Probiotic Extracellular Vesicles Enable Oral Alendronate Therapy for Glucocorticoid‐Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) involves impaired bone remodeling, intestinal dysbiosis, and immune imbalance, which together limit the long-term benefit of conventional oral bisphosphonate therapy. Here, we report LpEVs@ALN, a probiotic extracellular vesicle-based oral nanoplatform constructed by loading alendronate (ALN) into Lacticaseibacillus paracasei-derived extracellular vesicles. LpEVs@ALN maintains vesicle integrity and epithelial compatibility, improves ALN retention under acidic exposure, and enables sustained ALN release at intestinal pH conditions. In dexamethasone-suppressed BMSCs, LpEVs@ALN enhances osteogenic differentiation, as evidenced by increased ALP activity and matrix mineralization. In zebrafish GIOP models, LpEVs@ALN improves cranial mineralization, new bone formation, scale regeneration, and locomotor/shoaling performance; accompanied by reduced inflammatory tone, improved ALP/RANKL-associated bone turnover readouts, and rebalanced oxidative-stress indices. Microbiome profiling shows recovery of richness/diversity and reduced Proteobacteria dominance, while scale RNA-seq reveals broad reversal of glucocorticoid-driven dysregulation toward pro-osteogenic and anti-inflammatory programs. Integrated correlation analysis further linked microbial remodeling with systemic and skeletal responses, suggesting involvement of the gut-immune-bone axis. Collectively, LpEVs@ALN alleviates GIOP by combining ALN-mediated bone protection with probiotic extracellular vesicle-associated regulation of intestinal and systemic homeostasis, highlighting its potential as an oral therapeutic strategy for GIOP.