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There has been considerable interest in gene vectors and their role in regulating cellular activities and treating diseases since the advent of nucleic acid drugs. MicroRNA (miR) therapeutic strategies are research hotspots as they regulate gene expression post-transcriptionally and treat a range of diseases. An original tetrahedral framework nucleic acid (tFNA) analog, a bioswitchable miR inhibitor delivery system (BiRDS) carrying miR inhibitors, is previously established; however, it remains unknown whether BiRDS can be equipped with miR mimics. Taking advantage of the transport capacity of tetrahedral framework nucleic acid (tFNA) and upgrading it further, the treatment outcomes of a traditional tFNA and BiRDS at different concentrations on TGF-β- and bleomycin-induced fibrosis simultaneously in vitro and in vivo are compared. An upgraded traditional tFNA is designed by successfully synthesizing a novel BiRDS, carrying a miR mimic, miR-27a, for treating skin fibrosis and inhibiting the pyroptosis pathway, which exhibits stability and biocompatibility. BiRDS has three times higher efficiency in delivering miRNAs than the conventional tFNA with sticky ends. Moreover, BiRDS is more potent against fibrosis and pyroptosis-related diseases than tFNAs. These findings indicate that the BiRDS can be applied as a drug delivery system for disease treatment., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Osteonecrosis of the femoral head (ONFH) is recognized as a common refractory orthopedic disease that causes severe pain and poor quality of life in patients. Puerarin (Pue), a natural isoflavone glycoside, can promote osteogenesis and inhibit apoptosis of bone mesenchymal stem cells (BMSCs), demonstrating its great potential in the treatment of osteonecrosis. However, its low aqueous solubility, fast degradation in vivo, and inadequate bioavailability, limit its clinical application and therapeutic efficacy. Tetrahedral framework nucleic acids (tFNAs) are promising novel DNA nanomaterials in drug delivery. In this study, tFNAs as Pue carriers is used and synthesized a tFNA/Pue complex (TPC) that exhibited better stability, biocompatibility, and tissue utilization than free Pue. A dexamethasone (DEX)-treated BMSC model in vitro and a methylprednisolone (MPS)-induced ONFH model in vivo is also established, to explore the regulatory effects of TPC on osteogenesis and apoptosis of BMSCs. This findings showed that TPC can restore osteogenesis dysfunction and attenuated BMSC apoptosis induced by high-dose glucocorticoids (GCs) through the hedgehog and Akt/Bcl-2 pathways, contributing to the prevention of GC-induced ONFH in rats. Thus, TPC is a promising drug for the treatment of ONFH and other osteogenesis-related diseases., (© 2023 Wiley-VCH GmbH.)

As major complications of chemoradiotherapy, myelosuppression and hematopoietic-system damage severely affect immunologic function and can delay or even terminate treatment for cancer patients. Although several specific cytokines have been used for hematopoiesis recovery, their effect is limited, and they may increase the risk of tumor recurrence. In this study, osteogenic growth peptide functionalized tetrahedral framework nucleic-acid nanostructures (OGP-tFNAs) are prepared; they combine the positive hematopoiesis stimulating effect of OGP and the drug carrying function of tFNAs. The potential of OGP-tFNAs for hematopoietic stimulation and microenvironment regulation is investigated. It is shown that OGP-tFNAs can protect bone marrow stromal cells from 5-fluorouracil (5-FU)-induced DNA damage and apoptosis. OGP-tFNAs pretreatment activates the extracellularly regulated protein kinase signal and downregulates apoptosis-related proteins. OGP-tFNAs also alleviate the chemotherapy-induced inhibition of hematopoiesis-related cytokine expression, which is crucial for hematopoiesis reconstitution. In conclusion, OGP-tFNAs can protect hematopoietic cells and their microenvironment from chemotherapy-induced injuries and myelosuppression, while promoting hematopoiesis regeneration., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)