Research Progress on Tumor Microenvironment-Responsive siRNA Nanocarriers: Design Strategies, Delivery Efficiency, and Future Perspectives

Abstract: Gene silencing by RNA interference (RNAi) has emerged as a promising strategy for cancer therapy. Small interfering RNA (siRNA), a class of small regulatory RNAs that recognize and degrade complementary target messenger RNAs (mRNAs) in a sequence-specific manner at the post-transcriptional level, plays a critical role in regulating gene expression. However, the in vivo delivery of siRNA remains a formidable challenge due to its poor physiological stability, susceptibility to enzymatic degradation, inability to efficiently cross cellular membranes, non-specific off-target effects, and immunostimulation. Overcoming these barriers and enhancing the gene silencing efficiency of siRNA in target cells is essential for the clinical translation of RNAi technology. In recent years, tumor microenvironment (TME)-responsive nanocarriers have attracted considerable attention as a strategy to improve siRNA stability, enhance its enrichment and penetration at tumor sites, facilitate cellular uptake, and promote efficient gene silencing. This review comprehensively summarized the design principles and functional characteristics of TME-responsive siRNA delivery nanocarriers, with a focus on five major stimuli: pH, hypoxia, enzymes, glutathione (GSH), and reactive oxygen species (ROS). We critically analyze the advantages and limitations of existing nanocarrier systems, provide comparative insights through summary tables, and discuss future directions including multi-stimuli-responsive systems, combination therapies, and clinical translation challenges. This review aims to provide a systematic framework for understanding and advancing TME-responsive siRNA nanocarriers for tumor therapy. Keywords: tumor microenvironment, siRNA delivery, nanocarrier, RNA interference, cancer therapy, combination therapy, clinical translation