Local delivery and controlled release of miR-34a loaded in hydroxyapatite/mesoporous organosilica nanoparticles composite-coated implant wire to accelerate bone fracture healing.

ABSTRACT

Immediate mechanical stability is a prerequisite for fracture healing. In addition to bringing immediate mechanical stability in fracture site, implants with bioactive coating can release active substance to accelerate bone-fracture healing. However, limited drug-loading capacity of established coatings weakens their biological functions, which urges the engineering of more effective coating biomaterials for accelerating fracture healing. Herein, mesoporous organosilica nanoparticles (MONs), as miR-34a delivers, are loaded onto hydroxyapatite (HA)-coated Kirschner wire to engineer a HA/MONs@miR-34a composite coating. The composite coating can effectively deliver miR-34a into osteoclasts, generate gene dose-dependent inhibiting effect on differentiation and resorptive activity of osteoclasts by regulating multiple downstream gene expression at the early stage of fracture healing, which additionally exhibits decent bone regeneration potentials as evidenced in rat tibial fracture model. In particular, differentially expressed genes regulated by miR-34a are identified using RNA-seq followed by bioinformatics analysis. Functional enrichment analysis reveals that genes with altered expression mainly distribute in mainly distribute in DNA replication and cell cycle, which are associated with the development of osteoclasts. This work not only demonstrates the high clinical translation potential of HA/MONs@miR-34a to accelerate fracture healing, but also reveals the underlying molecular mechanism of regulating physiological functions of osteoclasts based on analysis of singlecell RNA sequencing.