Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency
Junqiu Shi, Haiyang Yin, Qingmei Sun, Runxin Teng, Yunqing Zhu, Jianzhong Du
Abstract
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.