Abstract
<title>Abstract</title> <p>Background Osteoporotic bone defects remain difficult to repair because impaired osteogenesis, poor vascularization, excessive osteoclast activity, and a pro-senescent, pro-inflammatory microenvironment occur simultaneously. Intermittent parathyroid hormone (iPTH) is a validated anabolic stimulus, but its pulsatile pharmacology limits direct local application. We therefore encoded the iPTH program into exosomes (iEXOs) derived from preconditioned bone marrow mesenchymal stem cells (BMSCs) and combined them with a thermosensitive hydrogel for local delivery. Results Multi-omics analysis revealed that iEXOs carried a remodeled proteomic, metabolomic, and lipidomic signature that recapitulated iPTH signaling. Integrated proteomic and metabolomic profiling identified phosphatidic acid (PA) as a key effector converging on Hippo/YAP signaling. Pharmacological perturbation confirmed that iEXOs activated the PA-PLD-LATS1/YAP axis in recipient cells, thereby promoting osteogenesis and angiogenesis while restraining osteoclastogenesis. After incorporation into a PEGylated poly(serine-sebacate) hydrogel grafted with oxidized mannan oligosaccharides (PESS-MOS, PM), iEXOs showed sustained local retention and anti-inflammatory activity. In ovariectomized rats with femoral defects, iEXO@PM significantly improved bone volume, mineral density, and neovascularization without detectable systemic toxicity. Conclusions Encoding pulsatile endocrine signals into stem cell-derived exosomes and delivering them through a thermosensitive hydrogel provides a localized, cell-free strategy for coordinated osteogenesis, angiogenesis, osteoclast restraint, and immunomodulatory repair of osteoporotic bone defects. The hydrogel further enables sustained local retention and controlled release, thereby enhancing the therapeutic efficacy of iEXOs.</p>