Recent Progress in the Endosomal Escape Mechanism and Chemical Structures of Polycations for Nucleic Acid Delivery

Abstract Nucleic acid‐based therapies are seeing a spiralling surge. Stimuli‐responsive polymers, especially pH‐responsive ones, are gaining widespread attention because of their ability to efficiently deliver nucleic acids. These polymers can be synthesized and modified according to target requirements, such as delivery sites and the nature of nucleic acids. In this regard, the endosomal escape mechanism of polymer–nucleic acid complexes (polyplexes) remains a topic of considerable interest owing to various plausible escape mechanisms. This review describes current progress in the endosomal escape mechanism of polyplexes and state‐of‐the‐art chemical designs for pH‐responsive polymers. The importance is also discussed of the acid dissociation constant (i.e., p K a ) in designing the new generation of pH‐responsive polymers, along with assays to monitor and quantify the endosomal escape behavior. Further, the use of machine learning is addressed in p K a prediction and polymer design to find novel chemical structures for pH responsiveness. This review will facilitate the design of new pH‐responsive polymers for advanced and efficient nucleic acid delivery.