Plant‐derived extracellular vesicle‐like particles as novel osteoanabolic agents: Activating bone morphogenetic protein 2/Smads signaling axis for bone regeneration in postmenopausal osteoporosis

Abstract Postmenopausal osteoporosis, marked by diminished bone regenerative capacity and elevated fracture risk, urgently requires innovative osteoanabolic strategies. Plant‐derived extracellular vesicle (PDEV)‐like particles (EVLPs) have emerged as promising therapeutic candidates due to their bioactive cargo and cross‐kingdom regulatory potential. Building on the traditional use of Dipsaci Radix (DR) in bone repair, this study investigates DR‐derived EVLPs (DREVLPs) as novel bone‐forming nanotherapeutics. We successfully isolated and characterized DREVLPs, demonstrating their remarkable osteogenic capacity through bone morphogenetic protein 2 (BMP2) pathway activation. In bone marrow mesenchymal stem cells (BMSCs), DREVLPs significantly upregulated RUNX2 and collagen I while triggering the BMP2/Smads signaling phosphorylation cascade. Oral administration in ovariectomized mice revealed precise skeletal targeting with DREVLPs preferentially accumulating in femurs and BMSCs. Treatment substantially preserved trabecular architecture, increasing bone volume fraction compared with untreated controls. Molecular analyses confirmed pathway activation through elevated BMP2, p‐Smad1/5/9, and osteogenic markers in bone tissue—effects comparable to clinical bisphosphonates but through anabolic rather than anti‐resorptive mechanisms. These findings establish plant EVLPs as a new category of bone‐forming agents, with DREVLPs representing a translatable oral nanotherapy that addresses the critical unmet need for safe anabolic treatments in postmenopausal osteoporosis through targeted activation of endogenous BMP2 signaling.