Hybrid extracellular vesicles for targeted delivery of therapeutic cargoes to combat osteoporotic bone loss

Osteoporosis arises from an imbalance between bone-resorbing osteoclasts and bone-forming osteoblasts, driving progressive bone loss. Here, we engineer bone-targeting hybrid vesicles by fusing extracellular vesicles (EVs) with lipid nanoparticles (LNPs) to enable coordinated delivery of complementary therapeutics. These vesicles present and carry Osteoprotegerin (OPG) protein and mRNA and are fused with adenosine (Ado)-loaded nanoparticles to form OPG- and Ado-loaded EV-LNP (OPG-EV-LNP-Ado). Acting as a decoy for receptor activator of nuclear factor kappa B ligand (RANKL), OPG directs bone-specific targeting and uptake, enhancing delivery to osteoblasts. Systemic administration results in preferential bone accumulation and significantly attenuates osteoporotic pathology, demonstrating a modular platform for targeted, multi-cargo therapy to restore bone homeostasis.