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

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.