Qu Xiao, Xie Zhou, Zhang Jun, Huang Yanran, Zhao Runhan, Li Ningdao, Wang Juan, Chen Liang, Cui Wenguo, Luo Xiaoji
Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, P. R. China.
Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, P. R. China.
Small. 2025 Jan;21(4):e2409936. doi: 10.1002/smll.202409936. Epub 2024 Dec 4.
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.
肠-骨轴是骨质疏松症治疗的一个有前景的靶点，但现有的递送系统缺乏精确靶向性。在此，利用气体微流控和离子交联技术开发了一种口服水凝胶微球系统（E7-Lipo@Alg/Cs），以通过肠-骨轴将药物递送至骨髓间充质干细胞（BMSC），调节线粒体衰老。将一种BMSC亲和肽偶联到包裹非瑟酮的脂质体上，然后将其包入藻酸盐-钙水凝胶微球中。壳聚糖通过静电吸附在微球表面，形成一种核壳结构，该结构可黏附于肠上皮细胞，耐受胃酸，并通过肠-骨轴促进向BMSC的靶向递送。在体外，该系统有效地增强了线粒体功能并逆转了BMSC衰老，而体内研究表明药物活性延长、成骨分化得以恢复且骨得以再生。RNA测序表明AMPK-SIRT1通路被激活，逆转了BMSC中的线粒体衰老并促进了老化骨组织的再生。这种口服水凝胶微球系统为调节线粒体功能和预防骨质流失提供了一种靶向且高效的策略，在骨质疏松症治疗方面具有巨大的临床潜力。
