Disrupted bone remodeling, weakened intrinsic bone-forming ability, and a lack of bone-targeting drugs are the main challenges in current clinical interventions for osteoporosis. In this study, we developed a hybrid nano-delivery system that combines a metal-organic framework loaded with betaine and engineered exosomes (BZ@Exos) to restore bone metabolic balance and improve bone microstructure. The engineered exosomes, which overexpress CXCR4 and CD47 proteins on their surface, have strong bone tissue targeting and can evade clearance by the mononuclear phagocyte system, while ZIF-8 can stably encapsulate betaine. Internalized betaine promotes TFEB nuclear translocation by targeting 14-3-3 proteins, enhancing autophagy flux in aged bone marrow mesenchymal stem cells (BMSCs) and promoting their osteogenic differentiation. Meanwhile, BZ@Exos significantly inhibit osteoclast-mediated bone resorption and restore bone metabolic balance. In vivo experiments showed that intravenous injection of BZ@Exos successfully reversed bone loss in ovariectomized rat models of osteoporosis and alleviated age-related phenotypes. This new therapeutic system integrates bone homeostasis remodeling, regeneration potential recovery, and precise targeting, offering a fresh perspective for treating osteoporosis.

Summary
The main challenges in osteoporosis intervention lie in insufficient bone targeting, declining endogenous bone-forming ability, and imbalanced bone resorption. We developed a hybrid delivery system combining metal-organic frameworks loaded with betaine and engineered exosomes. The exosomes co-express CXCR4 and CD47 on their surface, achieving bone targeting while evading clearance by the mononuclear phagocyte system; ZIF-8 stably encapsulates betaine. Once internalized, betaine targets 14-3-3 proteins, promotes TFEB nuclear translocation, enhances autophagy flux in aged bone marrow mesenchymal stem cells, restores osteogenic differentiation, and simultaneously suppresses osteoclast-mediated bone resorption. Intravenous administration reversed bone loss and alleviated aging phenotypes in ovariectomized rats.

This work integrates autophagy regulation with bone metabolism homeostasis repair through targeted exosome carriers, addressing osteoporosis from the root of stem cell aging. In the future, adjusting the ratio of exosome membrane proteins could optimize enrichment efficiency in different bone sites. As a natural small molecule, betaine has better long-term safety compared to synthetic drugs. This platform could also be applied to other stem cell aging-related bone diseases, such as delayed healing of age-related fractures or glucocorticoid-induced osteoporosis. The drug-loading stability of metal-organic frameworks is also suitable for carrying other bone-active molecules for combination therapy, but large-scale exosome production and batch consistency still need to be addressed.

We can custom-make various bio-functional nanomaterials, adjusting their size, structure, and surface modifications as needed. We provide full characterization, iterative planning, and complete technical support, backing research in targeted delivery, bioimaging, and integrated diagnostics and therapy.  
Engineer Zhang: 17715390137  
Engineer Chen: 18914047343