Non-coding RNA Trojan nanocarriers in CRC: Mechanistic crossroads and therapeutic challenges

Chemoresistance in colorectal cancer (CRC) represents a core bottleneck in clinical treatment, primarily driven by the cross-regulatory network formed by cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT). Non-coding RNAs (ncRNAs) play a central role in this regulatory network, providing crucial molecular targets for chemoresistance intervention. However, the clinical translation of ncRNAs is limited by delivery challenges. The nanoscale "Trojan Horse" drug delivery system achieves precise delivery through triple-targeting design: at the tissue level, tumor accumulation is realized via the enhanced permeability and retention effect and targeted modification; at the cellular level, it targets CSCs and other chemoresistant cells; at the molecular level, it interferes with core pathways of stemness, EMT, and chemoresistance. Additionally, this system enables synergistic combination of chemotherapy with gene therapy, immunotherapy, phototherapy, and other modalities through multi-drug co-delivery, while integrating theranostic functions to synchronize chemoresistance monitoring and treatment. This review systematically elaborates on the mechanisms of ncRNA-mediated regulation of CRC chemoresistance, the design strategies and application efficacy of the nanoscale "Trojan Horse" system, providing critical insights for overcoming CRC cross-resistance and advancing the clinical translation of ncRNA nanotherapies.