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。通过针对导致 PDAC 发生和进展的潜在分子异常，基因治疗提供了一种有前景的策略来克服传统放疗和化疗带来的挑战。本研究旨在探索特异性靶向 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) 被合理设计为纳米载体。这些 tFNA 通过截短的转铁蛋白受体适体 (tTR14) 进一步功能化，以增强 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、生物相容性和无毒性。体外实验表明，利用 tTR14 修饰的 tFNA 纳米载体成功进行了 CEBPA-saRNA 的细胞内递送，导致肿瘤抑制基因（即 CEBPA 及其下游效应子 P21）显着激活，从而显着抑制 PDAC 细胞增殖。此外，在 PDAC 小鼠模型中，tTR14 修饰的 tFNA 介导的 CEBPA-saRNA 递送有效上调了 CEBPA 和 P21 基因的表达，从而抑制了肿瘤生长。这些令人信服的发现强调了通过设计的 tFNA 纳米载体传递 saRNA 来诱导肿瘤抑制基因激活的潜在效用，作为 PDAC 的创新治疗方法。© 2024。作者。

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.© 2024. The Author(s).