Anti-CD3/anti-EGFR -activated T cells(Barbara Ann Karmanos Cancer Institute)

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.

Paclitaxel has been extensively used in clinics for cancer treatment. However, its limited solubility in aqueous solution and high occurrence of side effects have also been widely reported. In this study, we constructed a biocompatible RNA nanoparticle delivery system (3WJ-EGFR_apt) that includes 3WJ (3-way junction) nanoparticle with a size of 4.85 ± 0.59 nm as a backbone and an EGFR (epidermal growth factor receptor) aptamer for specific targeting to chordomas cells, which owns the encapsulation ability of drug paclitaxel (PTX) for cancer therapy. Confocal microscopy and flow cytometry results confirmed 3WJ-EGFR_apt nanoparticle exhibited excellent specific targeting to chordomas cell U-CH2 which is an EGFR(+) cell line; while the 3WJ nanoparticle lose the targeted ability. Both of the two nanoparticles own no sensitivity to lung cancer cell H520 which is an EGFR(-) cell line. Moreover, the 3WJ-EGFR_apt nanoparticle encapsulated drug PTX could enhance the inhibition efficiency of chordomas tumor cells U-CH2 as compared to free PTX alone. This work demonstrates that RNA-3WJ constructed with a targeting aptamer provides a compromising targeted drug delivery ability on chordomas cells for therapeutics.