Delivery of therapeutic miRNAs using nanoscale zeolitic imidazolate framework for accelerating vascularized bone regeneration

MicroRNAs (miRNAs), a promising therapeutic nucleic acid drugs being secreted extracellularly in exosomes, have been reported to elicit a regulatory role in a wide array of biological process, including osteogenesis and angiogenesis. However, poor cellular uptake and endosomal entrapment are still central issues that limited their therapeutic outcomes. Herein, nanoscale zeolitic imidazolate framework (ZIF) was attempted as a vector of miRNA delivery to achieve efficient cellular uptake and the release of payloads at a target intracellular site. Proangiogenic miR-21 and pro-osteogenic miR-5106 were selected as the model miRs and incorporated into [email protected] nanocomposites via a one-pot method. The results verified that ZIF-8 vector could not only exhibit a high-payload loading efficiency but also promote the cellular uptake, as well as improve the endosomal escape capability of miRNAs. The therapeutic effects of [email protected] were further systematically investigated. RNA sequencing analysis demonstrated that MAPK signaling pathway and PID-HIF1-TF pathway were upregulated by [email protected] transfection in HUVECs, finally leading to the promotion of angiogenesis, demonstrated by in vitro and in vivo evaluations. Moreover, the [email protected] significantly improved the osteogenic differentiation of BMSCs in vitro and efficiently enhanced bone formation in vivo. In summary, we envisage that the ease of fabrication, versatility, low cytotoxicity, promoted cellular uptake, and promising endosomal escape performance make the [email protected] nanocomposite be a potential vector for the efficient delivery of therapeutic nucleic acid drugs.