Tumor Microenvironment Responsive RNA Drug Delivery Systems: Intelligent Platforms for Sophisticated Release

Cancer is a significant health concern, increasingly showing insensitivity to traditional treatments, highlighting the urgent need for safer and more practical treatment options. Ribonucleic acid (RNA) gene therapy drugs have demonstrated promising potential in preclinical and clinical trials for antitumor therapy by regulating tumor-related gene expression. However, RNA's poor membrane permeability and stability restrict its effectiveness in entering and being utilized in cells. An appropriate delivery system is crucial for achieving targeted tumor effects. The tumor microenvironment (TME), characterized by acidity, hypoxia, enzyme overexpression, elevated glutathione (GSH) concentration, and excessive reactive oxygen species (ROS), is essential for tumor survival. Furthermore, these distinctive features can also be harnessed to develop intelligent drug delivery systems. Various nanocarriers that respond to the TME have been designed for RNA drug delivery, showing the advantages of tumor targeting and low toxicity. This Review discusses the abnormal changes of components in TME, therapeutic RNAs' roles, underlying mechanisms, and the latest developments in utilizing vectors that respond to microenvironments for treating tumors. We hope it provides insight into creating and optimizing RNA delivery vectors to improve their effectiveness.