Bone-targeted delivery of VEGF/BMP2 plasmids using GLG1-modified PLGA nanoparticles for osteoporosis therapy

Postmenopausal osteoporosis (PMOP), resulting from estrogen deficiency and excessive bone resorption, leads to increased bone fragility and fractures. Current treatments are hindered by suboptimal targeting and short drug half-lives. This study introduces a bone-targeted nanoparticle system, GLG1@NPs-VEGF/BMP2, which incorporates vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP2) plasmids, and is modified with Golgi complex-localized glycoprotein-1 (GLG1) to enhance bone-specific delivery.

PLGA nanoparticles (NPs) were loaded with VEGF/BMP2 plasmids and functionalized with GLG1. In vitro, particle characterization, osteogenic differentiation of MC3T3-E1 cells, and angiogenic effects on HUVECs were evaluated. In vivo, ovariectomized (OVX) rats were used to assess bone targeting, therapeutic efficacy, and biosafety.

The GLG1@NPs-VEGF/BMP2 complex exhibited sustained release and high plasmid loading efficiency. In vitro, it effectively upregulated VEGF/BMP2 expression, promoted osteogenic differentiation in MC3T3-E1 cells, and enhanced HUVEC proliferation, migration, and tube formation. In vivo, GLG1-mediated targeting increased nanoparticle accumulation in bone. OVX rats treated with GLG1@NPs-VEGF/BMP2 demonstrated improved trabecular microstructure, increased bone strength, and higher VEGF/BMP2/CD31 expression, with no evidence of systemic toxicity.

This approach, exploiting GLG1's bone-targeting capability, enhances VEGF/BMP2 delivery, restoring bone formation and angiogenesis in PMOP. GLG1@NPs-VEGF/BMP2 represents a promising strategy for precision therapy in osteoporosis.