KRAS突变是人类癌症中最常见的致癌驱动基因突变之一，包括非小细胞肺癌 (NSCLC)，并在癌症发病机制和治疗抗性中发挥了明确作用。有效抑制突变KRAS的开发是一项重大挑战。基于三路结合(3WJ)的多功能RNA纳米颗粒有潜力作为有效的体内siRNA传递平台，具有增强肿瘤靶向特异性和通过成像基团可视化生物分布的能力。本研究中，我们组装了新颖的EGFRapt-3WJ-siKRASG12C突变靶向纳米颗粒，可靶向表达EGFR的KRASG12C突变的人类NSCLC，以特异性方式抑制KRASG12C表达。我们发现，EGFRapt-3WJ-siKRASG12C纳米颗粒有效消耗了细胞中的KRASG12C表达，导致下游MAPK途径信号的减弱，细胞增殖、迁移/侵袭能力的减弱，以及NSCLC细胞对化疗和放疗的敏感性提高。在体内，这些纳米颗粒对KRASG12C NSCLC肿瘤移植模型诱导的肿瘤生长有抑制作用。这项研究表明，基于3WJ pRNA的平台具有抑制突变KRAS活性用于治疗KRAS驱动的人类癌症的潜力，并值得进一步进行临床转化研究的发展。 版权所有© 2023 作者。

KRAS mutations are one of the most common oncogenic driver mutations in human cancers, including non-small cell lung cancer (NSCLC), and have established roles in cancer pathogenesis and therapeutic resistance. The development of effective inhibitors of mutant KRAS represents a significant challenge. Three-way junction (3WJ)-based multi-functional RNA nanoparticles have the potential to serve as an effective in vivo siRNA delivery platform with the ability to enhance tumor targeting specificity and visualize biodistribution through an imaging moiety. Herein, we assembled novel EGFRapt-3WJ-siKRASG12C mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRASG12C mutation to silence KRASG12C expression in a tumor cell-specific fashion. We found that EGFRapt-3WJ-siKRASG12C nanoparticles potently depleted cellular KRASG12C expression, resulting in attenuation of downstream MAPK pathway signaling, cell proliferation, migration/invasion ability, and sensitized NSCLC cells to chemoradiotherapy. In vivo, these nanoparticles induced tumor growth inhibition in KRASG12C NSCLC tumor xenografts. Together, this study suggests that the 3WJ pRNA-based platform has the potential to suppress mutant KRAS activity for the treatment of KRAS-driven human cancers, and warrants further development for clinical translation.© 2023 The Authors.