Improved Messenger RNA Stability and Biocompatibility Through Self‐Gelatinizable Nucleic Acids

Recent advances in the chemical synthesis and modification of messenger RNA (mRNA) have generated growing interest in mRNA-based therapeutics. However, the inherent instability of mRNA in vivo and during storage remains a major challenge, requiring the development of safe and effective delivery systems. Lipid nanoparticles (LNPs) currently serve as the primary vehicle for mRNA delivery, with well-documented clinical success. Nevertheless, immunogenicity associated with certain components underscores the need for biocompatible alternatives. To address these stability and safety concerns, we developed an mRNA-loaded DNA hydrogel based on self-gelatinizable nucleic acid technology. The hydrogel is formed through the self-assembly of designed DNA units and provides an inherently biocompatible framework. mRNA loaded into the hydrogel exhibited sustained protein expression in myofibroblasts due to controlled mRNA release, while inducing negligible proinflammatory cytokine production or cytotoxicity in antigen-presenting cells. Additionally, the hydrogel markedly enhanced mRNA resistance to both nuclease degradation and storage-induced degradation. These findings demonstrate that mRNA-loaded DNA hydrogels can serve as a promising, biocompatible platform for next-generation mRNA therapeutics, achieving both enhanced stability and reduced immunogenicity.