Tetrahedral framework nucleic acid loaded celastrol ameliorates skin fibrosis by epithelial-mesenchymal transition prevention

Progressive skin fibrosis ultimately results in irreversible contractures, causing both joint dysfunction and cosmetic deformity. The key pathological features of skin fibrosis include persistent inflammation and abnormal accumulation of the extracellular matrix (ECM), with epithelial-mesenchymal transition (EMT) playing a critical role in disease progression. However, current therapeutic strategies for cutaneous fibrosis are largely palliative and often require repeated interventions, with limited efficacy. Celastrol (Cel) exerts anti-inflammatory and anti-fibrotic effects in skin tissue, but its clinical application is limited by poor bioavailability and a narrow therapeutic window. Tetrahedral framework nucleic acid (tFNA), a novel nanocarrier system, exhibits multiple advantages, including enhanced cellular uptake, improved cell viability, and intrinsic anti-fibrotic and anti-inflammatory properties. Therefore, this study applied tFNA-Cel complex (TCC) as an advanced nanotherapeutic agent, designed to exert a synergistic anti-fibrotic effect. In this study, an in vitro model of skin fibrosis was established using human keratinocyte (HaCaT) cells treated with 5 ng mL−1 transforming growth factor beta (TGF-β) for 24 h. The results showed that TCC significantly inhibited EMT progression by reducing α-smooth muscle actin (α-SMA) levels and increasing E-cadherin level. Compared to tFNA or Cel alone, TCC exhibited superior anti-fibrotic effects in the fibrosis model, as evidenced by modulation of SMAD family member 2 (SMAD2) signaling and collagen I expression. Furthermore, the TCC group showed lower levels of nuclear factor κB p65 (NF-κB p65), BCL-2-associated X protein (Bax), and reactive oxygen species (ROS) compared to the Cel or tFNA groups. These findings highlight TCC as a promising treatment for skin fibrosis, with its synergistic anti-fibrotic effects providing new therapeutic avenues.