Synthetic nanoparticles functionalized with cell membrane-mimicking, bone-targeting, and ROS-controlled release agents for osteoporosis treatment.

Postmenopausal osteoporosis is a common degenerative disease, with suboptimal clinical outcomes. The targets of current therapeutic agents are both nonspecific and diverse. We synthesized a novel nanoparticle (NP), ALN@BMSCM@PLGA-TK-PEG-SS31. After intravenous injection, the NP evaded immune phagocytosis, targeted bone tissue, and efficiently downregulated bone reactive oxygen species (ROS) generation. The core PLGA-TK-PEG-SS31 NP was ∼100 nm in diameter. The TK chemical bond breaks on exposure to ROS, releasing the novel mitochondrion-targeting peptide SS31. Outer bone marrow mesenchymal stem cell membranes (BMSCMs) were used to coat the NP with surface proteins to ensure membrane functionality. The circulation time was prolonged and immune phagocytosis was evaded. Embedding the DSPE-PEG-ALN lipid within the cell membrane enhanced the bone-targeting ability of the NP. Our results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 exerted dual effects on bone tissue in vitro, significantly inhibiting RANKL-induced osteoclastogenesis in the presence of H2O2 and promoting osteogenic differentiation in BMSCs. In a mouse model of ovariectomy-induced osteoporosis, ALN@BMSCM@PLGA-TK-PEG-SS31 significantly ameliorated oxidative stress and increased bone mass with no notable systemic side effects. These results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 is a promising treatment for osteoporosis.