THERAPEUTIC ROLE OF siRNA IN GASTRIC CANCER: GENE SILENCING MECHANISMS AND NANOCARRIER-BASED DELIVERY STRATEGIES.

Abstract

Gastric cancer (GC) continues to be a significant global contributor to cancer-related mortality, primarily due to late-stage diagnoses, tumor heterogeneity, and the frequent emergence of therapeutic resistance. Despite advancements in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, long-term survival rates remain unsatisfactory, underscoring the need for innovative, molecularly driven approaches. SiRNA has emerged as a promising gene-silencing tool capable of selectively downregulating oncogenic drivers and pathways associated with resistance via RNA interference. Preclinical studies using GC models demonstrate promising biological activity following siRNA-mediated suppression of various molecular targets - including CD44v6, Rac1, and ZNRD1-leading to reduced cell proliferation, inhibited migration and invasion, enhanced apoptosis, and increased chemosensitivity. However, the successful translation of siRNA-based strategies into clinical practice is fundamentally reliant on the development of efficient and safe delivery systems. Recent advancements in nanotechnology have enabled the development of multifunctional nanocarriers, including lipid-based nanoparticles, peptide-based systems, chitosanderived platforms, exosome-mimetic vesicles, layer-by-layer architectures, and stimuli-responsive theranostic nanoparticles. These engineered platforms are designed to enhance siRNA stability, improve tumor targeting, facilitate intracellular trafficking, and promote endosomal escape while minimizing off-target effects and immune activation. Preclinical findings suggest significant biological potential; however, additional research is required to address issues concerning biodistribution, safety, scalability, and regulatory standardization before clinical application. Overall, siRNA-based strategies may play a crucial role in the future development of precision-oriented therapeutic frameworks in GC research. Importantly, this review emphasizes the integration of molecular target selection with delivery system design in a GC-specific context. By systematically linking validated siRNA targets with corresponding nanocarrier strategies, this work provides a more application-oriented and translationally relevant perspective that is not typically addressed in conventional RNA interference or nanocarrier-focused reviews.