Bone-Targeting Nucleic Acid Delivery Polymer Vector for Effective Therapy of Bone Metastasis

Bone diseases, such as bone metastases, pose significant therapeutic challenges due to the distinct physiological environment of skeletal tissues, which complicates the targeted delivery of nucleic acid therapeutics. Existing delivery systems, including lipid nanoparticles (LNP) and polyethylenimine (PEI), struggle to achieve precise bone targeting effectively. To address this issue, we developed a polymer-based bone-targeting bioreducible nucleic acid delivery vector, poly[alendronic acid-<i>co</i>-(<i>N</i>,<i>N</i>'-bis(acryloyl)cystamine-<i>co</i>-4-amino-1-butanol)] (ALN-Pabol), which incorporates alendronic acid (ALN) for precise bone targeting. The ALN-Pabol exhibited a hydroxyapatite binding rate of 91.1%, significantly outperforming nontargeted Pabol/miRNA (73.5%) and commercial systems such as PEI/miRNA (58.3%) and Lipofectamine 2000/miRNA (64.7%). <i>In vivo</i> fluorescence imaging demonstrated its superior skeletal accumulation compared to nontargeted controls. In a murine breast cancer bone metastasis model, ALN-Pabol/miRNA polyplex reduced bone tumor weight by 79.1% relative to PBS controls and 36.8% compared to LNP/miRNA. Mechanistically, the polyplex dissociates in the high-glutathione tumor microenvironment, releasing therapeutic miRNA to suppress cancer cell proliferation and promote apoptosis. Simultaneously, ALN inhibits osteoclast activity, significantly mitigating osteolytic damage. Micro-CT analysis revealed near-complete restoration of bone volume and trabecular architecture to healthy levels. This work establishes ALN-Pabol as a highly promising delivery vector for bone-targeted gene therapy, bridging critical gaps in skeletal disease treatment and expanding potential applications in bone regeneration and cancer therapy.