Regulating Mitochondrial Aging via Targeting the Gut‐Bone Axis in BMSCs With Oral Hydrogel Microspheres to Inhibit Bone Loss

Abstract The gut‐bone axis is a promising target for osteoporosis treatment, yet existing delivery systems lack precise targeting. Herein, an oral hydrogel microsphere system (E7‐Lipo@Alg/Cs) is developed using gas microfluidic and ionic crosslinking technologies to deliver drugs to bone marrow mesenchymal stem cells (BMSCs) via the gut‐bone axis, regulating mitochondrial aging. A BMSC‐affine peptide is conjugated onto liposomes encapsulating Fisetin, followed by incorporation into alginate‐calcium hydrogel microspheres. Chitosan is electrostatically adsorbed onto the microsphere surface, creating a core‐shell structure that adheres to intestinal epithelial cells, withstands gastric acid, and facilitates targeted delivery to BMSCs through the intestinal‐bone axis. In vitro, the system effectively enhances mitochondrial function and reverses BMSC aging, while in vivo studies demonstrate prolonged drug activity, restored osteogenic differentiation, and bone regeneration. RNA‐seq indicates activation of the AMPK‐SIRT1 pathway, reversing mitochondrial aging in BMSCs and promoting aged bone tissue regeneration. This oral hydrogel microsphere system provides a targeted and efficient strategy for regulating mitochondrial function and preventing bone loss, offering significant clinical potential for osteoporosis treatment.