Magnetofection of miR-21 promoted by electromagnetic field and iron oxide nanoparticles via the p38 MAPK pathway contributes to osteogenesis and angiogenesis for intervertebral fusion

Abstract

Background Magnetofection-mediated gene delivery shows great therapeutic potential through the regulation of the direction and degree of differentiation. Lumbar degenerative disc disease (DDD) is a serious global orthopaedic problem. However, even though intervertebral fusion is the gold standard for the treatment of DDD, its therapeutic effect is unsatisfactory. Here, we described a novel magnetofection system for delivering therapeutic miRNAs to promote osteogenesis and angiogenesis in patients with lumbar DDD. Results Co-stimulation with electromagnetic field (EMF) and iron oxide nanoparticles (IONPs) enhanced magnetofection efficiency significantly. Moreover, in vitro, magnetofection of miR-21 into bone marrow mesenchymal stem cells (BMSCs) and human umbilical endothelial cells (HUVECs) influenced their cellular behaviour and promoted osteogenesis and angiogenesis. Then, gene-edited seed cells were planted onto polycaprolactone (PCL) and hydroxyapatite (HA) scaffolds (PCL/HA scaffolds) and evolved into the ideal tissue-engineered bone to promote intervertebral fusion. Finally, our results showed that EMF and polyethyleneimine (PEI)@IONPs were enhancing transfection efficiency by activating the p38 MAPK pathway. Conclusion Our findings illustrate that a magnetofection system for delivering miR-21 into BMSCs and HUVECs promoted osteogenesis and angiogenesis in vitro and in vivo and that magnetofection transfection efficiency improved significantly under the co-stimulation of EMF and IONPs. Moreover, it relied on the activation of p38 MAPK pathway. This magnetofection system could be a promising therapeutic approach for various orthopaedic diseases. Graphical Abstract

A novel extracellular vesicles production system harnessing matrix homeostasis and macrophage reprogramming mitigates osteoarthritis

“…Recently, nucleic acids, including mRNAs, non-coding RNAs, and miRNAs, have been identified in sEVs. MiRNAs are key sEVs components critical to OA progression by regulating inflammatory response, chondrocyte survival, and ECM deposition [ 30 ]. These miRNAs transported by sEVs can be internalized by recipient cells and consequently exert significant biological functions [ 31 ].…”

Recent advances of nanoparticles on bone tissue engineering and bone cells

“…Electromagnetic eld and IONPs enhanced transfection efficiency of miR-21 into BMSCs and human umbilical endothelial cells (HUVECs), and osteogenic differentiation of MSCs and angiogenesis of HUVECs were promote. 91 In conclusion, nanoparticles can minimize toxicity and improve in vivo stability due to their good biosafety, surface modiability and degradability. Nanoparticle-based gene delivery can effectively deliver target genes into the specic cells and affect cell proliferation and differentiation, thus promoting bone regeneration.…”

“… 120 Electromagnetic feld (EMF) and IONPs enhanced magnetofection efficiency of miR-21 into BMSCs and HUVECs, which improved the osteogenesis and angiogenesis and contributes to the intervertebral fusion. 91 The osteogenic differentiation of BMSCs was facilitated by HA NPs and wedelolactone with increased formation of ALP and mineralization and upregulation of osteogenic related genes. 121 Tantalum NPs could promote osteogenic differentiation of BMSCs and induce bone regeneration by activating the BMP2/Smad4/Runx2 signaling pathway.…”

Effective delivery of miR-150-5p with nucleus pulposus cell-specific nanoparticles attenuates intervertebral disc degeneration

“…With the rapid developments of nanomedicine, many biological delivery systems have been investigated for transferring miRNAs to treat IDD, including organic (polymeric or lipidic) nanoparticles [ 18 – 22 ], inorganic nanoparticles [ 23 , 24 ], nano-hydrogels [ 25 – 27 ], and extracellular vesicles (EVs) [ 28 – 30 ]. Different delivery systems possess different biological and release characteristics, and therefore hold promise for advancing the treatment of IDD [ 17 , 31 ].…”