Regulating Type H Vessel Formation and Bone Metabolism via Bone‐Targeting Oral Micro/Nano‐Hydrogel Microspheres to Prevent Bone Loss

Abstract 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‐1 α /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.