Engineered Pseudomonas mirabilis-Derived Outer Membrane Vesicles Targeting Bone Microenvironment to Improve Osteoporosis

<b>Introduction</b>: Osteoporosis (OP) is a prevalent condition marked by reduced bone density and a heightened risk of fractures. Current treatments often have side effects, underscoring the need for safer alternatives. Recent research highlights the significant role of gut microbiota and their metabolites in maintaining bone health. Notably, bacterial outer membrane vesicles (OMVs) have emerged as a promising platform due to their nanoscale sizes, low toxicity, drug-loading capabilities, and excellent biocompatibility. <b>Methods:</b> In this study, we developed a delivery system using OMVs derived from <i>Pseudomonas mirabilis</i> (PM). By anchoring bone-targeting peptides to the PM-OMVs membrane, we equipped these vesicles to deliver endogenous miRNAs to the bone microenvironment effectively. <b>Results and Discussion:</b> The bone-targeted PM-OMVs (PM-OMVs-BT) demonstrated exceptional bone-targeting abilities and exhibited a favorable safety profile in vivo. Additionally, LGG-OMVs-BT were successfully internalized by bone marrow stromal cells (BMSCs) without significant cytotoxicity, effectively promoting their osteogenic differentiation and mineralization. In conclusion, our study indicates that PM-OMVs-BT could offer a safe and effective treatment option for OP.