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 with lipid nanoparticles to enable coordinated delivery of complementary therapeutics. These vesicles present and carry osteoprotegerin (OPG) protein and mRNA, and are fused with adenosine-loaded nanoparticles to form OPG-EV-LNP-Ado. Acting as a decoy for 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.