Work

Engineered SHED-EVs delivering FtMt siRNA rescue mitophagy and bone formation in smoking-related osteoporosis

Year: 2026

Type: article

Abstract: Aims Tobacco smoking independently contributes to osteoporosis. Cigarette smoke–derived reactive oxygen species (ROS) and transition metals promote iron accumulation and impair mitophagy in bone marrow mesenchymal stem cells (BMSCs), causing mitochondrial dysfunction, reduced osteogenic differentiation, and iron-induced osteoporosis. The molecular pathways linking smoke exposure to impaired bone formation remain incompletely understood.Materials and methods We established a cigarette smoke extract (CSE)-induced bone-loss model in female C57BL/6J mice (n = 8/group) and performed femoral transcriptomic profiling. Bone-targeting extracellular vesicles from stem cells from human exfoliated deciduous teeth (SHED-EVs) were loaded with siRNA against mitochondrial ferritin (FtMt; siFtMt) to generate BT-siFtMt@SHED-EVs. The nanoplatform was characterized and tested in vitro and in vivo using micro-CT, JC-1, Alkaline Phosphatase/alizarin red S, immunostaining, RT-qPCR, Western blotting, and in silico docking (ZDOCK/RDOCK).Results CSE upregulated FtMt while suppressing mitophagy and osteogenic differentiation. BT-siFtMt@SHED-EVs restored mitochondrial membrane potential, reinstated mitophagic flux, and rescued BMSC osteogenesis. Systemically administered BT-siFtMt@SHED-EVs restored trabecular microarchitecture and bone mineral density and elevated osteogenic markers in CSE-exposed mice; these benefits were abolished by the mitophagy inhibitor Mdivi-1.Conclusions Targeted FtMt knockdown via bone-homing SHED-EVs reinstates mitochondrial quality control and ameliorates smoke-related bone loss, offering a precision mitochondrial medicine approach to osteoporosis.

Source: Nanomedicine

DOI: 10.1080/17435889.2026.2748269