mRNA Delivery by a pH‐Responsive DNA Nano‐Hydrogel

Abstract The delivery of mRNA to manipulate protein expression has attracted widespread attention, since that mRNA overcomes the problem of infection and mutation risks in transgenes and can work as drugs for the treatment of diseases. Although there are currently some vehicles that deliver mRNA into cells, they have not yet reached a good balance in terms of expression efficiency and biocompatibility. Here, a DNA nano‐hydrogel system for mRNA delivery is developed. The nano‐hydrogel is all composed of DNA except the target mRNA, so it has superior biocompatibility compared with those chemical vehicles. In parallel, the nano‐hydrogel can be compacted into a nanosphere under the crosslinking by well‐designed “X”‐shaped DNA scaffolds and DNA linkers, facilitating the delivery into cells through endocytosis. In addition, smart intracellular release of the mRNA is achieved by incorporating a pH‐responsive i‐motif structure into the nano‐hydrogel. Thus, taking the efficient delivery and release together, mRNA can be translated into the corresponding protein with a high efficiency, which is comparable to that of the commercial liposome but with a much better biocompatibility. Due to the excellent biocompatibility and efficiency, this nano‐hydrogel system is expected to become a competitive alternative for delivering functional mRNA in vivo.