Lipid nanoparticle-mediated RNAi targeting of KRAS mutants sensitises colorectal cancer cells to chemotherapy
- 1University of Technology Sydney
Abstract
KRAS mutations, including G12D, G12V and G13D, are major oncogenic drivers in colorectal cancer (CRC) and are associated with therapeutic resistance. However, approved KRAS inhibitors remain focused on G12C subtype, leaving these prevalent variants without approved targeted therapies. Here, we developed a lipid nanoparticle (LNP)-based RNA interference (RNAi) strategy to target these three KRAS variants using a single small interfering RNA (siRNA) sequence. The developed siRNA-LNPs reduced KRAS mRNA and protein expression in HCT116 (G13D), SW620 (G12V) and LS180 (G12D) cells, but not in KRAS wild-type HT29 cells, suppressing the cellular proliferation, clonogenic survival and migration. Transcriptomic profiling revealed changes in KRAS associated signalling, including suppression of cell-cycle and DNA repair programmes, providing a rationale for combining siRNA silencing with the fluoropyrimidine chemotherapeutic agent 5-fluorouracil (5-FU). The combination produced synergistic effects across all three KRAS-mutant CRC cell models and enhanced the apoptosis in both monolayer cultures and 3D spheroids. Collectively, these findings provide proof of concept for this combination strategy and support its further investigation as a potential therapeutic approach for KRAS-mutant CRC.
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BibTeX
@misc{wang2026lipid,
title = {{Lipid nanoparticle-mediated RNAi targeting of KRAS mutants sensitises colorectal cancer cells to chemotherapy}},
author = {Y. Wang and S. Su and K. Zahra and R. Sang and M. P. Molloy and G. Hutvagner and W. Deng},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759489},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759489v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Lipid nanoparticle-mediated RNAi targeting of KRAS mutants sensitises colorectal cancer cells to chemotherapy
AU - Y. Wang
AU - S. Su
AU - K. Zahra
AU - R. Sang
AU - M. P. Molloy
AU - G. Hutvagner
AU - W. Deng
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759489
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759489v1
AB - KRAS mutations, including G12D, G12V and G13D, are major oncogenic drivers in colorectal cancer (CRC) and are associated with therapeutic resistance. However, approved KRAS inhibitors remain focused on G12C subtype, leaving these prevalent variants without approved targeted therapies. Here, we developed a lipid nanoparticle (LNP)-based RNA interference (RNAi) strategy to target these three KRAS variants using a single small interfering RNA (siRNA) sequence. The developed siRNA-LNPs reduced KRAS mRNA and protein expression in HCT116 (G13D), SW620 (G12V) and LS180 (G12D) cells, but not in KRAS wild-type HT29 cells, suppressing the cellular proliferation, clonogenic survival and migration. Transcriptomic profiling revealed changes in KRAS associated signalling, including suppression of cell-cycle and DNA repair programmes, providing a rationale for combining siRNA silencing with the fluoropyrimidine chemotherapeutic agent 5-fluorouracil (5-FU). The combination produced synergistic effects across all three KRAS-mutant CRC cell models and enhanced the apoptosis in both monolayer cultures and 3D spheroids. Collectively, these findings provide proof of concept for this combination strategy and support its further investigation as a potential therapeutic approach for KRAS-mutant CRC.
ER -