Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency

Delivery vectors play an important role in delivering mRNA. However, it is an important challenge to enhance room-temperature storage stability and balance the conflicting requirements for excellent in vivo stability and mRNA release performance. In response to the above problems, we propose a “4 Q ” principle for designing mRNA delivery vectors. The overall delivery efficiency ( Q ) of mRNA is related to the stability of the delivery vector itself ( Q S, including storage stability and in vivo stability which was rarely considered previously), the performance of diffusion to the target cells ( Q D ), the ability to enter the cytoplasm through the cell membrane ( Q I ), and the performance of the intracellular release of mRNA ( Q R ). The efficiencies of each step are crucial to high overall delivery efficiency of intramuscular injection. Based on this “4 Q ” principle, we designed a new cationic polycatechol, poly( N, N′ -bis(acryloyl)cystamine- co -dopamine) (PBD). The PBD/mRNA polyplexes are stable at room temperature for more than 2 weeks ( Q S ↑). The in vivo transfection fluorescence intensity of polyplexes was 2 orders of magnitude higher than the commercially available mRNA delivery system (e.g., jetPEI/mRNA). Overall, this new “4 Q ” principle will be helpful for designing clinically transformative mRNA vectors with excellent storage stability and delivery efficiency.