A Novel Bioswitchable miRNA Mimic Delivery System: Therapeutic Strategies Upgraded from Tetrahedral Framework Nucleic Acid System for Fibrotic Disease Treatment and Pyroptosis Pathway Inhibition.

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-ß- 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.

Tetrahedral Framework Nucleic Acids Delivery of Pirfenidone for Anti-Inflammatory and Antioxidative Effects to Treat Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease, and developing an effective treatment remains a challenge. The limited therapeutic options are primarily delivered by the oral route, among which pirfenidone (PFD) improves pulmonary dysfunction and patient quality of life. However, its high dose and severe side effects (dyspepsia and systemic photosensitivity) limit its clinical value. Intratracheal aerosolization is an excellent alternative method for treating lung diseases because it increases the concentration of the drug needed to reach the focal site. Tetrahedral framework nucleic acid (tFNA) is a drug delivery system with exceptional delivery capabilities. Therefore, we synthesized a PFD-tFNA (Pt) complex using tFNA as the delivery vehicle and achieved quantitative nebulized drug delivery to the lungs via micronebulizer for lung fibrosis treatment. In vivo, Pt exhibited excellent immunomodulatory capacity and antioxidant effects. Furthermore, Pt reduced mortality, gradually restored body weight and improved lung tissue structure. Similarly, Pt also exhibited superior fibrosis inhibition in an in vitro fibrosis model, as shown by the suppression of excessive fibroblast activation and epithelial-mesenchymal transition (EMT) in epithelial cells exposed to TGF-ß1. Conclusively, Pt, a complex with tFNA as a transport system, could enrich the therapeutic regimen for IPF via intratracheal aerosolization inhalation.

Efficient Delivery of siRNA via Tetrahedral Framework Nucleic Acids: Inflammation Attenuation and Matrix Regeneration in Temporomandibular Joint Osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is the most common and severe subtype of temporomandibular disease characterized by inflammation and cartilage matrix degradation. Compared with traditional conservative treatment, small interfering RNAs (siRNAs) have emerged as a more efficient gene-targeted therapeutic tool for TMJOA treatment. Nuclear factor kappaB (NF-κB) is a transcription factor orchestrating the inflammatory processes in the pathogenesis of TMJOA. Employing siRNA-NF-κB could theoretically control the development of TMJOA. However, the clinical applications of siRNA-NF-κB are limited by its structural instability, poor cellular uptake, and short TMJ retention. To overcome these shortcomings, we developed a tetrahedral framework nucleic acid (tFNA) system carrying siRNA-NF-κB, named Tsi. The results indicated that Tsi exhibited excellent structural stability and excellent cellular uptake efficiency. It also demonstrated a superior NF-κB silencing effect over siRNA alone, attenuating the activation of NF-κB and upregulating the NRF2/HO-1 pathway. This system effectively reduced the release of inflammatory factors and reactive oxygen species (ROS), inhibiting cellular oxidative stress and apoptosis. In vivo, Tsi displayed enhanced TMJ retention capacity in comparison to siRNA alone and offered significant protective effects on both the cartilage matrix and subchondral bone, presenting a promising approach for TMJOA treatment.