Advancements and Challenges in Nucleic Acid Delivery through Redox-Controlled Release Systems

In cellular systems, maintaining a dynamic balance between oxidizing and reducing agents is crucial for redox homeostasis. This balance regulates essential physiological processes such as cell survival, growth, differentiation, and senescence. Disruptions to redox homeostasis, particularly oxidative stress caused by an imbalance of reactive oxygen species (ROS) and reactive nitrogen species, are strongly associated with age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. Oxidative stress is a defining characteristic of cancer cells, which often display elevated ROS levels, resulting in increased oxidative stress compared to normal cells. Nucleic acid-based therapies, such as siRNA, mRNA, and DNA, have garnered significant attention in cancer treatment due to their ability to specifically regulate cancer-related genes. However, these nucleic acids, being negatively charged macromolecules, are susceptible to degradation by serum nucleases and face difficulties crossing cell membranes. Therefore, effective delivery systems are essential for their successful intracellular uptake. Over the past several decades, various nanoparticles (NPs) have been developed to enhance nucleic acid delivery for therapeutic purposes. Among these, polymeric NPs responsive to the distinct redox environment of cancer cells have gained significant interest for their ability to undergo redox-triggered dissociation and enable the rapid release of drugs within cells. This chapter provides a comprehensive summary of recent advancements in redox-responsive NPs for nucleic acid delivery. It also discusses the future development of NP-mediated nucleic acid delivery systems and the challenges they face in clinical translation.