Targeting oncogenic KRAS in non‑small cell lung cancer with EGFR aptamer‑conjugated multifunctional RNA nanoparticles
EGFR‑aptamer‑conjugated three‑way junction RNA nanoparticles can specifically deliver KRASG12C‑targeting siRNA to non‑small cell lung cancer (NSCLC) cells, effectively silencing KRASG12C, inhibiting downstream MAPK signaling, and suppressing tumor growth both in vitro and in vivo.
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 EGFR_apt-3WJ-siKRAS^G12C mutation targeted nanoparticles to target EGFR-expressing human NSCLC harboring a KRAS^G12C mutation to silence KRAS^G12C expression in a tumor cell‑specific fashion. We found that EGFR_apt-3WJ-siKRAS^G12C nanoparticles potently depleted cellular KRAS^G12C 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 KRAS^G12C 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.
KRAS mutations, particularly KRASG12C, drive resistance to conventional therapies in NSCLC and are notoriously difficult to target directly. This study introduces a novel, tumor‑specific delivery vehicle that uses an EGFR aptamer to home siRNA specifically to KRASG12C‑mutant cells, achieving potent gene knockdown, downstream signaling inhibition, and tumor growth suppression in preclinical models. The platform offers a promising route to overcome KRAS‑driven drug resistance and could be adapted to other RAS mutations, advancing precision oncology.
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