PDF(Pubmed)
Abstract：
Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.
摘要：
胰腺癌,主要是胰腺导管腺癌（PDAC），仍然是一种高度致命的恶性肿瘤，治疗选择有限，预后不佳。通过靶向导致PDAC发育和进展的潜在分子异常，基因治疗为克服常规放疗和化疗带来的挑战提供了一个有希望的策略.这项研究旨在探索专门针对PDAC中CCAAT/增强子结合蛋白α（CEBPA）基因的小激活RNA（saRNA）的治疗潜力。为了克服与saRNA递送相关的挑战，四面体框架核酸（tFNA）被合理地设计为纳米载体。用截短的运铁蛋白受体适体(tTR14)进一步官能化这些tFNA以增强对PDAC细胞的靶向特异性。构建的基于tFNA的saRNA制剂表现出卓越的稳定性，高效的saRNA释放能力，大量的细胞摄取，生物相容性，和无毒。体外实验显示，利用tTR14修饰的tFNA纳米载体成功地在细胞内递送CEBPA-saRNA，导致抑癌基因的显著激活，即,CEBPA及其下游效应子P21,导致PDAC细胞增殖的显著抑制。此外，在PDAC的小鼠模型中，tTR14修饰的tFNA介导的CEBPA-saRNA的递送有效地上调了CEBPA和P21基因的表达，从而抑制肿瘤生长。这些令人信服的发现强调了通过设计的tFNA纳米载体递送的saRNA作为PDAC的创新治疗方法诱导肿瘤抑制基因激活的潜在效用。
