Postmenopausal osteoporosis is one of the most prevalent skeletal disorders in women and is featured by the imbalance between intraosseous vascularization and bone metabolism. In this study, a pH-responsive shell-core structured micro/nano-hydrogel microspheres loaded with polyhedral oligomeric silsesquioxane (POSS) using gas microfluidics and ionic cross-linking technology are developed. This micro/nano-hydrogel microsphere system (PDAP@Alg/Cs) can achieve oral delivery, intragastric protection, intestinal slow/controlled release, active targeting to bone tissue, and thus negatively affecting intraosseous angiogenesis and osteoclastogenesis. According to biodistribution data, PDAP@Alg/Cs can successfully enhance drug intestinal absorption and bioavailability through intestine adhesion and bone targeting after oral administration. In vitro and in vivo experiments reveal that PDAP@Alg/Cs promoted type H vessel formation and inhibited bone resorption, effectively mitigating bone loss by activating HIF-1α/VEGF signaling pathway and promoting heme oxygenase-1 (HO-1) expression. In conclusion, this novel oral micro/nano-hydrogel microsphere system can simultaneously accelerate intraosseous vascularization and decrease bone resorption, offering a brand-new approach to prevent postmenopausal osteoporosis.