miR-126-loaded ZIF-8 nanoparticles as a dual-functional approach for accelerating vascularized bone regeneration.

Background: Bone defects pose a significant clinical challenge due to their high morbidity and long-term disability. Simultaneous enhancement of osteogenesis and angiogenesis holds promise for accelerating bone regeneration. MicroRNAs (miRNAs), particularly miR-126, are critical regulators of angiogenesis; however, their therapeutic application requires efficient delivery systems. Designing miRNA carriers with intrinsic osteogenic activity remains a pivotal yet underexplored strategy.

Methods: Zeolitic imidazolate framework-8 (ZIF-8) was developed as a nanocarrier to deliver proangiogenic miR-126. The miR-126@ZIF-8 nanocomposites were synthesized via a one-pot method, and their physicochemical properties, miRNA loading efficiency, and cytotoxicity were systematically characterized. Cellular uptake, miR-126 release kinetics, and Zn dissolution was evaluated in vitro. Angiogenic and osteogenic effects were assessed through gene expression analysis, capillary-like tube formation assays, and mineralization studies.

Results And Discussion: The miR-126@ZIF-8 nanoparticles exhibited a high miRNA loading capacity, efficient cellular internalization, and minimal cytotoxicity. Upon intracellular delivery, the nanoparticles decomposed to release miR-126 and Zn, synergistically enhancing angiogenic (e.g., VEGF, HIF-1α) and osteogenic (e.g., RUNX2, OCN) gene expression. Functional assays demonstrated significant improvements in endothelial cell tube formation and osteoblast mineralization compared to controls.

Conclusion: Our work presents miR-126@ZIF-8 as a novel dual-functional platform that simultaneously promotes angiogenesis and osteogenesis. By combining the proangiogenic action of miR-126 with the osteoinductive potential of Zn, our nanocomposite offers a promising strategy for vascularized bone regeneration for the repair of bone defects.