Bioswitchable Delivery of microRNA by Framework Nucleic Acids: Application to Bone Regeneration

Abstract

MicroRNAs (miRs) play an important role in regulating gene expression. Limited by their instabilities, miR therapeutics require delivery vehicles. Tetrahedral framework nucleic acids (tFNAs) are potentially applicable to drug delivery because they prominently penetrate tissue and are taken up by cells. However, tFNA‐based miR delivery strategies have failed to separate the miRs after they enter cells, affecting miR efficiency. In this study, an RNase H‐responsive sequence is applied to connect a sticky‐end tFNA (stFNA) and miR‐2861, which is a model miR, to target the expression of histone deacetylase 5 (HDAC5) in bone marrow mesenchymal stem cells. The resultant bioswitchable nanocomposite (stFNA–miR) enables efficient miR‐2861 unloading and deployment after intracellular delivery, thereby inhibiting the expression of HDAC5 and promoting osteogenic differentiation. stFNA–miR also facilitated ideal bone repair via topical injection. In conclusion, a versatile miR delivery strategy is offered for various biomedical applications that necessitate modulation of gene expression.

Bone Mesenchymal Stem Cell-Derived sEV-Encapsulated Thermosensitive Hydrogels Accelerate Osteogenesis and Angiogenesis by Release of Exosomal miR-21

“…The role of SPRY2 in angiogenesis and the regulation of SPRY2 by the miR-23/27 cluster has been previously demonstrated ( Zhou et al, 2011 ), as well as the regulation of SPRY2 by miR-21 ( Thum et al, 2008 ). Li et al fabricated the resultant bioswitchable nanocomposite by integrating the sticky-end tFNA (stFNA) and miRs (miR-21, miR-124, miR-335, and miR-2861), further promoting bone regeneration via inhibiting the expression of HDAC5 ( Li S. et al, 2021 ). A similar research reported that exosomal miR-21 derived from umbilical MSC-sEVs promoted angiogenesis by upregulating the NOTCH1/DLL4 pathway ( Zhang et al, 2021 ).…”

The Interaction Between Intracellular Energy Metabolism and Signaling Pathways During Osteogenesis

“…For the foreseeable future, the application of multiomics technologies, such as transcriptomics, proteomics, and metabonomics, can systematically study the interaction between intracellular signaling pathways and metabolic pathways in osteogenesis from different dimensions. The development of corresponding targeted drugs against targets of energy metabolism during osteogenesis to promote bone regeneration is also worth investigating, such as the application of tFNA, and there are current studies that target mir-2861 to BMSCs to promote osteogenesis by inhibiting the expression of histone deacetylase 5 (hdac5) to maintain histone acetylation (Li et al, 2021;Zhang et al, 2021). The in-depth exploration of the interaction between intracellular energy metabolism and signaling pathways during osteogenesis will promote the development of basic biology and provide new therapeutic targets and strategies for osteoporosis.…”

LncRNA‐AK137033 inhibits the osteogenic potential of adipose‐derived stem cells in diabetic osteoporosis by regulating Wnt signaling pathway via DNA methylation

“… 39 The canonical Wnt pathway (Wnt/β‐catenin) and noncanonical Wnt pathway (Wnt/PCP and Wnt/Ca 2+ ) affect bone modeling and reconstruction by regulating the energy metabolism and osteogenesis of osteoblasts. 40 , 41 , 42 , 43 sFrp2 is an antagonist of the canonical Wnt pathway. It binds to Wnt ligands through a cysteine‐rich domain or C‐terminal netrin‐like domain, or forms nonfunctional complexes with frizzle‐related receptors to inhibit Wnt signaling.…”