Here, we report a hypoxia-responsive, bone-targeted supramolecular system (RLX@PnAC4A) that integrates site-selective drug delivery with redox regulation to enable coordinated matrix remodeling within the osteoporotic niche. PnAC4A was engineered through azobenzene functionalization and phosphonate modification, endowing the calixarene host with hypoxia-triggered reducibility, high-affinity bone targeting, and efficient RLX encapsulation. The resulting supramolecular assemblies exhibited stable host-guest interactions and selective drug release under hypoxic conditions. In vitro, RLX@PnAC4A preferentially restored intracellular redox homeostasis under hypoxic and inflammatory stress, enhanced osteogenic differentiation, and suppressed osteoclastogenesis in a microenvironment-dependent manner. Following systemic administration in ovariectomized (OVX) mice, RLX@PnAC4A rapidly accumulated in bone tissue and significantly improved trabecular microarchitecture, bone formation dynamics, and structural integrity compared with free RLX. Transcriptomic profiling further revealed that OVX induced a broadly immune-activated disease program, whereas PnAC4A alone established an extracellular matrix-associated conditioning state. Importantly, RLX@PnAC4A activated a dominant, therapy-specific transcriptional module enriched in extracellular matrix remodeling and pro-regenerative signaling, accompanied by directional rescue of key disease-associated nodes. Collectively, these findings demonstrate that RLX@PnAC4A functions as an active supramolecular regulator, exerting therapeutic efficacy through a hierarchically organized transcriptional architecture that couples bone targeting, redox modulation, and osteoblast-osteoclast coordination. This hypoxia -responsive calixarene platform establishes a mechanistically grounded strategy for precision intervention in postmenopausal osteoporosis.