Delivery System Based on Akkermansia Muciniphila Loaded Salidroside for the Treatment of Osteoporosis in Zebrafish Model.

Glucocorticoid-induced osteoporosis (GIOP) is a frequent cost of dexamethasone (Dex) therapy; salidroside (SAL) shows promise but suffers from rapid clearance and poor oral bioavailability. We present an oral, living co-therapy in which viable Akkermansia muciniphila is vacuum-loaded with intracellular SAL and protected by a pH-responsive Eudragit L100 enteric coat (SAL@AKK@EL100). This construct effectively retains probiotic activity, shields the cargo through gastric transit, and shows prolonged intracellular retention with gradual release. In Dex-challenged zebrafish, SAL@AKK@EL100 reversed behavioral dysregulation and improved skeletal mineralization, outperforming SAL or AKK alone. Integrative RNA-seq/16S analysis revealed that SAL@AKK@EL100 treatment was associated with modulation of pathways related to tight junctions, ECM-receptor interaction, actin cytoskeleton, glutathione metabolism, and unsaturated fatty acid biosynthesis, alongside remodeling of the gut microbiota. SAL@AKK@EL100 establishes a modular, microbiome-anchored platform that couples probiotic viability with drug gradual release for promising oral management of GIOP.